Inclusion Criteria:
1. Physician-confirmed asthma diagnosis with documented evidence of variable expiratory airflow limitation (e.g., from bronchodilator reversibility testing or other tests)
2. Written informed consent
3. Moderate-to-severe asthma (asthma patients with treatment of GINA Step 3-5)
4. Age 12 years old and above
Exclusion Criteria:
1. Previous diagnosis of chronic obstructive pulmonary disease (COPD) or other clinically relevant chronic respiratory disease other than asthma
2. Received an investigational therapy for asthma, allergy, atopic disease, or eosinophilic disease as part of a clinical trial during the 6 months prior to enrolment. (Once enrolled in the PRESENT Study, patients should not enrol in any investigational trials.)
3. Any significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, or may influence the results of the study, or the patient's ability to participate in the study
4. Disease or condition other than asthma that requires treatment with systemic or oral steroids
5. Patients with poor inhaler skills and adherence
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Inclusion Criteria:
1. Physician-confirmed asthma diagnosis with documented evidence of variable expiratory airflow limitation (e.g., from bronchodilator reversibility testing or other tests)
2. Written informed consent
3. Moderate-to-severe asthma, which is defined as asthma patients with maintenance. treatment of GINA Step 3-5.
4. Age 12 years old and above
Exclusion Criteria:
1. Previous diagnosis of chronic obstructive pulmonary disease (COPD) or other clinically relevant chronic respiratory disease other than asthma
2. Received an investigational therapy for asthma, allergy, atopic disease, or eosinophilic disease as part of a clinical trial during the 6 months prior to enrolment. (Once enrolled in the PRESENT Study, patients should not enrol in any investigational trials.)
3. Any significant disease or disorder which, in the opinion of the investigator, may either put the patient at risk because of participation in the study, or may influence the results of the study, or the patient's ability to participate in the study
4. Disease or condition other than asthma that requires treatment with systemic or oral steroids
5. Patients with poor inhaler skills and adherence
Inclusion Criteria:
* Pathologically documented Stage IIIB, IIIC, or Stage IV non-squamous non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGA) at the time of randomisation and meets the criteria for NSCLC:
* Participants must have documented negative test results for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) genomic alterations.
* Has no known tumour genomic alterations in neurotrophic tyrosine receptor kinase (NTRK), proto-oncogene B-raf (BRAF), rearranged during transfection (RET), mesenchymal-epithelial transition (MET) exon 14 skipping, Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C, human epidermal growth factor receptor 2 (HER2) or any other actionable driver oncogenes for which there are locally approved and available targeted first-line therapies.
* Prospectively assessed trophoblast cell surface protein 2 (TROP2) normalised membrane ratio (NMR) positive.
* Documentation of radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
* Participants must have received platinum based chemotherapy (PBC) in combination with anti-programmed death-protein 1 (anti-PD-1)/anti-programmed death-ligand 1 (anti-PD-L1) monoclonal antibody (mAb) as the only prior line of therapy or received PBC and anti-PD-1/anti-PD-L1 monoclonal antibody (in either order) sequentially as the only 2 prior lines of therapy.
* Provision of acceptable formalin fixed and paraffin embedded (FFPE) tumour sample for assessment of TROP2.
* At least one lesion not previously irradiated that qualifies as a Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1) target lesion (TL) at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate repeated measurements.
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
* Adequate bone marrow reserve and organ function within 7 days before randomisation.
Exclusion Criteria:
* Squamous, mixed NSCLC, or small cell lung cancer (SCLC) histology.
* NSCLC disease that is eligible for definitive local therapy alone.
* History of another primary malignancy other than NSCLC, except for malignancy treated with curative intent with no known active disease within 3 years before randomisation and of low potential risk for recurrence.
* Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 7 days prior to randomisation.
* Clinically significant corneal disease.
* Has active or uncontrolled hepatitis B or C virus infection.
* Known human immunodeficiency virus (HIV) infection that is not well controlled.
* Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
* History of non-infectious interstitial lung disease (ILD)/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
* Severe pulmonary function compromise per Investigator discretion.
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Inclusion Criteria:
\- Pathologically documented Stage IIIB, IIIC, or Stage IV non-squamous non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGA) at the time of randomisation and meets the criteria for NSCLC:
* Participants must have documented negative test results for EGFR (eg, exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutation), ALK, and ROS1 genomic alterations.
Note: If test results for EGFR, ALK, and ROS1 are not available, participants are required to undergo prospective testing performed centrally for these genomic alterations in a Sponsor-designated central laboratory.
* Has no known tumour genomic alterations in NTRK, BRAF V600, RET, MET exon 14 skipping, KRAS G12C, or HER2. Additionally, participants must not have known tumour genomic alteration of any other actionable driver oncogenes for which there are locally approved targeted first-line therapies.
Note: Participants whose tumours harbour BRAF (exception V600) or KRAS (exception G12C) mutations are eligible for the study.
* Prospectively assessed TROP2 NMR positive based on results from an appropriately validated investigational TROP2 RxDx device in a Sponsor- designated, regulatory compliant central laboratory.
* Documentation of radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
* Participants must have received platinum based chemotherapy (PBC) in combination with anti-programmed death-protein 1 (anti-PD-1)/anti-programmed death-ligand 1 (anti-PD-L1) monoclonal antibody (mAb) as the only prior line of therapy or received PBC and anti-PD-1/anti-PD-L1 monoclonal antibody (in either order) sequentially as the only 2 prior lines of therapy.
* Provision of acceptable formalin fixed and paraffin embedded (FFPE) tumour sample for assessment of TROP2.
* At least one lesion not previously irradiated that qualifies as a Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1) target lesion (TL) at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate repeated measurements.
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
* Adequate bone marrow reserve and organ function within 7 days before randomisation.
Exclusion Criteria:
* Squamous, mixed NSCLC, or small cell lung cancer (SCLC) histology.
* NSCLC disease that is eligible for definitive local therapy alone.
* History of another primary malignancy other than NSCLC, except for malignancy treated with curative intent with no known active disease within 3 years before randomisation and of low potential risk for recurrence.
* Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 7 days prior to randomisation.
* Clinically significant corneal disease.
* Has active or uncontrolled hepatitis B or C virus infection.
* Known human immunodeficiency virus (HIV) infection that is not well controlled.
* Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
* History of ILD/pneumonitis, including radiation pneumonitis (apart from radiation pneumonitis that did not require steroids), or drug-induced ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. Examples of suspected ILD/pneumonitis by imaging include the presence of lung parenchymal fibrosis, such as combined pulmonary fibrosis and emphysema (CPFE), and any radiographic features consistent with interstitial lung abnormalities, including but not limited to, extensive ground glass opacities, reticular opacities, traction bronchiectasis, and honeycombing.
* Has severe pulmonary function compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the study enrolment, severe asthma, severe COPD, restrictive lung disease, symptomatic pleural effusion, etc).
Inclusion Criteria:
* Participants must be 18 to 80 years of age inclusive, at the time of Screening
* Participants with pre-existing positive screening for R14 del PLN mutation
* Participants with screening Left ventricular eject fraction ≤ 45% as assessed by echocardiography
* Participants with New York Heart Association (NYHA) function class I-III
* Participants on stable medical therapy for at least 6 weeks prior to Screening and during the Screening period, with no significant improvement in heart failure
* Participants with implantable cardioverter-defibrillator (ICD) or Cardiac resynchronization therapy device (CRT-D)
* Participants with Body mass index (BMI) within the range 18-35 kg/m2
* Females of childbearing potential must not be lactating, and if heterosexually active must agree to use an approved method of highly effective contraception
* All females must have a negative pregnancy test at the Screening Visit.
Exclusion Criteria:
* Participants with positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody
* Known to have tested positive for Human immunodeficiency virus (HIV)
* Any known genetic mutation associated with hereditary electrical or structural disease
* Congenital long QT syndrome
* QTcF \< 350 ms
* Known Short QT syndrome (SQTS) or family history of SQTS
* Catecholaminergic polymorphic ventricular tachycardia (CPVT as calcium ion channelopathy) and recent hospitalization for heart failure or significant ventricular arrhythmia within 3 months
* Participants with sustained ventricular arrhythmia requiring treatment and considered clinically not stable by the Investigator
* History of subendocardial Late Gadolinium Enhancement (LGE) suggestive of previous myocardial infarction and/or significant coronary artery disease (50% \> stenosis in one major epicardial coronary artery or need for previous percutaneous coronary intervention or coronary artery bypass grafting)
* Routinely scheduled outpatient intravenous infusions for heart failure
* Uncontrolled hypertension
* Significant primary valvular disease
* Congenital heart disease
* Left ventricular wall thickness of \> 13 mm or with any relative with hypertrophic cardiomyopathy (HCM)
* Recent acute presentation of myocarditis
* Restrictive or peripartum cardiomyopathy; infiltrative disorders (sarcoidosis)
* Alcohol consumption in excess
* Any laboratory values with the following deviations:
1. Alanine Transaminase \>2 upper normal limit (ULN)
2. Aspartate Transaminase \>2 ULN
3. Total bilirubin \> 2 x ULN
4. Estimated GFR \< 30 mL/min/1.73 m2
5. Hemoglobin \<10g/dL
* Any vital sign values with the following deviations at Screening
1. Systolic blood pressure \> 160 mmHg
2. Diastolic blood pressure \> 100 mmHg
3. Pulse rate \> 100 beats per minute
* Toxin exposure, systemic disease known to cause Dilated Cardiomyopathy (DCM)
* History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity
* Any history of cardiotoxic drug exposure with documented cardiomyopathy
* Noncardiac condition that limits expected lifespan to less than 1 year
* Participation in another clinical study with a study intervention administered in the last 3 months
* Participants with a known hypersensitivity to AZD4063
* Participants who are part of a gene therapy trial
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Inclusion Criteria:
* Participants must be 18 to 80 years of age inclusive, at the time of Screening
* Participants with pre-existing positive screening for R14 del PLN mutation
* Participants with screening Left ventricular eject fraction ≤ 45% as assessed by echocardiography
* Participants with New York Heart Association (NYHA) function class I-III
* Participants on stable medical therapy for at least 6 weeks prior to Screening and during the Screening period, with no significant improvement in heart failure
* Participants with implantable cardioverter-defibrillator (ICD) or Cardiac resynchronization therapy device (CRT-D)
* Participants with Body mass index (BMI) within the range 18-35 kg/m2
* Females of childbearing potential must not be lactating, and if heterosexually active must agree to use an approved method of highly effective contraception
* All women of childbearing potential must have a negative pregnancy test at the Screening Visit.
Exclusion Criteria:
* Participants with positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody
* Known to have tested positive for Human immunodeficiency virus (HIV)
* Any known genetic mutation associated with hereditary electrical or structural disease
* Congenital long QT syndrome
* QTcF \< 350 ms
* Known Short QT syndrome (SQTS) or family history of SQTS
* Catecholaminergic polymorphic ventricular tachycardia (CPVT as calcium ion channelopathy) and recent hospitalization for heart failure or significant ventricular arrhythmia within 3 months
* Participants with sustained ventricular arrhythmia requiring treatment and considered clinically not stable by the Investigator
* History of subendocardial Late Gadolinium Enhancement (LGE) suggestive of previous myocardial infarction and/or significant coronary artery disease (50% \> stenosis in one major epicardial coronary artery or need for previous percutaneous coronary intervention or coronary artery bypass grafting)
* Routinely scheduled outpatient intravenous infusions for heart failure
* Uncontrolled hypertension
* Significant primary valvular disease
* Congenital heart disease
* Left ventricular wall thickness of \> 13 mm or with any relative with hypertrophic cardiomyopathy (HCM)
* Recent acute presentation of myocarditis
* Restrictive or peripartum cardiomyopathy; infiltrative disorders (sarcoidosis)
* Alcohol consumption in excess
* Any laboratory values with the following deviations:
1. Alanine Transaminase \>2 upper normal limit (ULN)
2. Aspartate Transaminase \>2 ULN
3. Total bilirubin \> 2 x ULN
4. Estimated GFR \< 30 mL/min/1.73 m2
5. Hemoglobin \<10g/dL
* Any vital sign values with the following deviations at Screening
1. Systolic blood pressure \> 160 mmHg
2. Diastolic blood pressure \> 100 mmHg
3. Pulse rate \> 100 beats per minute
* Toxin exposure, systemic disease known to cause Dilated Cardiomyopathy (DCM)
* History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity
* Any history of cardiotoxic drug exposure with documented cardiomyopathy
* Noncardiac condition that limits expected lifespan to less than 1 year
* Participation in another clinical study with a study intervention administered in the last 3 months
* Participants with a known hypersensitivity to AZD4063
* Participants who have previously received AZD4063 as part of this study
* Participants who are part of a gene therapy trial
Inclusion Criteria:
* Eligible for American Cancer Society lung cancer screening, as follows:
* Age 50-80 years old
* At least 20-pack year history of smoking
* Weight loss of 3-10%, defined as UWL, within any timeframe over the past in the 18 months prior to enrollment, that cannot be attributed to an underlying medical condition at the discretion of the enrolling investigator
* Note that patients who have 3-10% weight may still be enrolled if the enrolling investigator does not conclude that the weight loss can be attributed to the patient's intentional efforts.
* Documented weight loss can be self-reported or extracted from weights obtained during physician visits. However, if self-reported weight loss is contradicted by weight loss documented in the medical record (e.g. a patients states that (s)he lost 10 lbs in the past 6 months, but a weight documented in the medical record does not support that history), the measured and quantified weight change will be used to ascertain eligibility
* Life expectancy greater than 1 year, per assessment of the treating clinician.
Exclusion Criteria:
* Currently pregnant or trying to become pregnant via self-report
* Prior history of recent CT scan of the chest either through LDCT screening or with a scan of the chest (standard, not LDCT) performed within the past 12 months
* Prior history of NSCLC
○ Note that patients with a history of diagnosis of non-lung cancers are eligible for the study.
* Currently undergoing or referred for diagnostic evaluation due to clinical suspicion for malignancy (e.g., referred to a medical or surgical oncologist, or scheduled for biopsy on the basis of a suspicious imaging abnormality).
* Patients with a germline pathogenic genetic variant who have undergone whole body MRI within the past 12 months
* Unable to comply with study procedures
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Inclusion Criteria:
* Eligible for American Cancer Society lung cancer screening, as follows as per the discretion of the screening team:
* Age 50-80 years old
* At least 20-pack year history of smoking
* Weight loss of 3-10%, defined as UWL, within any timeframe over the past in the 18 months prior to enrollment, that cannot be attributed to an underlying medical condition at the discretion of the enrolling investigator
* Note that patients who have 3-10% weight may still be enrolled if the enrolling investigator does not conclude that the weight loss can be attributed to the patient's intentional efforts.
* Documented weight loss can be self-reported or extracted from weights obtained during physician visits. However, if self-reported weight loss is contradicted by weight loss documented in the medical record (e.g. a patients states that (s)he lost 10 lbs in the past 6 months, but a weight documented in the medical record does not support that history), the measured and quantified weight change will be used to ascertain eligibility
* Life expectancy greater than 1 year, per assessment of the treating clinician.
Exclusion Criteria:
* Currently pregnant or trying to become pregnant via self-report
* Prior history of recent CT scan of the chest either through LDCT screening or with a scan of the chest (standard, not LDCT) performed within the past 12 months
* Prior history of NSCLC
○ Note that patients with a history of diagnosis of non-lung cancers are eligible for the study.
* Currently undergoing or referred for diagnostic evaluation due to clinical suspicion for malignancy (e.g., referred to a medical or surgical oncologist, or scheduled for biopsy on the basis of a suspicious imaging abnormality).
* Patients with a germline pathogenic genetic variant who have undergone whole body MRI within the past 12 months
* Unable to comply with study procedures
Inclusion Criteria:
* 1: Patients should be ≥18 years old at diagnosis
* 2: Diagnosed as MCL or CLL who have received at least one prior therapy and CLL patients should be enrolled after the approval of NMPA (according to Chinese label)
* 3: Eligible for acalabrutinib treatment assessed by investigators (physician's evaluation) in clinical practice
* 4: Patient/legal guardian must be able to read, understand, and sign the informed consent form (ICF)
Exclusion Criteria:
* 1: Ineligible for acalabrutinib treatment assessed by investigators (physician's evaluation)
* 2: Progression after accepting other BTKi treatment before use of acalabrutinib
* 3: Concurrent participation in another interventional clinical study
* 4: Females of childbearing potential must practice highly effective contraception during treatment of acalabrutinib, and for at least 1 week after the last dose of acalabrutinib, and have a negative urine or serum pregnancy test ≤ 7 days before the first dose of study drug(s).
* 5: No requirement to use contraception for male subjects treated with acalabrutinib. a. A sterile male is considered a highly effective contraception method for female patients. b. Males with known "low sperm counts" (consistent with "sub-fertility") are not to be considered sterile for purposes of this study.
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Inclusion Criteria:
* 1: Patients should be ≥18 years old at diagnosis
* 2: Diagnosed as MCL who have received at least one prior therapy, OR diagnosed as CLL/SLL who are treatment-naïve or have received at least one prior therapy (per the local prescribing label for acalabrutinib)
* 3: Eligible for acalabrutinib treatment assessed by investigators (physician's evaluation) in clinical practice
* 4: Patient/legal guardian must be able to read, understand, and sign the informed consent form (ICF)
Exclusion Criteria:
* 1: Ineligible for acalabrutinib treatment assessed by investigators (physician's evaluation)
* 2: Progression after accepting other BTKi treatment before use of acalabrutinib
* 3: Concurrent participation in another interventional clinical study
* 4: Females of childbearing potential must practice highly effective contraception during treatment of acalabrutinib, and for at least 1 week after the last dose of acalabrutinib, and have a negative urine or serum pregnancy test ≤ 7 days before the first dose of study drug(s).
* 5: No requirement to use contraception for male subjects treated with acalabrutinib. a. A sterile male is considered a highly effective contraception method for female patients. b. Males with known "low sperm counts" (consistent with "sub-fertility") are not to be considered sterile for purposes of this study.
Key Inclusion Criteria:
* Age ≥ 18 years
* Relapsed/metastatic solid tumors treated with prior adequate standard of care therapy for tumor type and stage of disease or where in the opinion of the Investigator, a clinical trial is the best option for the next treatment based on response and/or tolerability to prior therapy.
* Measurable disease per RECIST v1.1
* Eastern Cooperative Oncology Group (ECOG) Performance Status: 0-1
* Life expectancy ≥ 12 weeks
* Adequate bone marrow, hepatic, and renal function as defined in the protocol
Additional Inclusion Criteria For Sub-Study 1 Part A:
• Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, ovarian cancer, BTC or endometrial cancer
Additional Inclusion Criteria For Sub-Study 1 Part B:
* Histologically or cytologically confirmed metastatic or locally advanced and recurrent disease for the respective cohort:
1. Cohort B1 (Biliary Tract Cancer)
2. Cohort B2 (Ovarian Cancer)
3. Cohort B3 (Breast Cancer)
4. Cohort B4 (Endometrial Cancer)
5. Cohort B5 (Squamous Non-Small Cell Lung Cancer)
Additional Inclusion Criteria For Sub-Study 2 Part A:
* Minimum body weight ≥ 30 kg.
* Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, ovarian cancer, BTC, endometrial cancer or squamous non-small cell lung cancer.
Additional Inclusion Criteria For Sub-Study 3 Part A:
* Minimum body weight ≥ 30 kg (for participants enrolled in cohorts including rilvegostomig only).
* Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, ovarian cancer, BTC, endometrial cancer or squamous non-small cell lung cancer.
Additional Inclusion Criteria For Sub-Study 4 Part A:
* Minimum body weight ≥ 30 kg (for participants enrolled in cohorts including rilvegostomig only).
* Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, endometrial cancer or squamous non-small cell lung cancer.
* Participants must have progressed following at least one but no more than 3 prior lines of treatment for metastatic or relapsed disease and have no satisfactory alternative treatment option as judged by the Investigator.
Key Exclusion Criteria:
* Treatment with any of the following:
1. Nitrosourea or mitomycin C within 6 weeks prior to the first dose of study treatment
2. Any investigational agents or study drugs from a previous clinical study within 5 half-lives or 28 days (whichever is shorter) prior to the first dose of study treatment
3. Any other anticancer treatment within the following time periods prior to the first dose of study intervention:
1. Cytotoxic treatment: 21 days
2. Non-cytotoxic drugs: 21 days or 5 half-lives (whichever is shorter)
3. Biological products including immuno-oncology agents: 28 days
* Spinal cord compression or a history of leptomeningeal carcinomatosis.
* Brain metastases unless treated, asymptomatic, stable, and not requiring continuous corticosteroids at a dose of \> 10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study.
* Active infection including tuberculosis and HBV, HCV or HIV
* History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
* Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
* Participants with any of the following cardiac criteria:
1. History of arrhythmia which is symptomatic or requires treatment (NCI CTCAE v5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation, or asymptomatic sustained ventricular tachycardia.
2. Uncontrolled hypertension.
3. Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months.
4. History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
5. Symptomatic heart failure (NYHA class ≥ 2).
6. Prior or current cardiomyopathy.
7. Severe valvular heart disease.
8. Mean resting QTcF \> 470 msec.
9. Risk factors for QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
* Patients with history of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML (as determined by prior diagnostic investigation)
Additional Exclusion Criteria For Sub-Study 2 Part A:
* Thromboembolic event within 3 months before the first dose of study intervention - No longer applicable per amendment 7
* Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
* Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
* History of organ transplant
Additional Exclusion Criteria For Sub-Study 2 Part B
• Previous treatment with any therapy that contains a TOP1i (eg. irinotecan, topotecan, trastuzumab deruxtecan, etc.)
Additional Exclusion Criteria For Sub-Study 3 Part A:
* Concomitant use of medications or herbal supplements known to be strong cytochrome P (CYP) 3A4 inducers/inhibitors.
* Any history of persisting (\> 2 weeks) severe cytopenia due to any cause
* Patients with any known predisposition to bleeding
* Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of saruparib.
* Previous treatment with any therapy that contains a TOP1i (eg. irinotecan, topotecan, trastuzumab deruxtecan, etc.)
Additional Exclusion Criteria For Sub-Study 4 Part A:
* Patients have received prior therapy with AZD9574 or more than 1 prior line of any other PARPi-based regimen
* Concomitant use of medications or herbal supplements known to be strong cytochrome P (CYP) 3A4 inducers/inhibitors.
* Previous treatment with rilvegostomig for the cohort treated with rilvegostomig
* Previous treatment with any therapy that contains a TOP1i (eg. irinotecan, topotecan, trastuzumab deruxtecan, etc.)
* Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9574
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Key Inclusion Criteria :
* Age ≥ 18 years
* Relapsed/metastatic solid tumors treated with prior adequate standard of care therapy for tumor type and stage of disease or where in the opinion of the Investigator, a clinical trial is the best option for the next treatment based on response and/or tolerability to prior therapy.
* Measurable disease per RECIST v1.1
* Eastern Cooperative Oncology Group (ECOG) Performance Status: 0-1
* Life expectancy ≥ 12 weeks
* Adequate bone marrow, hepatic, and renal function as defined in the protocol
Additional Inclusion Criteria For Sub-Study 1 Part A:
• Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, ovarian cancer, BTC or endometrial cancer
Additional Inclusion Criteria For Sub-Study 1 Part B:
* Histologically or cytologically confirmed metastatic or locally advanced and recurrent disease for the respective cohort:
1. Cohort B1 (Biliary Tract Cancer)
2. Cohort B2 (Ovarian Cancer)
3. Cohort B3 (Breast Cancer)
4. Cohort B4 (Endometrial Cancer)
5. Cohort B5 (Squamous Non-Small Cell Lung Cancer)
Additional Inclusion Criteria For Sub-Study 2 Part A:
* Minimum body weight ≥ 30 kg.
* Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, ovarian cancer, BTC, endometrial cancer or squamous non-small cell lung cancer.
Additional Inclusion Criteria For Sub-Study 3 Part A:
* Minimum body weight ≥ 30 kg (for participants enrolled in cohorts including rilvegostomig only).
* Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, ovarian cancer, BTC, endometrial cancer or squamous non-small cell lung cancer.
Additional Inclusion Criteria For Sub-Study 4 Part A:
* Minimum body weight ≥ 30 kg (for participants enrolled in cohorts including rilvegostomig only).
* Histologically or cytologically confirmed metastatic or locally advanced/recurrent breast cancer, endometrial cancer or squamous non-small cell lung cancer.
* Participants must have progressed following at least one but no more than 3 prior lines of treatment for metastatic or relapsed disease and have no satisfactory alternative treatment option as judged by the Investigator.
Key Exclusion Criteria:
* Treatment with any of the following:
1. Nitrosourea or mitomycin C within 6 weeks prior to the first dose of study treatment
2. Any investigational agents or study drugs from a previous clinical study within 5 half-lives or 28 days (whichever is shorter) prior to the first dose of study treatment
3. Any other anticancer treatment within the following time periods prior to the first dose of study intervention:
1. Cytotoxic treatment: 21 days
2. Non-cytotoxic drugs: 21 days or 5 half-lives (whichever is shorter)
3. Biological products including immuno-oncology agents: 28 days
* Spinal cord compression or a history of leptomeningeal carcinomatosis.
* Brain metastases unless treated, asymptomatic, stable, and not requiring continuous corticosteroids at a dose of \> 10 mg prednisone/day or equivalent for at least 4 weeks prior to start of study.
* Active infection including tuberculosis and HBV, HCV or HIV
* History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
* Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
* Participants with any of the following cardiac criteria:
1. History of arrhythmia which is symptomatic or requires treatment (NCI CTCAE v5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation, or asymptomatic sustained ventricular tachycardia.
2. Uncontrolled hypertension.
3. Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months.
4. History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
5. Symptomatic heart failure (NYHA class ≥ 2).
6. Prior or current cardiomyopathy.
7. Severe valvular heart disease.
8. Mean resting QTcF \> 470 msec.
9. Risk factors for QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
* Patients with history of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML (as determined by prior diagnostic investigation)
Additional Exclusion Criteria For Sub-Study 2 Part A:
* Thromboembolic event within 3 months before the first dose of study intervention - No longer applicable per amendment 7
* Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
* Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
* History of organ transplant
Additional Exclusion Criteria For Sub-Study 2 Part B
• Previous treatment with any therapy that contains a TOP1i (eg. irinotecan, topotecan, trastuzumab deruxtecan, etc.)
Additional Exclusion Criteria For Sub-Study 3 Part A:
* Concomitant use of medications or herbal supplements known to be strong cytochrome P (CYP) 3A4 inducers/inhibitors.
* Any history of persisting (\> 2 weeks) severe cytopenia due to any cause
* Patients with any known predisposition to bleeding
* Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of saruparib.
* Previous treatment with any therapy that contains a TOP1i (eg. irinotecan, topotecan, trastuzumab deruxtecan, etc.)
Additional Exclusion Criteria For Sub-Study 4 Part A:
* Patients have received prior therapy with AZD9574 or more than 1 prior line of any other PARPi-based regimen
* Concomitant use of medications or herbal supplements known to be strong cytochrome P (CYP) 3A4 inducers/inhibitors.
* Previous treatment with rilvegostomig for the cohort treated with rilvegostomig
* Previous treatment with any therapy that contains a TOP1i (eg. irinotecan, topotecan, trastuzumab deruxtecan, etc.)
* Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9574
Early termination was due to insufficient tumor uptake thought to be limited by the binding affinity of EGFR, The termination is not related to any safety or quality concerns.
Inclusion Criteria:
Core Inclusion criteria:
1. Adequate adult (ECOG) or adolescent (Karnofsy or Lanksy) Performance Score assessments
2. Adequate organ and bone marrow function.
Module 1 Cohort 1:
1. Age:
1. Part A (dose escalation): aged ≥ 18 years at the time of signing the informed consent.
2. Part B (optimization): aged ≥ 12 years of age. Adolescent participants must weigh ≥ 40 kg.
2. Histologically confirmed diagnosis of cHL based on WHO criteria
3. Previous treatment with at least 2 prior lines of therapy for the treatment of cHL (including at least 2 cycles of BV and anti-PD1) and have documented r/r active disease requiring treatment.
4. Participants must provide FFPE baseline tumour tissue.
5. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesion ( \>1.5 cm for nodal lesion and \>1 cm for extranodal lesion).
Module 1 Cohort 2:
1. Participants must be at least 50 years of age or older at study entry.
2. Histologically confirmed diagnosis of cHL based on WHO criteria
3. Ann Arbor stages III or IV.
4. Participant must have previously received at least 4 cycles of SoC combination therapy with A-AVD, N-AVD, AVD, or ABVD (based on regional SOC, per investigator) as finite first-line induction therapy, and achieved at least a PR post-induction therapy.
5. Participants must provide FFPE baseline tumour tissue.
Module 1 Cohort 3:
1. Participants must be aged ≥ 18 years at the time of signing the informed consent.
2. Histologically confirmed diagnosis of PTCL NOS, systemic ALCL, or AITL based on WHO criteria.
3. Participants must have received at least 1 prior line of therapy for the treatment of PTCL and have exhausted all available therapies with demonstrated clinical benefit. Participants with ALCL must have received prior BV treatment.
4. Participants must provide FFPE baseline tumour tissue
a. Ability to provide an on-treatment biopsy (if the tumour is suitable for biopsy).
5. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (\> 1.5 cm for nodal lesion and \>1 cm for extranodal lesion).
Module 2 Cohort 1:
1. Participants must be aged ≥ 18 years at the time of signing the informed consent.
2. Histologically confirmed diagnosis of cHL based on WHO criteria
3. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (\> 1.5 cm for nodal lesion and \>1 cm for extranodal lesion).
4. Participant must have received at least 1 prior line of therapy for the treatment of cHL and have documented r/r active disease requiring treatment.
5. Participants must provide FFPE baseline tumour tissue.
Exclusion Criteria:
Core Exclusion criteria:
1. Any significant laboratory finding or any severe and uncontrolled medical condition.
2. Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression.
3. Serologic active HBV or HCV infection.
4. Known to have tested positive for HIV.
5. Active gastrointestinal disease or other condition that will interfere with oral therapy.
6. Any of the following ECG cardiac criteria: Mean resting QTcF \> 470 msec, clinically important abnormalities in rhythm, conduction or morphology, and/or any factors that increase the risk of QTc prolongation or risk of arrhythmic events.
7. Undergone any of the following procedures within 6 months prior to first dose:
1. Coronary artery bypass graft,
2. Percutaneous coronary intervention or heart valve replacement or repairment,
3. Vascular stent implantation (venous stent is eligible),
4. Acute coronary syndrome / myocardial infarction,
5. Unstable or poorly controlled angina pectoris,
6. Ventricular arrhythmias requiring continuous therapy,
7. Uncontrolled atrial fibrillation,
8. Haemorrhagic or thrombotic stroke (including transient ischaemic attacks) or any other CNS bleeding.
9. Acute venous or atrial thromboembolic event (unless considered stable or adequately treated with at least 3months of therapeutic anticoagulation).
8. Severe valvular heart disease.
9. Congestive heart failure Grade II to Grade IV.
10. Prior or current cardiomyopathy.
11. Uncontrolled hypertension.
12. History of significant haemoptysis or haemorrhage within4 weeks of the first dose of study treatment.
13. Unresolved toxicities of Grade \> 1 from prior anti cancer therapy (excluding peripheral neuropathy, vitiligo, alopecia and endocrine disorders that are controlled with replacement hormone therapy, and asymptomatic laboratory abnormalities), unless immune-mediated.
14. History of another primary malignancy.
15. Received the following anticancer therapies: anti-lymphoma therapy (within 21 days), radiation therapy(within 28 days), allo-HSCT (within 180 days), auto-HSCT/cellular therapy (within 60 days), or MAT2A or PRMT5 inhibitor
16. Requires ongoing immunosuppressive therapy, including systemic corticosteroids.
Module 2 Cohort 1:
1. History of confirmed ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment or any evidence of clinically active ILD or pneumonitis.
2. ≥Grade 3 immune-mediated AE while receiving prior checkpoint inhibitor immunotherapy, or any unresolved ≥Grade 2 immune-mediated AE.
3. History of immune-mediated myocarditis or pericarditis.
4. Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
5. Active or prior documented pathologically confirmed autoimmune or inflammatory disorders
6. Refractory to prior checkpoint inhibitor therapy (within 12 weeks of last dose)
7. Eligible for allogeneic or autologous stem cell transplant.
8. Received an allogeneic HSCT within 5 years of the first dose of study treatment; must not have active Graft-versus-host disease.
9. Participants with a known hypersensitivity to pembrolizumab or any of the excipients of the product.
→
Inclusion Criteria:
Core Inclusion criteria:
1. Adequate adult (ECOG) or adolescent (Karnofsy or Lanksy) Performance Score assessments
2. Adequate organ and bone marrow function.
Module 1 Cohort 1:
1. Age:
1. Part A (dose escalation): aged ≥ 18 years at the time of signing the informed consent.
2. Part B (optimization): aged ≥ 12 years of age. Adolescent participants must weigh ≥ 40 kg.
2. Histologically confirmed diagnosis of cHL based on WHO criteria
3. Previous treatment with at least 2 prior lines of therapy for the treatment of cHL (including at least 2 cycles of BV and anti-PD1) and have documented r/r active disease requiring treatment.
4. Participants must provide FFPE baseline tumour tissue.
5. At least 1 radiographically measurable, and/or FDG-avid lymphoma lesion ( \>1.5 cm for nodal lesion and \>1 cm for extranodal lesion).
Module 1 Cohort 2:
1- Participants must be at least 50 years of age or older at study entry. 2- Histologically confirmed diagnosis of cHL based on WHO criteria 3- Ann Arbor stages III or IV. 4- Participant must have previously received at least 4 cycles of SoC combination therapy with A-AVD, N-AVD, AVD, or ABVD (based on regional SOC, per investigator) as finite first-line induction therapy, and achieved at least a PR post-induction therapy.
5- Participants must provide FFPE baseline tumour tissue.
Module 1 Cohort 3:
1. Participants must be aged ≥ 18 years at the time of signing the informed consent.
2. Histologically confirmed diagnosis of PTCL NOS, systemic ALCL, or AITL based on WHO criteria.
2a- If pre-screening for MTAP deficiency is initiated, all participants must be MTAP deficient as determined by a local test.
3- Participants must have received at least 1 prior line of therapy for the treatment of PTCL and have exhausted all available therapies with demonstrated clinical benefit. Participants with ALCL must have received prior BV treatment.
4- Participants must provide FFPE baseline tumour tissue
1. Ability to provide an on-treatment biopsy (if the tumour is suitable for biopsy).
5- At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (\> 1.5 cm for nodal lesion and \>1 cm for extranodal lesion).
Module 2 Cohort 1:
1- Participants must be aged ≥ 18 years at the time of signing the informed consent.
2- Histologically confirmed diagnosis of cHL based on WHO criteria 3- At least 1 radiographically measurable, and/or FDG-avid lymphoma lesions (\> 1.5 cm for nodal lesion and \>1 cm for extranodal lesion).
4- Participant must have received at least 1 prior line of therapy for the treatment of cHL and have documented r/r active disease requiring treatment.
5- Participants must provide FFPE baseline tumour tissue.
Exclusion Criteria:
Core Exclusion criteria:
1. Any significant laboratory finding or any severe and uncontrolled medical condition.
2. Active CNS involvement by lymphoma, leptomeningeal disease, or spinal cord compression.
3. Serologic active HBV or HCV infection.
4. Known to have tested positive for HIV.
5. Active gastrointestinal disease or other condition that will interfere with oral therapy.
6. Any of the following ECG cardiac criteria: Mean resting QTcF \> 470 msec, clinically important abnormalities in rhythm, conduction or morphology, and/or any factors that increase the risk of QTc prolongation or risk of arrhythmic events.
7. Undergone any of the following procedures within 6 months prior to first dose:
a) Coronary artery bypass graft, b) Percutaneous coronary intervention or heart valve replacement or repairment, c) Vascular stent implantation (venous stent is eligible), d) Acute coronary syndrome / myocardial infarction, e) Unstable or poorly controlled angina pectoris, f) Ventricular arrhythmias requiring continuous therapy, g) Uncontrolled atrial fibrillation, h) Haemorrhagic or thrombotic stroke (including transient ischaemic attacks) or any other CNS bleeding.
i) Acute venous or atrial thromboembolic event (unless considered stable or adequately treated with at least 3months of therapeutic anticoagulation).
8. Severe valvular heart disease.
9. Congestive heart failure Grade II to Grade IV.
10. Prior or current cardiomyopathy.
11. Uncontrolled hypertension.
12. History of significant haemoptysis or haemorrhage within4 weeks of the first dose of study treatment.
13. Unresolved toxicities of Grade \> 1 from prior anti cancer therapy (excluding peripheral neuropathy, vitiligo, alopecia and endocrine disorders that are controlled with replacement hormone therapy, and asymptomatic laboratory abnormalities), unless immune-mediated.
14. History of another primary malignancy.
15. Received the following anticancer therapies: anti-lymphoma therapy (within 21 days), radiation therapy(within 28 days), allo-HSCT (within 180 days), auto-HSCT/cellular therapy (within 60 days), or MAT2A or PRMT5 inhibitor
16. Requires ongoing immunosuppressive therapy, including systemic corticosteroids.
17. Psychiatric illness/social situations/substance abuse disorders that would limit compliance with study requirements or compromise the ability to give written informed consent.
18. Use of prescription medications that are known as:
1. Strong or moderate inhibitors or inducers of CYP3A4, sensitive substrates of CYP3A4, inhibitors or substrates of CYP2D6, inhibitors and sensitive substrates of CYP2C8, and NTI substrates of CYP3A4, CYP2D6, and CYP2C8.
19. Received live, attenuated vaccine within 30 days prior to first dose of treatment.
20. Known hypersensitivity to AZD3470 or any of the excipients of the product.
21. Involvement in planning or conduct of the study (applies to both AstraZeneca staff and site staff).
22. Judgement by investigator that the participant is unlikely to comply with study procedures, restrictions, and requirements.
23. Previous enrolment in the present study.
24. Pregnant (confirmed with positive pregnancy test) or breastfeeding or intends to become pregnant during the study.
25. Concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up period of an interventional study.
Module 2 Cohort 1:
<!-- -->
1. History of confirmed ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment or any evidence of clinically active ILD or pneumonitis.
2. ≥Grade 3 immune-mediated AE while receiving prior checkpoint inhibitor immunotherapy, or any unresolved ≥Grade 2 immune-mediated AE.
3. History of immune-mediated myocarditis or pericarditis.
4. Experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
5. Active or prior documented pathologically confirmed autoimmune or inflammatory disorders
6. Refractory to prior checkpoint inhibitor therapy (within 12 weeks of last dose)
7. Eligible for allogeneic or autologous stem cell transplant.
8. Received an allogeneic HSCT within 5 years of the first dose of study treatment; must not have active Graft-versus-host disease.
9. Participants with a known hypersensitivity to pembrolizumab or any of the excipients of the product.
Inclusion Criteria:
1. Patients who have been diagnosed with COPD.
2. Patients who have newly initiated treatment with Breztri according to the approved label in Korea
3. Provision of signed and dated written informed consent by the patient or legally acceptable representative
Exclusion Criteria:
1. Other off-label indications outside of the locally approved prescribing information
2. Pregnant and/or breast feeding
3. Current participation in any interventional trial
→
Inclusion Criteria:
1. Patients who have been diagnosed with COPD or asthma.
2. Patients who have newly initiated treatment with Breztri according to the approved label in Korea
3. Provision of signed and dated written informed consent by the patient or legally acceptable representative
Exclusion Criteria:
1. Other off-label indications outside of the locally approved prescribing information
2. Pregnant and/or breast feeding
3. Current participation in any interventional trial
Inclusion Criteria:
* Individuals aged 40 to 62 years old and are still working
* In risk population, which means they exposure at least 2 risk factors of lung cancer, following:
* smoking
* expose second-hand smoke
* expose air pollution, bio-mass fuels
* expose arsenic
* expose radon
* expose asbestos
* having chronic pulmonary illness
* having HIV
* have family member's history of lung cancer (relatives within 3 generations)
* Have mobile phone registered Zalo account
Exclusion Criteria:
* Individual smoked or had history of smoking more than 30 packs per year because they will be advised to do low dose CT scan. That is based on the guideline from Vietnam Misnitry of Health101
* Pregnant woman. It is for safety reason because we will recommend the (+) cases or (-) cases with symptoms do LDCT or CT scan for lung cancer, that can affect the pregnancy. Therefore, if they are pregnant, we will invite them to meet obstetricians.
* History of lung cancer or TB
* Who have problem in mental health is diagnosed by doctor.
→
Inclusion Criteria:
* Individuals aged 40 to 62 years old and are still working
* In risk population, which means they exposure at least 2 risk factors of lung cancer, following:
* smoking
* expose second-hand smoke
* expose air pollution, bio-mass fuels
* expose arsenic
* expose radon
* expose asbestos
* having chronic pulmonary illness
* having HIV
* have family member's history of lung cancer (relatives within 3 generations)
* Have mobile phone registered Zalo account
Exclusion Criteria:
* Individual smoked or had history of smoking more than 30 packs per year because they will be advised to do low dose CT scan. That is based on the guideline from Vietnam Misnitry of Health101
* Pregnant woman. It is for safety reason because research team will recommend the (+) cases or (-) cases with symptoms do LDCT or CT scan for lung cancer, that can affect the pregnancy. Therefore, if they are pregnant, research team will invite them to meet obstetricians.
* History of lung cancer or TB
* Who have problem in mental health is diagnosed by doctor.
Inclusion Criteria:
1. Patients ≥18 years with histology-proven advanced, or R/M ACC.
2. Evidence of locally advanced disease not amenable to curative intent surgery or radiotherapy, or recurrent/metastatic disease
3. ACC-I subtype defined by at least one of the following:
1. Presence of an activating NOTCH mutation per in-house or any CLIA-certified or commercially available next-generation sequencing assay
2. Solid histology and clinical course characterized by \< 3 years from diagnosis to initial recurrence or progression or de novo metastatic disease with extra-pulmonary metastasis
3. Negative TP63 tumor expression by IHC (\<10% of tumor cells)
4. Measurable disease per RECIST 1.1
5. Performance status ECOG of 0 or 1
6. Patient has provided informed consent.
7. Adequate bone marrow, hepatic, and renal function with the most recent laboratory assessments 8. Contraceptive use by the participant or the participant's partner should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
(a) Male participants: (i) Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom (plus spermicide, if available) from enrollment throughout the study and for 8 months following the last dose of study drug. It is strongly recommended for the female partner of a male participant to also use a highly effective method of contraception throughout this period, as described in Table 3. In addition, male participants must refrain from sperm donation while on study and for 8 months (5 half-lives plus 6 months) following the last dose of study drug.
(b) Female participants: (i) Females of childbearing potential must have a negative urine or serum pregnancy test prior to receiving the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
(ii) Female participants of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly, from enrollment throughout the study and for 8 months following the last dose of study drug. It is strongly recommended for the male partner of a female participant to also use male condom (plus spermicide, if available) throughout this period. Cessation of contraception after this point should be discussed with a responsible physician.
9\. Patients can be treatment-naïve or have received up to 3 lines of prior systemic therapy in the setting ofR/M disease, however, a maximum of two prior lines of chemotherapy or antibody-drug conjugate (ADC) are allowed. Exceptions include prior B7-H4-targeting ADC or any prior agent with a topoisomerase inhibitor
1 mode of action; those represent exclusion criteria (exclusion criteria #18).
Exclusion Criteria:
1. Treatment with any of the following as detailed below in Table 2:
Table 2 . Washout period from prior therapies Treatment Washout period Nitrosourea or mitomycin C Within 6 weeks prior to the first dose of study intervention Any investigational agents or study drugs from a previous clinical study Within 5 half-lives or 28 days (whichever is shorter) prior to the first dose of study drug Any other anticancer treatment Within the following time periods prior to the first dose of study intervention: Cytotoxic treatment: 21 days Non-cytotoxic drugs: 21 days or 5 half-lives (whichever is shorter) Biological products including immuno-oncology agents: 28 days Radiotherapy Wide field of radiation (including whole brain radiotherapy) within 4 weeks or limited field radiotherapy (including stereotactic radiotherapy or gamma-knife) for palliation is allowed up to 14 days prior to the first dose of study intervention. Participants who have not recovered from radiotherapy-related toxicity will not be eligible Major surgery (as defined by the Investigator) At least 28 days prior to the first dose of study intervention
2. Unresolved toxicities of Grade ≥ 2 (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE version 5.0) from prior therapy (excluding vitiligo, alopecia, endocrine disorders that are controlled with replacement hormone therapy, and lymphopenia unless it is accompanied by clinical signs of infection or the indication for prophylaxis with antibiotic/antiviral/antifungal therapy). Participants with chemotherapy-induced Grade 2 neuropathy may be eligible at discretion of the Investigator.
3. Active infection, including tuberculosis, SARS-CoV-2, and known infections with hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency. Participants with a past or resolved HBV/HCV infection are eligible if all the following criteria are met:
1. Negative for HBsAg and positive for total hepatitis B core antibody (anti-HBc) or Positive for HBsAg, but for \> 6 months have had normal transaminases and HBV DNA levels between 0-2000 IU/mL (inactive carrier state) and willing to start and maintain antiviral treatment for at least the duration of the study.
2. HBV DNA levels \> 2000 IU/mL but on prophylactic antiviral treatment for the past 3 months and will maintain the antiviral treatment during the study.
3. Participants testing positive for HCV antibody are eligible only if the polymerase chain reaction test result is negative for HCV RNA.
4. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5. Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement or prior pneumonectomy (complete) or require supplemental oxygen (including intermittent or discretionary use).
6. Patients with history of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML (as determined by prior diagnostic investigation). Specific screening for MDS/AML is not required.
7. Participants with any of the following cardiac criteria:
1. History of clinically significant arrhythmia (such as multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (NCI CTCAE version 5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.
NOTE: abnormalities in serum electrolytes that can increase the risk of arrhythmic events (ie, sodium, potassium, calcium, magnesium) should be corrected before starting the study intervention
2. Uncontrolled hypertension.
3. Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months of the start of study treatment.
4. History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
5. Symptomatic heart failure (as defined by New York Heart Association class ≥ 2).
6. Prior or current cardiomyopathy.
7. Severe valvular heart disease.
8. Resting corrected QT interval using Fridericia's formula (QTcF) \> 470 msec
9. Any factors that increase the risk of corrected QT (interval) (QTc) prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
10. Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study intervention or during the scheduled ECG assessments (see \<\< https://www.crediblemeds.org/ \>\>).
8. Active CNS disease (patients with asymptomatic or treated CNS lesions who have been off corticosteroids, radiation, or other CNS-directed therapy for at least 4 weeks prior to start of study treatment are not considered active)
9. Uncontrolled intercurrent illness within the last 12 months of start of study treatment, including but not limited to serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.
10. Has substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the Investigator.
11. Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note:
Participants, if enrolled, should not receive live attenuated vaccine whilst receiving study intervention and up to 30 days after the last dose of study intervention. Participants can receive COVID-19 vaccines, at the discretion of the Investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines.
Note: If a COVID-19 vaccine is administered it should be done \> 72 hours prior to study intervention initiation.
12. For women only - currently pregnant (confirmed with positive pregnancy test), lactating, breastfeeding, or intend to become pregnant during the study.
13. Red blood cell transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening.
14. Current participation in another interventional clinical study
15. History of previous malignancy other than malignancy treated with curative intent and low risk of recurrence. Patients with the following diagnoses represents an exception and may enroll if ≥ 2 years with no evidence of active disease before the first dose of the study drug or if treatment is not indicated:
1. Non-melanoma skin cancers with no current evidence of disease
2. Melanoma in situ with no current evidence of disease
3. Treated or localized, low-risk, cancer of the prostate with prostate-specific antigen of \<1 ng/mL
4. Treated or localized well-differentiated thyroid cancer (stage I)
5. Cervical carcinoma in situ
6. Treated ductal/lobular carcinoma in situ of the breast
7. Treated or localized, low grade, renal cell carcinoma (stage I)
16. Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient
17. Cognitively impaired patients who are incompetent to consent.
18. Prior exposure to a B7-H4 targeting ADC, or any prior agent with a topoisomerase inhibitor 1 mode of action.
→
Inclusion Criteria:
1. Patients ≥18 years with histology-proven advanced, or R/M ACC.
2. Evidence of locally advanced disease not amenable to curative intent surgery or radiotherapy, or recurrent/metastatic disease
3. ACC-I subtype defined by at least one of the following:
1. Presence of an activating NOTCH mutation per in-house or any CLIA-certified or commercially available next-generation sequencing assay
2. Solid histology (any amount of solid component) and clinical course characterized by \< 3 years from diagnosis to initial recurrence or progression or de novo metastatic disease with extra-pulmonary metastasis
3. Negative TP63 tumor expression by IHC (\<10% of tumor cells)
4. Measurable disease per RECIST 1.1
5. Performance status ECOG of 0 or 1
6. Patient has provided informed consent.
7. Adequate bone marrow, hepatic, and renal function with the most recent laboratory assessments 8. Contraceptive use by the participant or the participant's partner should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
(a) Male participants: (i) Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom (plus spermicide, if available) from enrollment throughout the study and for 8 months following the last dose of study drug. It is strongly recommended for the female partner of a male participant to also use a highly effective method of contraception throughout this period, as described in Table 3. In addition, male participants must refrain from sperm donation while on study and for 8 months (5 half-lives plus 6 months) following the last dose of study drug.
(b) Female participants: (i) Females of childbearing potential must have a negative urine or serum pregnancy test prior to receiving the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
(ii) Female participants of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly, from enrollment throughout the study and for 8 months following the last dose of study drug. It is strongly recommended for the male partner of a female participant to also use male condom (plus spermicide, if available) throughout this period. Cessation of contraception after this point should be discussed with a responsible physician.
9\. Patients can be treatment-naïve or have received up to 4 lines of prior systemic therapy in the setting of R/M disease, however, a maximum of two prior lines of chemotherapy or antibody-drug conjugate (ADC) are allowed. Exceptions include prior B7-H4-targeting ADC or any prior agent with a topoisomerase inhibitor 1 mode of action; those represent exclusion criteria (exclusion criteria #18).
Exclusion Criteria:
1. Treatment with any of the following as detailed below in Table 2:
Table 2 . Washout period from prior therapies Treatment Washout period Nitrosourea or mitomycin C Within 6 weeks prior to the first dose of study intervention Any investigational agents or study drugs from a previous clinical study Within 5 half-lives or 28 days (whichever is shorter) prior to the first dose of study drug Any other anticancer treatment Within the following time periods prior to the first dose of study intervention: Cytotoxic treatment: 21 days Non-cytotoxic drugs: 21 days or 5 half-lives (whichever is shorter) Biological products including immuno-oncology agents: 28 days Radiotherapy Wide field of radiation (including whole brain radiotherapy) within 4 weeks or limited field radiotherapy (including stereotactic radiotherapy or gamma-knife) for palliation is allowed up to 14 days prior to the first dose of study intervention. Participants who have not recovered from radiotherapy-related toxicity will not be eligible Major surgery (as defined by the Investigator) At least 28 days prior to the first dose of study intervention
2. Unresolved toxicities of Grade ≥ 2 (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE version 5.0) from prior therapy (excluding vitiligo, alopecia, endocrine disorders that are controlled with replacement hormone therapy, and lymphopenia unless it is accompanied by clinical signs of infection or the indication for prophylaxis with antibiotic/antiviral/antifungal therapy). Participants with chemotherapy-induced Grade 2 neuropathy may be eligible at discretion of the Investigator.
3. Active infection, including tuberculosis, SARS-CoV-2, and known infections with hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency. Participants with a past or resolved HBV/HCV infection are eligible if all the following criteria are met:
1. Negative for HBsAg and positive for total hepatitis B core antibody (anti-HBc) or Positive for HBsAg, but for \> 6 months have had normal transaminases and HBV DNA levels between 0-2000 IU/mL (inactive carrier state) and willing to start and maintain antiviral treatment for at least the duration of the study.
2. HBV DNA levels \> 2000 IU/mL but on prophylactic antiviral treatment for the past 3 months and will maintain the antiviral treatment during the study.
3. Participants testing positive for HCV antibody are eligible only if the polymerase chain reaction test result is negative for HCV RNA.
4. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5. Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement or prior pneumonectomy (complete) or require supplemental oxygen (including intermittent or discretionary use).
6. Patients with history of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML (as determined by prior diagnostic investigation). Specific screening for MDS/AML is not required.
7. Participants with any of the following cardiac criteria:
1. History of clinically significant arrhythmia (such as multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (NCI CTCAE version 5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.
NOTE: abnormalities in serum electrolytes that can increase the risk of arrhythmic events (ie, sodium, potassium, calcium, magnesium) should be corrected before starting the study intervention
2. Uncontrolled hypertension.
3. Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months of the start of study treatment.
4. History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
5. Symptomatic heart failure (as defined by New York Heart Association class ≥ 2).
6. Prior or current cardiomyopathy.
7. Severe valvular heart disease.
8. Resting corrected QT interval using Fridericia's formula (QTcF) \> 470 msec
9. Any factors that increase the risk of corrected QT (interval) (QTc) prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
10. Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study intervention or during the scheduled ECG assessments (see \<\< https://www.crediblemeds.org/ \>\>).
8. Active CNS disease (patients with asymptomatic or treated CNS lesions who have been off corticosteroids, radiation, or other CNS-directed therapy for at least 4 weeks prior to start of study treatment are not considered active)
9. Uncontrolled intercurrent illness within the last 12 months of start of study treatment, including but not limited to serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.
10. Has substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the Investigator.
11. Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note:
Participants, if enrolled, should not receive live attenuated vaccine whilst receiving study intervention and up to 30 days after the last dose of study intervention. Participants can receive COVID-19 vaccines, at the discretion of the Investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines.
Note: If a COVID-19 vaccine is administered it should be done \> 72 hours prior to study intervention initiation.
12. For women only - currently pregnant (confirmed with positive pregnancy test), lactating, breastfeeding, or intend to become pregnant during the study.
13. Red blood cell transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening.
14. Current participation in another interventional clinical study
15. History of previous malignancy other than malignancy treated with curative intent and low risk of recurrence. Patients with the following diagnoses represents an exception and may enroll if ≥ 2 years with no evidence of active disease before the first dose of the study drug or if treatment is not indicated:
1. Non-melanoma skin cancers with no current evidence of disease
2. Melanoma in situ with no current evidence of disease
3. Treated or localized, low-risk, cancer of the prostate with prostate-specific antigen of \<1 ng/mL
4. Treated or localized well-differentiated thyroid cancer (stage I)
5. Cervical carcinoma in situ
6. Treated ductal/lobular carcinoma in situ of the breast
7. Treated or localized, low grade, renal cell carcinoma (stage I)
16. Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient
17. Cognitively impaired patients who are incompetent to consent.
18. Prior exposure to a B7-H4 targeting ADC, or any prior agent with a topoisomerase inhibitor 1 mode of action.
Inclusion Criteria:
1. Patients ≥18 years with histology-proven advanced, or R/M ACC.
2. Evidence of locally advanced disease not amenable to curative intent surgery or radiotherapy, or recurrent/metastatic disease
3. ACC-I subtype defined by at least one of the following:
1. Presence of an activating NOTCH mutation per in-house or any CLIA-certified or commercially available next-generation sequencing assay
2. Solid histology (any amount of solid component) and clinical course characterized by \< 3 years from diagnosis to initial recurrence or progression or de novo metastatic disease with extra-pulmonary metastasis
3. Negative TP63 tumor expression by IHC (\<10% of tumor cells)
4. Measurable disease per RECIST 1.1
5. Performance status ECOG of 0 or 1
6. Patient has provided informed consent.
7. Adequate bone marrow, hepatic, and renal function with the most recent laboratory assessments 8. Contraceptive use by the participant or the participant's partner should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
(a) Male participants: (i) Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom (plus spermicide, if available) from enrollment throughout the study and for 8 months following the last dose of study drug. It is strongly recommended for the female partner of a male participant to also use a highly effective method of contraception throughout this period, as described in Table 3. In addition, male participants must refrain from sperm donation while on study and for 8 months (5 half-lives plus 6 months) following the last dose of study drug.
(b) Female participants: (i) Females of childbearing potential must have a negative urine or serum pregnancy test prior to receiving the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
(ii) Female participants of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly, from enrollment throughout the study and for 8 months following the last dose of study drug. It is strongly recommended for the male partner of a female participant to also use male condom (plus spermicide, if available) throughout this period. Cessation of contraception after this point should be discussed with a responsible physician.
9\. Patients can be treatment-naïve or have received up to 4 lines of prior systemic therapy in the setting of R/M disease, however, a maximum of two prior lines of chemotherapy or antibody-drug conjugate (ADC) are allowed. Exceptions include prior B7-H4-targeting ADC or any prior agent with a topoisomerase inhibitor 1 mode of action; those represent exclusion criteria (exclusion criteria #18).
Exclusion Criteria:
1. Treatment with any of the following as detailed below in Table 2:
Table 2 . Washout period from prior therapies Treatment Washout period Nitrosourea or mitomycin C Within 6 weeks prior to the first dose of study intervention Any investigational agents or study drugs from a previous clinical study Within 5 half-lives or 28 days (whichever is shorter) prior to the first dose of study drug Any other anticancer treatment Within the following time periods prior to the first dose of study intervention: Cytotoxic treatment: 21 days Non-cytotoxic drugs: 21 days or 5 half-lives (whichever is shorter) Biological products including immuno-oncology agents: 28 days Radiotherapy Wide field of radiation (including whole brain radiotherapy) within 4 weeks or limited field radiotherapy (including stereotactic radiotherapy or gamma-knife) for palliation is allowed up to 14 days prior to the first dose of study intervention. Participants who have not recovered from radiotherapy-related toxicity will not be eligible Major surgery (as defined by the Investigator) At least 28 days prior to the first dose of study intervention
2. Unresolved toxicities of Grade ≥ 2 (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE version 5.0) from prior therapy (excluding vitiligo, alopecia, endocrine disorders that are controlled with replacement hormone therapy, and lymphopenia unless it is accompanied by clinical signs of infection or the indication for prophylaxis with antibiotic/antiviral/antifungal therapy). Participants with chemotherapy-induced Grade 2 neuropathy may be eligible at discretion of the Investigator.
3. Active infection, including tuberculosis, SARS-CoV-2, and known infections with hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency. Participants with a past or resolved HBV/HCV infection are eligible if all the following criteria are met:
1. Negative for HBsAg and positive for total hepatitis B core antibody (anti-HBc) or Positive for HBsAg, but for \> 6 months have had normal transaminases and HBV DNA levels between 0-2000 IU/mL (inactive carrier state) and willing to start and maintain antiviral treatment for at least the duration of the study.
2. HBV DNA levels \> 2000 IU/mL but on prophylactic antiviral treatment for the past 3 months and will maintain the antiviral treatment during the study.
3. Participants testing positive for HCV antibody are eligible only if the polymerase chain reaction test result is negative for HCV RNA.
4. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5. Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement or prior pneumonectomy (complete) or require supplemental oxygen (including intermittent or discretionary use).
6. Patients with history of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML (as determined by prior diagnostic investigation). Specific screening for MDS/AML is not required.
7. Participants with any of the following cardiac criteria:
1. History of clinically significant arrhythmia (such as multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (NCI CTCAE version 5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.
NOTE: abnormalities in serum electrolytes that can increase the risk of arrhythmic events (ie, sodium, potassium, calcium, magnesium) should be corrected before starting the study intervention
2. Uncontrolled hypertension.
3. Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months of the start of study treatment.
4. History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
5. Symptomatic heart failure (as defined by New York Heart Association class ≥ 2).
6. Prior or current cardiomyopathy.
7. Severe valvular heart disease.
8. Resting corrected QT interval using Fridericia's formula (QTcF) \> 470 msec
9. Any factors that increase the risk of corrected QT (interval) (QTc) prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
10. Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study intervention or during the scheduled ECG assessments (see \<\< https://www.crediblemeds.org/ \>\>).
8. Active CNS disease (patients with asymptomatic or treated CNS lesions who have been off corticosteroids, radiation, or other CNS-directed therapy for at least 4 weeks prior to start of study treatment are not considered active)
9. Uncontrolled intercurrent illness within the last 12 months of start of study treatment, including but not limited to serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.
10. Has substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the Investigator.
11. Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note:
Participants, if enrolled, should not receive live attenuated vaccine whilst receiving study intervention and up to 30 days after the last dose of study intervention. Participants can receive COVID-19 vaccines, at the discretion of the Investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines.
Note: If a COVID-19 vaccine is administered it should be done \> 72 hours prior to study intervention initiation.
12. For women only - currently pregnant (confirmed with positive pregnancy test), lactating, breastfeeding, or intend to become pregnant during the study.
13. Red blood cell transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening.
14. Current participation in another interventional clinical study
15. History of previous malignancy other than malignancy treated with curative intent and low risk of recurrence. Patients with the following diagnoses represents an exception and may enroll if ≥ 2 years with no evidence of active disease before the first dose of the study drug or if treatment is not indicated:
1. Non-melanoma skin cancers with no current evidence of disease
2. Melanoma in situ with no current evidence of disease
3. Treated or localized, low-risk, cancer of the prostate with prostate-specific antigen of \<1 ng/mL
4. Treated or localized well-differentiated thyroid cancer (stage I)
5. Cervical carcinoma in situ
6. Treated ductal/lobular carcinoma in situ of the breast
7. Treated or localized, low grade, renal cell carcinoma (stage I)
16. Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient
17. Cognitively impaired patients who are incompetent to consent.
18. Prior exposure to a B7-H4 targeting ADC, or any prior agent with a topoisomerase inhibitor 1 mode of action.
→
Inclusion Criteria:
1. Patients ≥18 years with histology-proven advanced, or R/M ACC.
2. Evidence of locally advanced disease not amenable to curative intent surgery or radiotherapy, or recurrent/metastatic disease
3. ACC-I subtype defined by at least one of the following:
a. Presence of an activating NOTCH mutation per in-house or any CLIA-certified or commercially available next-generation sequencing assay b. Solid histology (any amount of solid component) and clinical course characterized by \< 3 years from diagnosis to initial recurrence or progression or de novo metastatic disease with extra-pulmonary metastasis c. Negative TP63 tumor expression by IHC (\<10% of tumor cells)
4. Measurable disease per RECIST 1.1
5. Performance status ECOG of 0 or 1
6. Patient has provided informed consent.
7. Adequate bone marrow, hepatic, and renal function with the most recent laboratory assessments 8. Contraceptive use by the participant or the participant's partner should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
1. Male participants:
(i) Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a male condom (plus spermicide, if available) from enrollment throughout the study and for 8 months following the last dose of study drug. It is strongly recommended for the female partner of a male participant to also use a highly effective method of contraception throughout this period, as described in Table 3. In addition, male participants must refrain from sperm donation while on study and for 8 months (5 half-lives plus 6 months) following the last dose of study drug.
(b) Female participants: (i) Females of childbearing potential must have a negative urine or serum pregnancy test prior to receiving the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
(ii) Female participants of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective method of birth control (defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly, from enrollment throughout the study and for 8 months following the last dose of study drug. It is strongly recommended for the male partner of a female participant to also use male condom (plus spermicide, if available) throughout this period. Cessation of contraception after this point should be discussed with a responsible physician.
9\. Patients can be treatment-naïve or have received up to 4 lines of prior systemic therapy in the setting of R/M disease, however, a maximum of two prior lines of chemotherapy or antibody-drug conjugate (ADC) are allowed. Exceptions include prior B7-H4-targeting ADC or any prior agent with a topoisomerase inhibitor 1 mode of action; those represent exclusion criteria (exclusion criteria #18).
Exclusion Criteria:
1\) Treatment with any of the following as detailed below in Table 2:
Table 2. Washout period from prior therapies
TREATMENT
1. Nitrosourea or mitomycin C
2. Any investigational agents or study drugs from a previous clinical study
3. Any other anticancer treatment
4. Radiotherapy
5. Major surgery (as defined by the Investigator) At least 28 days prior to the first dose of study
WASHOUT PERIOD
1. Within 6 weeks prior to the first dose of study intervention
2. Within 5 half-lives or 28 days (whichever is shorter) prior to the first dose of study drug
3. Within the following time periods prior to the first dose of study intervention:
Cytotoxic treatment: 21 days Non-cytotoxic drugs: 21 days or 5 half-lives (whichever is shorter) Biological products including immuno-oncology agents: 28 days
4. Wide field of radiation (including whole brain radiotherapy) within 4 weeks or limited field radiotherapy (including stereotactic radiotherapy or gamma-knife) for palliation is allowed up to 14 days prior to the first dose of study intervention. Participants who have not recovered from radiotherapy-related toxicity will not be eligible.
5. At least 28 days prior to the first dose of study intervention
2\) Unresolved toxicities of Grade ≥ 2 (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE version 5.0) from prior therapy (excluding vitiligo, alopecia, endocrine disorders that are controlled with replacement hormone therapy, and lymphopenia unless it is accompanied by clinical signs of infection or the indication for prophylaxis with antibiotic/antiviral/antifungal therapy). Participants with chemotherapy-induced Grade 2 neuropathy may be eligible at discretion of the Investigator.
3\) Active infection, including tuberculosis, SARS-CoV-2, and known infections with hepatitis B virus (HBV), hepatitis C virus (HCV) or human immunodeficiency. Participants with a past or resolved HBV/HCV infection are eligible if all the following criteria are met:
a) Negative for HBsAg and positive for total hepatitis B core antibody (anti-HBc) or Positive for HBsAg, but for \> 6 months have had normal transaminases and HBV DNA levels between 0-2000 IU/mL (inactive carrier state) and willing to start and maintain antiviral treatment for at least the duration of the study.
b) HBV DNA levels \> 2000 IU/mL but on prophylactic antiviral treatment for the past 3 months and will maintain the antiviral treatment during the study.
c) Participants testing positive for HCV antibody are eligible only if the polymerase chain reaction test result is negative for HCV RNA.
4\) Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5\) Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement or prior pneumonectomy (complete) or require supplemental oxygen (including intermittent or discretionary use).
6\) Patients with history of myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML (as determined by prior diagnostic investigation). Specific screening for MDS/AML is not required.
7\) Participants with any of the following cardiac criteria:
1. History of clinically significant arrhythmia (such as multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (NCI CTCAE version 5.0 Grade 3); symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.
NOTE: abnormalities in serum electrolytes that can increase the risk of arrhythmic events (ie, sodium, potassium, calcium, magnesium) should be corrected before starting the study intervention
2. Uncontrolled hypertension.
3. Acute coronary syndrome/acute myocardial infarction, unstable angina pectoris, coronary intervention procedure with percutaneous coronary intervention, or coronary artery bypass grafting within 6 months of the start of study treatment.
4. History of brain perfusion problems (eg, carotid stenosis) or stroke, or transient ischemic attack in the last 6 months prior to screening.
5. Symptomatic heart failure (as defined by New York Heart Association class ≥ 2).
6. Prior or current cardiomyopathy.
7. Severe valvular heart disease.
8. Resting corrected QT interval using Fridericia's formula (QTcF) \> 470 msec
9. Any factors that increase the risk of corrected QT (interval) (QTc) prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age.
10. Concomitant medications known to prolong QTc should be used with caution and cannot be used starting with the first dose of study intervention or during the scheduled ECG assessments (see \<\< https://www.crediblemeds.org/ \>\>).
8\) Active CNS disease (patients with asymptomatic or treated CNS lesions who have been off corticosteroids, radiation, or other CNS-directed therapy for at least 4 weeks prior to start of study treatment are not considered active) 9) Uncontrolled intercurrent illness within the last 12 months of start of study treatment, including but not limited to serious chronic GI conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the participant to give written informed consent.
10\) Has substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study in the opinion of the Investigator.
11\) Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Participants, if enrolled, should not receive live attenuated vaccine whilst receiving study intervention and up to 30 days after the last dose of study intervention. Participants can receive COVID-19 vaccines, at the discretion of the Investigator, following a benefit/risk evaluation for the individual participant and in accordance with local rules and regulations and vaccination guidelines.
Note: If a COVID-19 vaccine is administered it should be done \> 72 hours prior to study intervention initiation.
12\) For women only - currently pregnant (confirmed with positive pregnancy test), lactating, breastfeeding, or intend to become pregnant during the study.
13\) Red blood cell transfusion dependence, defined as requiring more than 2 units of packed RBC transfusions during the 4-week period prior to screening.
14\) Current participation in another interventional clinical study 15) History of previous malignancy other than malignancy treated with curative intent and low risk of recurrence. Patients with the following diagnoses represents an exception and may enroll if ≥ 2 years with no evidence of active disease before the first dose of the study drug or if treatment is not indicated:
a. Non-melanoma skin cancers with no current evidence of disease b. Melanoma in situ with no current evidence of disease c. Treated or localized, low-risk, cancer of the prostate with prostate-specific antigen of \<1 ng/mL d. Treated or localized well-differentiated thyroid cancer (stage I) e. Cervical carcinoma in situ f. Treated ductal/lobular carcinoma in situ of the breast g. Treated or localized, low grade, renal cell carcinoma (stage I) 16) Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient 17) Cognitively impaired patients who are incompetent to consent. 18) Prior exposure to a B7-H4 targeting ADC, or any prior agent with a topoisomerase inhibitor 1 mode of action.
Inclusion Criteria
* Confirmed diagnosis of patients with non-squamous NSCLC stage IIIB/IIIC not eligible for curative-intent therapies or stage IV/M1 (a/m NSCLC) with or without actionable genomic mutations (i.e., EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, RET, HER-2)
* Aged at least 18 years at first diagnosis of a/m NSCLC
* For the AGA subgroup, having received platinum-based chemotherapy, having received at least one target approved therapy.
* For the non\_AGA subgroup,should have received either sequential or concurrent use of ICI and PTC)
* Patient must have received at least line of therapy of an active agent after failing PTC.
Exclusion Criteria
* Patients with evidence of other primary malignancies (apart from basal cell carcinoma and melanoma) within 1 year prior to the index date will be excluded from both the study cohorts.
* Patients who participated in an investigational clinical trial for the treatment of any cancer, including NSCLC, or any early access program from 2018 onward.
→
Inclusion Criteria
* Confirmed diagnosis of non-squamous NSCLC, Stage IIIB/IIIC incurable or IV/M1.
* Age ≥ 18 years at diagnosis of advanced/metastatic disease.
AGA Cohort: Presence of actionable mutations and all of the following:
* failure of platinum-based chemotherapy,
* failure of ≥ 1 line of approved target therapy or no targeted therapy available at the clinic,
* additional systemic treatment after platinum + target therapy combination.
Non-AGA Cohort: Absence of actionable mutations and all of the following:
* failure of platinum-based chemotherapy,
* failure of immunotherapy concurrent or sequential to platinum,
* additional systemic treatment after platinum + immunotherapy combination.
Exclusion Criteria
* Patients with evidence of other primary malignancies (except basal cell carcinoma and melanoma) within 1 year prior to the index date will be excluded from both study cohorts.
* Patients who participated in a clinical investigational study for the treatment of any cancer, including NSCLC, or any early access program from 2018 onwards.
Inclusion Criteria:
* Capable of giving assent (signing the assent form) to participate in the study. The caregiver of the patient must be capable of giving written informed consent for the patient's participation in the study. Consent and assent forms must be completed prior to any study-specific procedures.
* Patient and the caregiver (where applicable) must be willing to and be able to answer questionnaires that are part of the study procedures.
* Male or female patients aged ≥ 6 to \< 18 years old.
* Patients with physician-diagnosed severe eosinophilic asthma for at least 12 months prior to Visit 1.
* Patients with a diagnosis of severe asthma confirmed, evaluated, and managed by the clinical site/site network for ≥ 6 months prior to Visit 1.
* Patients with an exacerbation history of asthma exacerbations (defined as a requirement for systemic corticosteroids and/or hospitalisation) within 12 months prior to Visit 1, OR,
1. 2 asthma exacerbations (defined as a requirement for systemic corticosteroids and/or hospitalisation) per year within the 2 years prior to Visit 1 AND, one or more of the following:
2. Currently on stable maintenance oral corticosteroids (OCS) used for at least 3 months prior to Visit 1, OR,
3. At least one of the 2 exacerbations that occurred in the year prior to Visit 1 resulted in hospitalisation.
* Patients on well-documented, stable treatment for asthma with high dose ICS and at least one additional controller medication, such as long-acting β2 agonists (LABA), leukotriene receptor antagonists (LTRA), long-acting muscarinic antagonists (LAMA), or theophylline, since at least 6 months prior to Visit 1.
* Eosinophilic airway inflammation that is related to asthma characterised as eosinophilic in nature as indicated by peripheral blood eosinophil count of ≥ 300 cells/μL during screening OR a blood eosinophil count of 150 to 299 cells/μL during screening and documentation of elevated eosinophils in bronchoalveolar lavage (BAL), sputum, bronchial biopsy, or historical eosinophil count ≥ 300 cells/μL within the 2 years prior to Visit 1.
* ≥ 70% compliance with maintenance asthma medication during the screening period based on the Paediatric Asthma Symptom - Observer reported (PASO) or Asthma Daily Diary.
* At least 50% daily PASO or Asthma Daily Diary completion during the entire screening period, with at least 50% PASO or Asthma Daily Diary completion in the 14-day period prior to randomisation.
* ACQ-IA ≥ 1.5 at screening and Visit 2a.
* Body weight ≥ 15 kg.
* Females of childbearing potential (FOCBP) who are sexually active, as judged by the investigator, must commit to consistent and correct use of a highly effective method of contraception.
Exclusion Criteria:
* Clinically important pulmonary disease other than asthma or patients who have ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
* Life-threatening asthma.
* Asthma exacerbation requiring use of systemic corticosteroids or increase in maintenance dose of OCS within 2 weeks prior to Visit 2a or acute upper/lower respiratory infection that requires antibiotics or antiviral medication within 2 weeks prior to the first dose of the IP (Visit 2b).
* Any disorder that is not stable in the opinion of the investigator and could affect the safety of the patient during the study, influence the findings of the studies or their interpretations or impede the patient's ability to complete the entire duration of the study.
* History of anaphylaxis to any biologic therapy.
* Current malignancy, or history of malignancy.
* A helminth parasitic infection.
* Use of immunosuppressive medication.
* Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.
* Receipt of any marketed or investigational biologic within 5 half-lives prior to Visit 2.
* Previously received benralizumab (MEDI-563).
* Participation in another interventional clinical study.
* Patients with known hypersensitivity to benralizumab or any of the excipients of the product.
* Currently pregnant, breastfeeding, or lactating females.
* Previous randomisation in the present study.
→
Inclusion Criteria:
* Capable of giving assent (signing the assent form) to participate in the study. The caregiver of the patient must be capable of giving written informed consent for the patient's participation in the study. Consent and assent forms must be completed prior to any study-specific procedures.
* Patient and the caregiver (where applicable) must be willing to and be able to answer questionnaires that are part of the study procedures.
* Male or female patients aged ≥ 6 to \< 18 years old.
* Patients with physician-diagnosed severe eosinophilic asthma for at least 12 months prior to Visit 1.
* Patients with a diagnosis of severe asthma confirmed, evaluated, and managed by the clinical site/site network for ≥ 6 months prior to Visit 1.
* Patients with an exacerbation history of asthma exacerbations (defined as a requirement for systemic corticosteroids and/or hospitalisation) within 12 months prior to Visit 1, OR,
1. 2 asthma exacerbations (defined as a requirement for systemic corticosteroids and/or hospitalisation) per year within the 2 years prior to Visit 1 AND, one or more of the following:
2. Currently on stable maintenance oral corticosteroids (OCS) used for at least 3 months prior to Visit 1, OR,
3. At least one of the 2 exacerbations that occurred in the year prior to Visit 1 resulted in hospitalisation.
* Patients on well-documented, stable treatment for asthma with high dose ICS and at least one additional controller medication, such as long-acting β2 agonists (LABA), leukotriene receptor antagonists (LTRA), long-acting muscarinic antagonists (LAMA), or theophylline, since at least 6 months prior to Visit 1.
* Eosinophilic airway inflammation that is related to asthma characterised as eosinophilic in nature as indicated by peripheral blood eosinophil count of ≥ 300 cells/μL during screening OR a blood eosinophil count of 150 to 299 cells/μL and documentation of elevated eosinophils in bronchoalveolar lavage (BAL), sputum or bronchial biopsy within the 2 years prior to Visit 1.
* ≥ 70% compliance with maintenance asthma medication during the screening period based on the Paediatric Asthma Symptom - Observer reported (PASO) or Asthma Daily Diary.
* At least 70% daily PASO or Asthma Daily Diary completion during the entire screening period, with at least 50% PASO or Asthma Daily Diary completion in the 14-day period prior to randomisation.
* Pre-BD FEV1 ≤ 95% of the predicted normal value or pre-BD FEV1/forced vital capacity (FVC) ratio \< 0.85 required at Visit 1. Patients with ≥ 25 % increase in pre-BD FEV1 value during the screening period will be screen failed.
* ACQ-IA ≥ 1.5 with no meaningful improvement (ACQ-IA change ≤ -0.5) between screening and Visit 2a.
* Body weight ≥ 15 kg.
* Females of childbearing potential (FOCBP) who are sexually active, as judged by the investigator, must commit to consistent and correct use of a highly effective method of contraception.
Exclusion Criteria:
* Clinically important pulmonary disease other than asthma or patients who have ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
* Life-threatening asthma.
* Asthma exacerbation requiring use of systemic corticosteroids or increase in maintenance dose of OCS within 2 weeks prior to Visit 2a or acute upper/lower respiratory infection that requires antibiotics or antiviral medication within 2 weeks prior to the first dose of the IP (Visit 2b).
* Any disorder that is not stable in the opinion of the investigator and could affect the safety of the patient during the study, influence the findings of the studies or their interpretations or impede the patient's ability to complete the entire duration of the study.
* History of anaphylaxis to any biologic therapy.
* Current malignancy, or history of malignancy.
* A helminth parasitic infection.
* Use of immunosuppressive medication.
* Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.
* Receipt of any marketed or investigational biologic within 5 half-lives prior to Visit 1.
* Previously received benralizumab (MEDI-563).
* Participation in another interventional clinical study.
* Patients with known hypersensitivity to benralizumab or any of the excipients of the product.
* Currently pregnant, breastfeeding, or lactating females.
* Previous randomisation in the present study.
Inclusion Criteria:
1. Participant must be 16 years of age or older, at the time of signing the informed consent.
2. Participants with a documented diagnosis of CRSwNP.
3. Endoscopic nasal polypectomy is performed during the screening period.
4. Voluntarily participate and sign the informed consent form as described in A 3.
5. No history or current psychiatric disorders, with normal cognitive functions including understanding, expression, and orientation.
Exclusion Criteria:
1. Any significant disease or disorder that the investigator believes may place the patient at risk or may affect the study results or the patient's ability to participate in the study.
2. Currently participating in an interventional study.
3. Patients who are unable to independently complete questionnaires due to language barriers or mental status.
→
Inclusion Criteria:
1. Participant must be 16 years of age or older, at the time of signing the informed consent.
2. Participants with a documented diagnosis of bilateral CRSwNP.
3. ESS is performed during the screening period.
4. Voluntarily participate and sign the ICF.
5. No history or current psychiatric disorders, with normal cognitive functions including understanding, expression, and orientation.
Exclusion Criteria:
1. Any significant disease or disorder that the investigator believes may place the patient at risk or may affect the study results or the patient's ability to participate in the study.
2. Use of biologic therapy for CRSwNP within 3 months prior to surgery.
3. Currently participating in an interventional study.
4. Patients who are unable to independently complete questionnaires due to language barriers or mental status.
Inclusion Criteria:
Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Aged ≥18 years and over. Predicted life expectancy ≥ 3 months. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Have biopsy proven clear cell RCC. Have a surgically resectable tumour as determined by the treating Urologist Have any T or N status, M0. Have any T or N status, M1 (but if M1, the subject must be deemed suitable for cytoreductive nephrectomy at time of enrolment).
No prior exposure to PARP inhibitors (including but not limited to olaparib), tyrosine kinase inhibitors (including but not limited to cediranib, sunitinib, pazopanib, axitinib or cabozantinib), immunotherapy or immune checkpoint inhibitors (including but not limited to other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies), nor prior treatment with an mammalian target of rapamycin (mTOR) inhibitor (including, but not limited to everolimus, temsirolimus, or sirolimus). Prior cytokine therapy (eg, IL-2, IFN-α) or treatment with cytotoxics is allowed.
At least 1 measurable lesion according to RECIST Version 1.1 at screening that can be accurately assessed at baseline by CT or MRI and is suitable for repeated assessment. A previously irradiated lesion cannot be considered a target lesion. Radiographic disease assessment can be performed up to 28 days prior to the first dose of trial treatment. It is acceptable for the measurable lesion to be planned for removal at surgery.
Have adequate organ and marrow function, as defined below (measured within 28 days of first dose of trial medication):
Haemoglobin ≥ 100 g/L Platelet count ≥ 135 x 109/L Neutrophil count ≥ 1.8 x 109/L Peripheral blood smear with no features of myelodysplastic syndrome or acute myeloid leukemia.
Serum creatinine ≤1.5x the institutional ULN concurrent with creatinine clearance ≥51mL/min (calculated by Cockcroft and Gault equation)
Adequate hepatic function:
Alanine Aminotransferase (ALT) ≤2.5x the institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤5x the institutional ULN, AND Total bilirubin ≤1.5x the institutional ULN unless in the presence of Gilbert's syndrome (persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), AND
Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
For women of childbearing potential a negative urine or serum pregnancy test must be performed within 28 days of study treatment and confirmed prior to treatment on day 1.
Patient is willing and able to comply with the protocol for the duration of the trial.
Exclusion Criteria:
Patients with brain metastases. A scan to confirm the absence of brain metastases is not required.
Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
History of leptomeningeal carcinomatosis. Body weight \<30kg Contraindication to cediranib, olaparib, durvalumab or chimeric or humanized antibodies or fusion proteins.
Specifically patients with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not enter the study.
History of hypersensitivity to active or inactive excipients of cediranib, olaparib or durvalumab.
Other invasive malignancy within the last 2 years. Patients with previous history of malignancies with a negligible risk of metastasis or death and treated with expected curative intent are eligible at discretion of clinical team, for example:
Carcinoma in situ of the cervix. Basal or squamous cell skin cancer. Localized low to intermediate risk prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse; or prostate cancer (Stage T1/T2a, Gleason ≤ 6 and PSA \< 10 ng/mL) undergoing active surveillance and treatment naïve.
Major surgery within 4 weeks prior to first dose of study drug (excluding placement of vascular access).
Patients must have recovered from side effects of any major surgery. Minor surgery (not including the diagnostic biopsy) within 2 weeks prior to first dose of trial treatment.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
Concurrent enrollment in another clinical trial unless it is an observational (non-interventional) or translational clinical study, or during the follow-up period of an interventional clinical study.
Receipt of the last dose of anticancer therapy or radiotherapy chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolisation, monoclonal antibodies) ≤28 days prior to the first dose of study drug (If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigators).
Gastrointestinal abnormalities including:
refractory nausea and vomiting, inability to take oral medication; requirement for intravenous alimentation; prior surgical procedures affecting absorption including total gastric resection; treatment for active peptic ulcer disease in the past 6 months; active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 120 days without evidence of resolution documented by endoscopy or colonoscopy; malabsorption syndromes. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors, or inducers or substrates for CYP1A2 (see Section 10.8, concomitant therapy).
Concomitant medications known to prolong the QT interval (see Appendices 4, 5 and 6, concomitant therapy) or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age), history of Torsades de pointes.
Poorly controlled hypertension (persistently elevated \> 150/100mmHg, either systolic or diastolic or both, despite anti-hypertensive medication) ECG with mean resting QTc of ≥470ms (Fridericia; as per local reading) on two or more time points within a 24 hour period or family history of long QT syndrome.
Requirement of anticoagulant therapy with oral vitamin K antagonists. Therapeutic use of low molecular weight heparin is allowed.
Any of the following within 12 months prior to study entry:
myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, Peripheral arterial embolus.
Active or prior documented autoimmune or inflammatory disorders (except vitiligo), for example:
Intestinal: Inflammatory Bowel Disease (Colitis (including ulcerative colitis), Crohn's Disease), Diverticulitis (with the exception of Diverticulosis), Coeliac Disease (except patients with coeliac disease controlled by diet alone), irritable Bowel Disease Vascular: any type of vasculitic disorder, e.g. Wegener syndrome, granulomatosis with polyangiitis.
Endocrine: any endocrine alteration related to an autoimmune process e.g. Hashimoto syndrome, Grave's disease. NOTE: patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement treatment may be included.
Respiratory: Active Pneumonitis (of any origin: inflammatory or infectious), Sarcoidosis syndrome.
Dermatological: Psoriasis, Lupus/SLE (unless the skin condition has never required systemic therapy).
Other: Rheumatoid Arthritis, Hypophysitis, Uveitis. History of organ transplant that requires use of immunosuppressive medications or any medical condition in which immunosuppressive agents were administered, including but, not limited to: Systemic corticosteroids, methotrexate, azathioprine.
Tumour necrosis factor alpha (TNF-α) blockers Patients with autoimmune conditions without active disease in the past 5 years may be included but only after discussion with the Study Physician.
Current or prior use of immunosuppressive agents within 28 days of first day of study drug, with the exceptions of intranasal or inhaled corticosteroids, or systemic corticosteroids at physiological doses which are not to exceed 10mg/day prednisolone (or an equivalent corticosteroid). The following exceptions are allowed:
Intranasal, inhaled, topical or local steroid injections (e.g. intra articular injection).
Systemic corticosteroids at physiological doses not to exceed 10mg/day prednisolone (or equivalent).
Steroids for premedication of hypersensitivity reactions (e.g. as CT premedication) .
Immunocompromised patients (e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV), or have a history of active primary immunodeficiency).
Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation.
Receipt of live, attenuated vaccine within the last 30 days. Note: enrolled patients should not receive live vaccine while receiving investigational agent nor within 30 days of last dose of investigational agent.
Active infection including tuberculosis (clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV1/2 antibodies).
Subjects with a past or resolved HBV infection (defined as: presence of hepatitis B core antibody -anti-HBc- and absence of hepatitis B surface antigen -HbsAg-) are eligible.
As judged by the Investigator, any patient considered a poor medical risk due to a serious uncontrolled medical or psychiatric disorder, non-malignant systemic disease or on-going or active infection.
Persistent toxicities (≥Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia and vitiligo.
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
For Durvalumab-containing arms only: Patient with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the investigator.
Women who are pregnant, or are lactating or breastfeeding. Women of childbearing potential and male participants who are unwilling to use adequate contraception from screening and for 180 days after the last dose of study drug.
Patients with contraindication to MRI including; contraindicated metallic implants, contraindicated coronary stents and pacemakers. Inability to lie flat or still in an MRI scanner for whatever reason (e.g. claustrophobia) Judgement by the Investigator that the patient should not participate in the trial.
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Inclusion Criteria Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
* Aged ≥18 years and over.
* Predicted life expectancy ≥ 16 weeks.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
* Have biopsy proven clear cell RCC, either as part of the screening process or if undertaken prior to screening no more than 6 weeks prior to consent.
* Allow access to archival Formalin-Fixed Paraffin-Embedded (FFPE) tumour tissue from any previous renal tumour biopsy
* Have a surgically resectable tumour as determined by the treating urologist
* T1b or above, N0 and M0; OR have any T status where either N1 or M1 (but the participant must be deemed suitable for cytoreductive nephrectomy at time of enrolment).
* No prior exposure to PARP inhibitors (including but not limited to olaparib), tyrosine kinase inhibitors (including but not limited to cediranib, sunitinib, pazopanib, axitinib, bevacizumab and cabozantinib), immunotherapy or immune checkpoint inhibitors (including but not limited to other anti-CTLA-4, anti-TIGIT, anti-PD-1, or anti-PD-L1 antibodies), nor prior treatment with a mammalian target of rapamycin (mTOR) inhibitor (including, but not limited to everolimus, temsirolimus, or sirolimus). Prior cytokine therapy (e.g. IL-2, IFN-α) or treatment with cytotoxics is NOT allowed.
* At least 1 measurable lesion according to RECIST Version 1.1 at screening that can be accurately assessed at screening by MRI and is suitable for repeated assessment. A previously irradiated lesion cannot be considered a target lesion. Radiographic disease assessment can be performed up to 28 days prior to the first dose of trial treatment. It is acceptable for the measurable lesion to be planned for removal at surgery. CT reported RECIST assessments are acceptable at screening for participants with chest metastases.
* Have adequate organ and marrow function, as defined below (measured within 28 days of first dose of trial medication):
o Haemoglobin ≥ 90 g/L
* Platelet count ≥ 100 x 109/L
* Neutrophil count ≥ 1.5 x 109/L Creatinine clearance ≥45mL/min (calculated by Cockcroft and Gault equation: where estimated creatinine clearance = (140-age\[years\]) x weight (kg) (xF)a serum creatinine (mg/dL) x 72a where F=0.85 for females and 1 for males). Participants with 2+ proteinuria on dipstick must also have UPC \<0.5 on 2 consecutive samples.
* Adequate hepatic function:
* Alanine Aminotransferase (ALT) (SGPT) ≤2.5x the institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤5x the institutional ULN, AND.
* AST ≤2.5x the institutional ULN unless liver metastases are present, in which case it must be ≤5x the institutional ULN, AND.
* Total bilirubin ≤1.5x the institutional ULN unless in the presence of known or suspected Gilbert's syndrome- the inclusion of potential participants with known/suspected Gilbert's syndrome must be discussed with the Trial Oncologist prior to their inclusion in the trial. For patients with known Gilbert's syndrome the threshold for receiving rilvegostomig/volrustomig is total bilirubin ≤ 1.5x the institutional ULN.
* Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal participants. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause. The following age-specific requirements apply:
* Women \<50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
* Women ≥50 years of age would be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
* For women of childbearing potential, a negative serum pregnancy test must be performed within 14 days of trial treatment and confirmed prior to treatment on Day 1.
* Male participants must be willing to use a condom during treatment and for 3 months after the last dose of trial treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female participants and female partners of male participants should also be willing to use a highly effective form of contraception (see Section 11.8for acceptable methods) if they are of childbearing potential.
* Participant is willing and able to comply with the protocol for the duration of the trial.
* Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
SPECIFIC INCLUSION CRITERIA FOR OLAPARIB CONTAINING ARMS:
* Haemoglobin must be ≥ 100 g/L
* If abnormalities in the Full Blood Count (and it is clinically indicated): Peripheral blood smear with no features of myelodysplastic syndrome or acute myeloid leukaemia
* Serum creatinine must be ≤1.5x the institutional ULN concurrent with creatinine clearance ≥51mL/min (calculated by Cockcroft and Gault equation as above) or based on a 24-hour urine creatinine clearance test.
SPECIFIC INCLUSION CRITERIA FOR OLAPARIB PLUS CEDIRANIB ARM ONLY:
• Urine protein: creatinine ratio (UPC) ≤1 OR ≤2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart. Patients with ≥2+ proteinuria on dipstick must also have UPC \<0.5 on 2 consecutive samples (ensure that the units for the protein and creatinine measurements are in the same units before calculating this ratio e.g., both are g/L).
SPECIFIC INCLUSION CRITERIA FOR VOLRUSTOMIG:
* Body weight (WT) \> 35 kg
* Adequate organ and marrow function (in the absence of transfusions or growth factor support within 14 days prior to enrolment).
* Adequate hepatic function:
* Alanine Aminotransferase (ALT) (SGPT) ≤2.5x the institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤3x the institutional ULN, AND
* AST ≤2.5x the institutional ULN unless liver metastases are present, in which case it must be ≤3x the institutional ULN.
Exclusion Criteria
* cT1a N0 M0-staged Renal Cell Cancer
* Participants with brain metastases. A scan to confirm the absence of brain metastases is not required.
* Participants with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days prior to start of first dose of treatment.
* History of leptomeningeal carcinomatosis.
* Body weight ≤30kg
* Contraindication to cediranib, olaparib, volrustomig and rilvegostomig or chimeric or humanized antibodies or fusion proteins (specifically participants with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not enter the trial).
* History of hypersensitivity to active or inactive excipients of cediranib, olaparib or volrustomig and rilvegostomig.
* Other invasive malignancy within the last 2 years. Participants with previous history of malignancies with a negligible risk of metastasis or death and treated with expected curative intent are eligible at discretion of clinical team, for example:
* Carcinoma in situ of the cervix.
* Basal or squamous cell skin cancer.
* Localized low to intermediate risk prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse; or prostate cancer (Stage T1/T2a, Gleason ≤ 6 and PSA \< 10 ng/mL) undergoing active surveillance and treatment naïve.
* Major surgery within 4 weeks prior to first dose of trial drug (excluding placement of vascular access). If participants have undergone major surgery more than 4 weeks prior to the scheduled first dose of trial drug, they must have fully recovered from the procedure.
* Minor surgery (not including the diagnostic biopsy) within 2 weeks prior to first dose of trial treatment
* Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
* Concurrent enrolment in another clinical trial unless it is an observational (non-interventional NOT involving CTIMPs) or translational clinical trial, or during the follow-up period of an interventional clinical trial.
* Receipt of the last dose of anticancer therapy or radiotherapy, chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolisation, monoclonal antibodies) ≤28 days prior to the first dose of trial drug.
* Gastrointestinal abnormalities including:
o refractory nausea and vomiting,
* inability to take oral medication;
* requirement for intravenous alimentation;
* prior surgical procedures affecting absorption including total gastric resection;
* treatment for active peptic ulcer disease in the past 6 months prior to the first dose of trial treatment;
* active gastrointestinal bleeding, unrelated to cancer, as evidenced by haematemesis, haematochezia or melaena in the past 120 days prior to the first dose of trial treatment without evidence of resolution documented by endoscopy or colonoscopy;
* malabsorption syndromes.
* Any of the following within 12 months prior to trial consent:
o myocardial infarction,
o clinically significant arrhythmia,
* uncontrolled angina,
* coronary/peripheral artery bypass graft,
* symptomatic congestive heart failure,
* cerebrovascular accident or transient ischemic attack,
* peripheral arterial embolus.
* Current or prior use of immunosuppressive agents within 28 days prior to the first dose of trial treatment, including anti-TNF and anti-IL17 agents, with the exceptions of intranasal or inhaled corticosteroids, or systemic corticosteroids at physiological doses which are not to exceed 10mg/day prednisolone (or an equivalent corticosteroid). The following exceptions are allowed:
o Intranasal, inhaled, topical or local steroid injections (e.g. intra articular injection).
* Systemic corticosteroids at physiological doses not to exceed 10mg/day prednisolone (or equivalent).
* Steroids for premedication of hypersensitivity reactions (e.g. as CT scan premedication).
* Immunocompromised participants (e.g., participants who are known to be serologically positive for human immunodeficiency virus (HIV) or have a history of active primary immunodeficiency).
* Active infection including tuberculosis (clinical history, physical examination and radiographic findings, and Tuberculosis (TB) testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV1/2 antibodies).
o Participants with a past or resolved HBV infection (defined as: presence of hepatitis B core antibody -anti-HBc- and absence of hepatitis B surface antigen -HbsAg-) are eligible.
* As judged by the Investigator, any participant considered a high medical risk, for example due to a serious uncontrolled medical or psychiatric disorder, non-malignant systemic disease or on-going or active infection.
* Persistent toxicities (≥Common Terminology Criteria for Adverse Event (CTCAE V5.0) grade 2) caused by previous cancer therapy, excluding alopecia and vitiligo.
o Participants with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Chief Investigator.
* Participants with contraindication to MRI including; contraindicated metallic implants, contraindicated coronary stents and pacemakers. Inability to lie flat or still in an MRI scanner for whatever reason (e.g., claustrophobia).
* Judgement by the Investigator that the participant should not participate in the trial.
* Involvement in the planning and/or conduct of the trial.
SPECIFIC EXCLUSION CRITERIA FOR CEDIRANIB AND/OR OLAPARIB CONTAINING ARMS:
* Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors, or inducers or substrates for CYP1A2 (see Section 10.7 Concomitant therapy and Appendices 4 and 5 for full details).
* Concomitant medications known to prolong the QT interval (see Appendices 4\& 5) or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age), history of Torsades de pointes.
* Resting ECG indicating uncontrolled, potentially reversible cardiac conditions as judged by the investigator (e.g., unstable ischaemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \>500ms, electrolyte disturbances, resting QTc of ≥470ms (Fridericia; as per local reading), etc.) on two or more time points within a 24-hour period or family history of long QT syndrome.
* Requirement of anticoagulant therapy with oral vitamin K antagonists. o Therapeutic use of low molecular weight heparin is allowed.
* Poorly controlled hypertension (persistently elevated \> 150/100mmHg (or \> 140/90 FOR OLAPARIB PLUS CEDIRANIB ARM ONLY), either systolic or diastolic or both, despite anti-hypertensive medication)
* Clinically significant signs and/or symptoms of bowel obstruction within 3 months prior to starting treatment
* History of intra-abdominal abscess within 3 months prior to starting the first dose of trial treatment
* History of GI perforation. Participants with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired, there has been no evidence of fistula for at least 6 months prior to starting the first dose of trial treatment, and participant is deemed to be at low risk of recurrent fistula.
SPECIFIC EXCLUSION CRITERIA FOR CEDIRANIB MONOTHERAPY OR CEDIRANIB- CONTAINING ARMS ONLY:
* Left ventricular ejection fraction (LVEF) \< lower limit of normal (LLN) per institutional guidelines, or \<55%, if threshold for normal not otherwise specified by institutional guidelines, for participants with the below risk factors (an Echocardiogram should be performed at baseline and if clinically indicated):
o Prior treatment with anthracyclines
* Prior treatment with trastuzumab
* Prior central thoracic RT, including exposure of heart to therapeutic doses of ionising RTM
* Prior history of other significant impaired cardiac function
SPECIFIC EXCLUSION CRITERIA FOR VOLRUSTOMIG AND RILVEGOSTOMIG ARMS ONLY:
* Participant with irreversible toxicity not reasonably expected to be exacerbated by treatment with volrustomig and rilvegostomig may be included only after consultation with the Trial Oncologist.
* History of organ transplant that requires use of immunosuppressive medications or any medical condition in which immunosuppressive agents were administered, including but not limited to: systemic corticosteroids, methotrexate, azathioprine.
* Receipt of live, attenuated vaccine within the last 30 days. Note: enrolled participants should not receive live, attenuated vaccine while receiving volrustomig or rilvegostomig nor within 30 days of last dose of volrustomig or rilvegostomig.
* Active or prior documented autoimmune or inflammatory disorders (except vitiligo), for example:
* Intestinal: Inflammatory Bowel Disease (Colitis (including ulcerative colitis), Crohn's Disease), Diverticulitis, Coeliac Disease (except participants with coeliac disease controlled by diet alone),
* Vascular: any type of vasculitic disorder, e.g. Wegener syndrome, granulomatosis with polyangiitis.
* Endocrine: any endocrine alteration related to an autoimmune process e.g. Hashimoto syndrome, Grave's disease. NOTE: participants with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement treatment may be included.
* Respiratory: Active Pneumonitis (of any origin: inflammatory or infectious), Sarcoidosis syndrome.
* Dermatological: Psoriasis, Lupus/SLE (unless the skin condition has never required systemic therapy).
* Other: Rheumatoid Arthritis, Hypophysitis, Uveitis.
* Participants with autoimmune conditions without active disease in the past 5 years may be included but only after discussion with the Trial Oncologist.
* Participants with persistent toxicities (≥Common Terminology Criteria for Adverse Event (CTCAE v 5.0) grade 2) caused by previous cancer therapy, excluding alopecia and vitiligo, which are not reasonably expected to be exacerbated by treatment with volrustomig and rilvegostomig may be included only after consultation with the Chief Investigator.
Key Inclusion Criteria:
* Age ≥ 18 at the time of signing the informed consent
* Histologically confirmed diagnosis of adenocarcinoma of the stomach, gastro-esophageal junction, esophagus, or pancreas
* Must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
* Must show positive CLDN18.2 expression in tumor cells as determined by central immunohistochemistry (IHC)
* Eastern Cooperative Oncology Group Performance status (ECOG PS): 0-1 at screening
* Predicted life expectancy of ≥ 12 weeks
* Adequate organ and bone marrow function measured within 28 days prior to first dose as defined by the protocol
* Contraceptive use by men or women should be consistent with local regulations, as defined by the protocol
* Must have received at least one prior line of systemic therapy in the advanced/metastatic setting
Key Exclusion Criteria:
* Unresolved toxicity from prior anticancer therapy of Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2 except for those defined by the protocol
* Participant experienced unacceptable cytokine release syndrome (CRS) or Immune Effector Cell Associated Neurotoxicity (ICANS) following prior T cell engagers (TCE) or chimeric antigen receptor T (CAR-T) cell therapy
* Previous history of hemophagocytic lymphohistiocytosis (HLH) / macrophage activation syndrome (MAS)
* Active or prior documented autoimmune or inflammatory disorders within 3 years of start of treatment
* central nervous system (CNS) metastases or CNS pathology, as defined by the protocol, within 3 months prior to consent
* Infectious disease including active human immunodeficiency virus (HIV), active hepatitis B/C, uncontrolled infection with EBV, uncontrolled active systemic fungal, bacterial or other infection
* Cardiac conditions as defined by the protocol
* History of thromboembolic event within the past 3 months prior to the scheduled first dose of study intervention
* Participant requires chronic immunosuppressive therapy
* Participants on anticoagulation therapy with long-acting anticoagulants or other class of anticoagulants at therapeutic doses
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Key Inclusion Criteria:
* Age ≥ 18 at the time of signing the informed consent
* Histologically confirmed diagnosis of adenocarcinoma of the stomach, gastro-esophageal junction, esophagus, or pancreas
* Must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
* Must show positive CLDN18.2 expression in tumor cells as determined by central immunohistochemistry (IHC)
* Eastern Cooperative Oncology Group Performance status (ECOG PS): 0-1 at screening
* Predicted life expectancy of ≥ 12 weeks
* Adequate organ and bone marrow function measured within 28 days prior to first dose as defined by the protocol
* Contraceptive use by men or women should be consistent with local regulations, as defined by the protocol
* Must have received at least one prior line of systemic therapy in the advanced/metastatic setting
Key Exclusion Criteria:
* Unresolved toxicity from prior anticancer therapy of Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 2 except for those defined by the protocol
* Participant experienced unacceptable cytokine release syndrome (CRS) or Immune Effector Cell Associated Neurotoxicity (ICANS) following prior T cell engagers (TCE) or chimeric antigen receptor T (CAR-T) cell therapy
* Previous history of hemophagocytic lymphohistiocytosis (HLH) / macrophage activation syndrome (MAS)
* Active or prior documented autoimmune or inflammatory disorders within 3 years of start of treatment
* central nervous system (CNS) metastases or CNS pathology, as defined by the protocol, within 3 months prior to consent
* Infectious disease including active human immunodeficiency virus (HIV), active hepatitis B/C, uncontrolled infection with EBV, uncontrolled active systemic fungal, bacterial or other infection
* Cardiac conditions as defined by the protocol
* History of thromboembolic event within the past 3 months prior to the scheduled first dose of study intervention
* Participant requires chronic immunosuppressive therapy
* Participants on anticoagulation therapy with long-acting anticoagulants or other class of anticoagulants at therapeutic doses Module 3 - Active or ongoing interstitial lung disease / pneumonitis, serious chronic gastrointestinal conditions Module 3 - Any of the following cardiac conditions as determined by investigator: Complex ventricular arrhythmia, symptomatic heart failure, Cardiomyopathy, myocardial infarction or unstable angina (within past 6 months) and uncontrolled hypertension.
Module 3 - Known allergy or hypersensitivity to rilvegostomig or its excipients Module 3 - Prior exposure to an anti-TIGIT therapy
Inclusion Criteria:
1. Provision of signed and dated written informed consent prior to any study-specific procedures.
2. Adults aged 18-75, inclusive when signing the informed consent.
3. Documented physician-diagnosis of asthma for at least 12 months.
4. Treated with medium or high dose ICS in combination with LABA.
5. Demonstration of uncontrolled asthma through ACQ-6 score ≥ 1.5 .
6. Pre-bronchodilator FEV1 ≥ 40% to ≤ 90% of predicted normal.
7. Documented exacerbation history in the last 12 months and biomarker requirements of:
1. 2 severe exacerbations OR
2. 1 severe exacerbation and:
(i) Eosinophils ≥ 150 cells/µl or (ii) FeNo ≥ 25 ppb
8. Participants need to demonstrate a ≥70% compliance for Asthma Daily Diary.
9. Women of Child Bearing Potential (WOCBP) must have a negative pregnancy test.
10. Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Exclusion Criteria:
1. Completed treatment for respiratory infection with antibiotics in the 4 weeks prior to Visit 1.
2. Clinically significant pulmonary disease other than asthma .
3. Current smokers, former smokers with \>10 pack-years history.
4. Clinically significant aortic stenosis or pulmonary arterial hypertension.
5. Active tuberculosis, hepatitis, HIV, or current diagnosis of cancer or immune complex disease.
6. Unstable cardiovascular disorders.
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Inclusion Criteria:
1. Provision of signed and dated written informed consent prior to any study-specific procedures.
2. Adults aged 18-75, inclusive when signing the informed consent.
3. Documented physician-diagnosis of asthma for at least 12 months.
4. Treated with medium or high dose ICS in combination with LABA.
5. Demonstration of uncontrolled asthma through ACQ-6 score ≥ 1.5 .
6. Pre-bronchodilator FEV1 ≥ 40% to ≤ 90% of predicted normal.
7. Documented exacerbation history in the last 12 months and biomarker requirements of:
1. ≥ 2 severe exacerbations OR
2. 1 severe exacerbation and:
(i) Eosinophils ≥ 150 cells/µl or (ii) FeNo ≥ 25 ppb
8. Participants need to demonstrate a ≥70% compliance for Asthma Daily Diary.
9. Women of Child Bearing Potential (WOCBP) must have a negative pregnancy test.
10. Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Exclusion Criteria:
1. Completed treatment for respiratory infection with antibiotics in the 4 weeks prior to Visit 1.
2. Clinically significant pulmonary disease other than asthma .
3. Current smokers, former smokers with \>10 pack-years history.
4. Clinically significant aortic stenosis or pulmonary arterial hypertension.
5. Active tuberculosis, hepatitis, HIV, or current diagnosis of cancer or immune complex disease.
6. Unstable cardiovascular disorders.
Inclusion criteria:
1. Age ≥4 to \<18 years, or ≥18 years at the time of enrollment;
2. Signed ICF for patients ≥18 years, or legal representatives (parents) of patients aged ≥4 to \<18 years;
3. Written informed assent (for patients aged ≥14 to \<18 years only);
4. No history of HPP treatment with enzyme-replacement therapy;
5. Diagnosis of HPP confirmed by:
* reduced alkaline phosphatase (ALP) activity relative to age- and sex-specific reference ranges, confirmed by at least two separate measurements, AND
* the identification of a monoallelic pathogenic, likely pathogenic, or variant of uncertain significance in the ALPL gene on genetic testing.
Exclusion Criteria:
1. Confirmed conditions presenting with clinical features overlapping with HPP, including but not limited to: cerebral palsy, Duchenne muscular dystrophy, limb-girdle muscular dystrophy (Erb-Roth dystrophy), acquired secondary myopathies of various etiologies;
2. Сurrent participation in any clinical study (patients participating in other non interventional studies may be included);
3. Homozygous or compound heterozygous mutation in the ALPL gene
4. In the opinion of the investigator, the patient is not able to return for follow-up visits or obtain required follow-up studies.
5. Pregnant and breastfeeding women.
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Inclusion criteria:
1. Age ≥4 to \<18 years, or ≥18 years at the time of enrollment;
2. Signed ICF for patients ≥18 years, or legal representatives (parents) of patients aged ≥4 to \<18 years;
3. Written informed assent (for patients aged ≥14 to \<18 years only);
4. No history of HPP treatment with enzyme-replacement therapy;
5. Diagnosis of symptomatic HPP confirmed by the presence of ALL of the following criteria:
1. reduced alkaline phosphatase (ALP) activity relative to age- and sex-specific reference ranges, confirmed by at least two separate measurements;
2. the identification of a monoallelic pathogenic, likely pathogenic, or variant of uncertain significance in the ALPL gene on genetic testing;
3. presence of clinically relevant manifestations\*, consistent with HPP, confirmed by at least one of the following: i. Musculoskeletal pain requiring medical intervention or limiting activities of daily living, present at screening or documented within the previous 12 months (e.g., based on medical records, functional test results, treatment prescriptions and/or rehabilitation interventions); chronic or recurrent pain lasting ≥3 months may be considered based on medical history beyond the 12-month period prior to screening, provided appropriate documentation is available; ii. Muscle weakness and/or reduced physical function (e.g., impaired mobility, increased fatigue), present at screening or documented within the previous 12 months (e.g., based on medical records, functional test results, treatment prescriptions and/or rehabilitation interventions); iii. History of fractures, pseudofractures, or delayed fracture healing, confirmed by medical documentation and/or imaging studies performed within 24 months prior to screening (provided no subsequent interventions have occurred that may have altered the findings; if such interventions have occurred, repeat imaging may be performed at the investigator's discretion, if applicable within routine clinical practice); iv. Skeletal abnormalities (e.g., radiographic signs of rickets/osteomalacia), confirmed by medical documentation and/or imaging studies performed within 24 months prior to screening (provided no subsequent interventions have occurred that may have altered the findings; if such interventions have occurred, repeat imaging may be performed at the investigator's discretion, if applicable within routine clinical practice); v. Dental manifestations (e.g., premature loss of deciduous teeth with intact roots before the age of 5 years without significant trauma), confirmed by medical and/or dental records; vi. Limitation in mobility, endurance, or activities of daily living, present at screening or documented within the previous 12 months based on routine clinical assessment using questionnaires, scales, functional tests and/or other relevant clinical tools used in routine practice; such tools may include, for example, the 6-minute walk test (6MWT), Timed Up-and-Go test, Chair-Rise test, Borg scale, IPAQ, PedsQL, EQ 5D-3L, bioimpedance measurements, and other methods used in routine clinical practice; if symptoms are present at screening, confirmation may be based on clinical assessments performed within 3 months prior to screening (provided there are no clinically significant changes in the patient's condition) or at the screening visit; vii. Need for analgesics, physiotherapy, and/or other supportive care for clinical manifestations of HPP, present at screening or during the period prior to screening, confirmed by at least one of the following criteria (based on medical records):
* regular use of analgesics (≥3 times per week for at least 4 consecutive weeks) within the previous 6 months, or escalation of analgesic therapy within the previous 6 months;
* ≥1 structured course of physiotherapy and/or rehabilitation interventions prescribed for musculoskeletal manifestations of HPP within the previous 12 months, or ongoing sessions according to specialist recommendations;
* use of non-pharmacological and/or medical measures to reduce symptoms and support function, including orthoses, insoles, assistive devices, local injections, or other symptomatic interventions; viii. Other clinical manifestations associated with HPP, in the investigator's opinion, present at screening or documented within the previous 12 months (based on clinical assessment and/or medical records).
Exclusion Criteria:
1. Confirmed conditions presenting with clinical features overlapping with HPP, including but not limited to: cerebral palsy, Duchenne muscular dystrophy, limb-girdle muscular dystrophy (Erb Roth dystrophy), acquired secondary myopathies of various etiologies;
2. Current participation in any clinical study (patients participating in other non interventional studies may be included);
3. Homozygous or compound heterozygous mutation in the ALPL gene;
4. Monoallelic pathogenic, likely pathogenic, or variant of uncertain significance in the ALPL gene in the absence of clinically relevant manifestations of HPP at the time of screening and/or in medical history consistent with the inclusion criterion #5;
5. In the opinion of the investigator, the patient is not able to return for follow-up visits or obtain required follow-up studies;
6. Pregnant and breastfeeding women.
Newly Diagnosed Inclusion Criteria:
* Age ≥ 18 years.
* Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry \[IHC\] or sequencing for IDH) established following either a surgical resection or biopsy. An MRI scan with the required imaging sequences performed within 21 days prior to randomization preferably. The post-operative MRI scan performed within 96 hours of surgery or the MRI scan performed for radiation therapy planning may serve as the MRI scan performed during screening if all required imaging sequences were obtained.
* Karnofsky performance status ≥ 60% performed within a 14-day window prior to randomization.
* Availability of tumor tissue representative of GBM from definitive surgery or biopsy.
Recurrent Inclusion Criteria:
* Age ≥ 18 years.
* Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry \[IHC\] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).
* Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria.
* Two scans to confirm progression are required: at least 1 scan at the time of progression and 1 scan prior to the time of progression.
* Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
* Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.
Newly Diagnosed Exclusion Criteria:
* Received any prior treatment for glioma including: a. Prior prolifeprospan 20 with carmustine wafer. b. Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent. c. Prior radiation treatment for GBM or lower-grade glioma. d. Prior chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional, concurrent, active therapy for GBM outside of the trial.
* Extensive leptomeningeal disease.
* QTc \> 470 msec
* History of another malignancy in the previous 2 years, with a disease-free interval of \< 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.
Recurrent Exclusion Criteria:
* Early disease progression prior to 3 months (12 weeks) from the completion of RT.
* More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is considered one line of chemotherapy.)
* Received any prior treatment with lomustine, agents part of any of the experimental arms, and bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF receptor-mediated targeted agent.
* Any prior treatment with prolifeprospan 20 with carmustine wafer.
* Any prior treatment with an intracerebral agent.
* Receiving additional, concurrent, active therapy for GBM outside of the trial
* Extensive leptomeningeal disease.
* QTc \> 470 msec
* History of another malignancy in the previous 2 years, with a disease-free interval of \< 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.
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Newly Diagnosed Inclusion Criteria:
* Age ≥ 18 years.
* Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry \[IHC\] or sequencing for IDH) established following either a surgical resection or biopsy. An MRI scan with the required imaging sequences performed within 21 days prior to randomization preferably. The post-operative MRI scan performed within 96 hours of surgery or the MRI scan performed for radiation therapy planning may serve as the MRI scan performed during screening if all required imaging sequences were obtained.
* Karnofsky performance status ≥ 60% performed within a 14-day window prior to randomization.
* Availability of tumor tissue representative of GBM from definitive surgery or biopsy.
Recurrent Inclusion Criteria:
* Age ≥ 18 years.
* Histologically confirmed Grade IV GBM, inclusive of gliosarcoma (WHO criteria; IDH wild-type by immunohistochemistry \[IHC\] or sequencing for IDH) at first or second recurrence after initial standard, control or experimental therapy that includes at a minimum radiation therapy (RT).
* Evidence of recurrent disease demonstrated by disease progression using slightly modified Response Assessment in Neuro-Oncology (RANO) criteria.
* Two scans to confirm progression are required: at least 1 scan at the time of progression and 1 scan prior to the time of progression.
* Karnofsky performance status ≥ 70% performed within a 14-day window prior to randomization.
* Availability of tumor tissue representative of GBM from initial definitive surgery and/or, recurrent surgery, if performed.
Newly Diagnosed Exclusion Criteria:
* Received any prior treatment for glioma including: a. Prior prolifeprospan 20 with carmustine wafer. b. Prior intracerebral, intratumoral, or cerebral spinal fluid (CSF) agent. c. Prior radiation treatment for GBM or lower-grade glioma. d. Prior chemotherapy or immunotherapy for GBM or lower-grade glioma. Receiving additional, concurrent, active therapy for GBM outside of the trial.
* Extensive leptomeningeal disease.
* QTc \> 470 msec
* History of another malignancy in the previous 2 years, with a disease-free interval of \< 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.
Recurrent Exclusion Criteria:
* Early disease progression prior to 3 months (12 weeks) from the completion of RT.
* More than 2 prior lines for chemotherapy administration. (NOTE: In the 1st line adjuvant setting, combination of temozolomide (TMZ) with an experimental agent, is considered one line of chemotherapy.)
* Received any prior treatment with lomustine, agents part of any of the experimental arms, or bevacizumab or other vascular endothelial growth factor (VEGF) or VEGF receptor-mediated targeted agent.
* Any prior treatment with prolifeprospan 20 with carmustine wafer.
* Any prior treatment with an intracerebral agent.
* Receiving additional, concurrent, active therapy for GBM outside of the trial
* Extensive leptomeningeal disease.
* QTc \> 470 msec
* History of another malignancy in the previous 2 years, with a disease-free interval of \< 2 years. Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.
Inclusion Criteria:
1. Participant must be ≥ 18 years (and above legal age) at the time of screening.
2. Inoperable or metastatic HR-positive, HER2 IHC 0 breast cancer (per ASCO/CAP guidelines, on local laboratory results); ie, is documented as HR-positive (either ER and/or PgR positive \[ER or PgR ≥ 1%\]) and HER2 IHC 0 (defined as including HER2 null with no staining or incomplete and faint/barely perceptible membrane staining in ≤ 10% of tumour cells) based on a fresh, or recent tissue sample obtained no more than 6 weeks prior to or during the screening period.
3. Progressed on and not suitable for further endocrine therapy per investigator assessment.
4. ECOG performance status of 0 or 1, with no deterioration over the previous 2 weeks prior to the first dose of study intervention.
5. Minimum life expectancy of 12 weeks at screening.
6. Provision of acceptable tumour sample (newly acquired tumour biopsy at baseline or a tumour biopsy sample collected within 6 weeks prior to screening) as defined in the Laboratory Manual
7. Participants must have measurable disease as per RECIST 1.1 or evaluable disease. Lesions that will be subject to mandatory biopsy before, during, and after the dosing cannot be considered as TLs as per RECIST requirements.
8. Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention.
1. Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
2. Absolute neutrophil count ≥ 1.5×109/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).
3. Platelet count ≥ 100×109/L (platelet transfusion is not allowed within 1 week prior to screening assessment).
4. Serum albumin ≥ 2.5 g/dL.
5. TBL ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinaemia).
6. Except in the setting of HBV, ALT and AST ≤ 2.5 × ULN; for participants with hepatic metastases, ALT and AST ≤ 5 × ULN. See Exclusion Criterion 8 for requirements in the setting of HBV.
7. Calculated CrCL ≥ 30 mL/min as determined by Cockcroft Gault (using actual body weight).
9. Male and/or female assigned at birth, inclusive of all gender identities.
10. Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies;
(a) Male participants: (i) Use of a condom plus an additional contraceptive method, or avoid intercourse throughout the duration of treatment and for at least 4 months after the last dose of Dato-DXd, in addition to the female partner using a highly effective contraceptive method.
(ii) Starting at the time of first dose of Dato-DXd, male participants must not freeze or donate sperm at any time during this study and for at least 4 months after the last dose of Dato-DXd. Preservation of sperm should be considered prior to the first dose of study intervention.
(b) Female participants:Female participants not of child-bearing potential (ii) Female participants receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for WOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to study enrolment; (iii) WOCBP must use one highly effective form of contraception or avoid intercourse throughout the duration of treatment and for at least 7 months after the last dose of Dato-DXd. All WOCBP must have a negative serum pregnancy test documented during screening.
(iv) Starting at the time of first dose of Dato-DXd, female participants must not donate, or retrieve for their own use, ova at any time during this study and for at least 7 months after the last dose of Dato-DXd. Preservation of ova should be considered prior to the first dose of study intervention.
11. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
12. All races, genders, and ethnic groups are eligible for this study.
Exclusion Criteria:
1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases and ongoing or active infection), history of allogenic organ transplant, and/or substance abuse which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
2. History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) and curatively treated in situ disease.
3. Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved to Grade ≤ 1 or baseline. Note: participants may be enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to Grade \> 2 for at least 3 months prior to the first dose of study intervention and managed with SoC treatment) which the investigator deems related to previous anticancer therapy):
1. Chemotherapy-induced neuropathy
2. Fatigue
3. Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies, which may include but are not limited to hypothyroidism/hyperthyroidism, Type I diabetes, hyperglycaemia, adrenal insufficiency, or adrenalitis; and skin hypopigmentation (vitiligo) Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss).
4. Spinal cord compression or brain metastases (unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 2 weeks prior to the first dose of study intervention). Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants must have recovered from the acute toxic effect of radiotherapy (eg, dizziness and signs of increased intracranial pressure). A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and the first dose of study intervention. A minimum of 3 days must have elapsed between the end of corticosteroid therapy for CNS metastatic disease and the first dose of study intervention.
5. Leptomeningeal carcinomatosis or metastasis.
6. Has significant third-space fluid retention (eg, ascites or pleural effusion) and is not amenable for required repeated drainage.
7. Clinically significant corneal disease.
8. Has active or uncontrolled hepatitis B or C virus infection. Participants are eligible if they:
1. Have been curatively treated for HCV infection as demonstrated clinically and by viral serologies
2. Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis
3. Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii of criterion 'd' below:
4. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below:
(i) HBV DNA viral load \< 2000 IU/mL (ii) Have normal transaminase values or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT \< 3 × ULN, which are not attributable to HBV infection (iii) Start or maintain antiviral treatment if clinically indicated as per the investigator
9. Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥ 350, no history of AIDS defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/EC.
10. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible).
11. Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination, and radiographic findings, or tuberculosis testing in line with local practice).
12. Resting ECG with clinically abnormal findings.
13. Uncontrolled or significant cardiac disease including:
1. Myocardial infarction or uncontrolled/unstable angina within 6 months before the first dose of study intervention.
2. Congestive heart failure (New York Heart Association Class II to IV).
3. Uncontrolled hypertension (resting systolic blood pressure \> 180 mmHg or diastolic blood pressure \> 110 mmHg).
4. Cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (NCI CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the investigator judgement with cardiologist consultation recommended.
14. History of non-infectious ILD/pneumonitis, including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
15. Has clinically severe pulmonary function compromise (ie, requiring any supplemental oxygen), resulting from intercurrent pulmonary illnesses including but not limited to the following:
1. Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial enrolment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc)
2. Any autoimmune, connective tissue, or inflammatory disorder with potential pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc)
3. Prior pneumonectomy
16. Prior exposure to the following anticancer therapies:
1. Any TROP2-targeted therapy.
2. Any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I.
3. Any chemotherapy in the metastatic setting.
17. Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period of \> 14 days before the first dose of study intervention.
18. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumour embolisation, or monoclonal antibodies ≤ 3 weeks \[for small molecule targeted agents: ≤ 2 weeks or 5 half-lives, whichever is longer, prior to the first dose of study intervention\]). Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded.
19. Any concurrent anticancer treatment with the exception of bisphosphonates, denosumab for the treatment of bone metastases.
Concurrent use of hormonal therapy for non cancer related conditions (eg, HRT) is allowed.
20. Received prior radiotherapy to the chest within 4 weeks of the start of study intervention or has ongoing radiation-related toxicities requiring corticosteroids.
21. Received prior radiotherapy to the brain within 2 weeks of start of study intervention or received radiotherapy to the chest within 4 weeks of start of study intervention or has ongoing radiation-related toxicities requiring corticosteroids.
22. Curative radiotherapy; however, palliative radiotherapy for optimal symptom control or pain management is allowed.
23. Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications \> 10 mg/day of prednisone or equivalent, except for managing AEs; inhaled steroids, intra-articular steroid injections, and other topical steroid formulations are permitted in this study.
24. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within ≤ 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
25. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks (unless the safety profile is known prior to the first dose of study intervention), enrolment into a prior Dato-DXd study regardless of treatment assignment, or concurrent enrolment in another clinical study (unless the study is observational \[non-interventional\], or the participant is in the follow-up period of an interventional study).
26. Participants with a known history of severe hypersensitivity reactions to either the drug or inactive excipients (including but not limited to polysorbate 80) of Dato-DXd.
27. Participants with a known history of severe hypersensitivity reactions to other monoclonal antibodies.
28. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
29. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
30. Previous enrolment in the present study.
31. For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding or planning to become pregnant.
32. Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention.
33. Participants for whom the use of steroid-containing mouthwash in contraindicated.
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Inclusion Criteria:
1. Participant must be ≥ 18 years (and above legal age) at the time of screening.
2. Inoperable or metastatic HR-positive, HER2 IHC 0 breast cancer (per ASCO/CAP guidelines, on local laboratory results); ie, is documented as HR-positive (either ER and/or PgR positive \[ER or PgR ≥ 1%\]) and HER2 IHC 0 (defined as including HER2 null with no staining or incomplete and faint/barely perceptible membrane staining in ≤ 10% of tumour cells) based on a fresh, or recent tissue sample. Tumour status must be confirmed using the most recent tumour biopsy (preferably fresh biopsy).
A fresh biopsy may only be omitted if not medically feasible due to documented clinical reasons, such as anatomical inaccessibility, unacceptable procedural risk, or patient refusal after appropriate discussion. In such cases, the most recent available tumour sample may be used. The specific reason for not obtaining a fresh biopsy must be prospectively documented and may be subject to sponsor review.
3. Progressed on and not suitable for further endocrine therapy per investigator assessment.
4. ECOG performance status of 0 or 1, with no deterioration over the previous 2 weeks prior to the first dose of study intervention.
5. Minimum life expectancy of 12 weeks at screening.
6. Provision of acceptable tumour sample (newly acquired tumour biopsy at baseline or the latest archival biopsy available if a fresh biopsy is not feasible) as defined in the Laboratory Manual
7. Participants must have measurable disease as per RECIST 1.1 or evaluable disease. Lesions that will be subject to mandatory biopsy before, during, and after the dosing cannot be considered as TLs as per RECIST requirements.
8. Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention.
1. Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
2. Absolute neutrophil count ≥ 1.5×109/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).
3. Platelet count ≥ 100×109/L (platelet transfusion is not allowed within 1 week prior to screening assessment).
4. Serum albumin ≥ 2.5 g/dL.
5. TBL ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinaemia).
6. Except in the setting of HBV, ALT and AST ≤ 2.5 × ULN; for participants with hepatic metastases, ALT and AST ≤ 5 × ULN. See Exclusion Criterion 8 for requirements in the setting of HBV.
7. Calculated CrCL ≥ 30 mL/min as determined by Cockcroft Gault (using actual body weight).
9. Male and/or female assigned at birth, inclusive of all gender identities.
10. Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies;
(a) Male participants: (i) Use of a condom plus an additional contraceptive method, or avoid intercourse throughout the duration of treatment and for at least 4 months after the last dose of Dato-DXd, in addition to the female partner using a highly effective contraceptive method.
(ii) Starting at the time of first dose of Dato-DXd, male participants must not freeze or donate sperm throughout the duration of treatment and for at least 4 months after the last dose of Dato-DXd. Preservation of sperm should be considered prior to the first dose of study intervention.
(b) Female participants:Female participants not of child-bearing potential (ii) Female participants receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for WOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to study enrolment; (iii) WOCBP must use one highly effective form of contraception or avoid intercourse throughout the duration of treatment and for at least 7 months after the last dose of Dato-DXd. All WOCBP must have a negative serum pregnancy test documented during screening.
(iv) Starting at the time of first dose of Dato-DXd, female participants must not donate, or retrieve for their own use, ova throughout the duration of treatment and for at least 7 months after the last dose of Dato-DXd. Preservation of ova should be considered prior to the first dose of study intervention.
11. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
12. All races, genders, and ethnic groups are eligible for this study.
Exclusion Criteria:
1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases and ongoing or active infection), history of allogenic organ transplant, and/or substance abuse which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
2. History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) and curatively treated in situ disease.
3. Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved to Grade ≤ 1 or baseline. Note: participants may be enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to Grade \> 2 for at least 3 months prior to the first dose of study intervention and managed with SoC treatment) which the investigator deems related to previous anticancer therapy):
1. Chemotherapy-induced neuropathy
2. Fatigue
3. Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies, which may include but are not limited to hypothyroidism/hyperthyroidism, Type I diabetes, hyperglycaemia, adrenal insufficiency, or adrenalitis; and skin hypopigmentation (vitiligo) Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss).
4. Spinal cord compression or brain metastases (unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 2 weeks prior to the first dose of study intervention). Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants must have recovered from the acute toxic effect of radiotherapy (eg, dizziness and signs of increased intracranial pressure). A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and the first dose of study intervention. A minimum of 3 days must have elapsed between the end of corticosteroid therapy for CNS metastatic disease and the first dose of study intervention.
5. Leptomeningeal carcinomatosis or metastasis.
6. Has significant third-space fluid retention (eg, ascites or pleural effusion) and is not amenable for required repeated drainage.
7. Clinically significant corneal disease.
8. Has active or uncontrolled hepatitis B or C virus infection. Participants are eligible if they:
1. Have been curatively treated for HCV infection as demonstrated clinically and by viral serologies
2. Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis
3. Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii of criterion 'd' below:
4. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below:
(i) HBV DNA viral load \< 2000 IU/mL (ii) Have normal transaminase values or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT \< 3 × ULN, which are not attributable to HBV infection (iii) Start or maintain antiviral treatment if clinically indicated as per the investigator
9. Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥ 350, no history of AIDS defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/EC.
10. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible).
11. Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination, and radiographic findings, or tuberculosis testing in line with local practice).
12. Resting ECG with clinically abnormal findings.
13. Uncontrolled or significant cardiac disease including:
1. Myocardial infarction or uncontrolled/unstable angina within 6 months before the first dose of study intervention.
2. Congestive heart failure (New York Heart Association Class II to IV).
3. Uncontrolled hypertension (resting systolic blood pressure \> 180 mmHg or diastolic blood pressure \> 110 mmHg).
4. Cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (NCI CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the investigator judgement with cardiologist consultation recommended.
14. History of non-infectious ILD/pneumonitis, including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
15. Has clinically severe pulmonary function compromise (ie, requiring any supplemental oxygen), resulting from intercurrent pulmonary illnesses including but not limited to the following:
1. Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial enrolment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc)
2. Any autoimmune, connective tissue, or inflammatory disorder with potential pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc)
3. Prior pneumonectomy
16. Prior exposure to the following anticancer therapies:
1. Any TROP2-targeted therapy.
2. Any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I.
3. Any chemotherapy in the metastatic setting.
17. Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period of \> 14 days before the first dose of study intervention.
18. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumour embolisation, or monoclonal antibodies ≤ 3 weeks \[for small molecule targeted agents: ≤ 2 weeks or 5 half-lives, whichever is longer, prior to the first dose of study intervention\]). Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded.
19. Any concurrent anticancer treatment with the exception of bisphosphonates, denosumab for the treatment of bone metastases.
Concurrent use of hormonal therapy for non cancer related conditions (eg, HRT) is allowed.
20. Received prior radiotherapy to the chest within 4 weeks of the start of study intervention or has ongoing radiation-related toxicities requiring corticosteroids.
21. Received prior radiotherapy to the brain within 2 weeks of start of study intervention or received radiotherapy to the chest within 4 weeks of start of study intervention or has ongoing radiation-related toxicities requiring corticosteroids.
22. Curative radiotherapy; however, palliative radiotherapy for optimal symptom control or pain management is allowed.
23. Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications \> 10 mg/day of prednisone or equivalent, except for managing AEs; inhaled steroids, intra-articular steroid injections, and other topical steroid formulations are permitted in this study.
24. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within ≤ 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
25. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks (unless the safety profile is known prior to the first dose of study intervention), enrolment into a prior Dato-DXd study regardless of treatment assignment, or concurrent enrolment in another clinical study (unless the study is observational \[non-interventional\], or the participant is in the follow-up period of an interventional study).
26. Participants with a known history of severe hypersensitivity reactions to either the drug or inactive excipients (including but not limited to polysorbate 80) of Dato-DXd.
27. Participants with a known history of severe hypersensitivity reactions to other monoclonal antibodies.
28. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
29. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
30. Previous enrolment in the present study.
31. For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding or planning to become pregnant.
32. Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention.
33. Participants for whom the use of steroid-containing mouthwash in contraindicated.
Inclusion Criteria:
1. Participant must be ≥ 12 years of age at the time of signing the informed consent/assent
2. Weight ≥ 35 kg
3. Bronchiectasis diagnosed by a physician and confirmed by CT demonstrating abnormal bronchial dilation in ≥ 1 lobe. Note: A historical CT scan within the past 5 years is acceptable. If not available, a CT scan should be conducted at screening to confirm eligibility.
4. Participants who are receiving appropriate standard of care therapy per local guidelines and have a documented history of ≥ 2 moderate exacerbations or ≥ 1 severe exacerbation in the preceding 12 months requiring antibiotics
5. Participants who are clinically stable and free from an exacerbation of bronchiectasis for 4 weeks prior to randomization
6. Participants with pre- or post-bronchodilator FEV1 ≥ 25% predicted value at screening.
7. Presence of positive (PCR or culture) PsA in an airway sample at least once in the last 24 months prior to screening
8. Presence of culture positive PsA in sputum at least within 5 weeks of randomization. Participants who have previously received PsA eradication therapy, as determined appropriate by their treating provider, but remain colonized with PsA are eligible for the study.
9. Capable of giving signed informed consent/assent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
Exclusion Criteria:
1. Primary lung diagnosis other than bronchiectasis
2. Evidence of active tuberculosis or active nontuberculous mycobacteria being treated or requiring treatment. Participants currently receiving treatment for active TB or nontuberculous mycobacteria may be considered after completion of an appropriate course of therapy
3. Evidence of an active allergic bronchopulmonary aspergillosis being treated or requiring treatment
4. Need for long term supplemental oxygen. Oxygen use for ambulation and relief of breathlessness after exercise is allowed
5. Malignancy, current or within the previous 5 years, except for stable prostate cancer, adequately treated non-invasive basal cell and squamous cell carcinoma of the skin and cervical carcinoma in situ treated with apparent success more than one year prior to enrolment
6. AIDS or Advanced human immunodeficiency virus disease (CD4 count of \< 200 cells/mm3)
7. History of severe adverse reaction associated with a mAb, and/or history of severe allergic reaction (eg, anaphylaxis that required the use of epinephrine/adrenaline or hospitalization), and/or history of immune complex disease (Type III hypersensitivity reactions) to monoclonal antibody administration
8. Treatment with long term anti-PsA antibiotics, macrolides, or DPP-1 inhibitors, which are newly initiated within the 3 months prior to screening
9. Chronic immunosuppressive therapy (including prednisolone \> 5 mg or equivalent) newly initiated within the last 3 months
10. Receipt of investigational products indicated for the treatment or prevention of bronchiectasis exacerbations or expected receipt during the study
11. Participants with CF on CFTR modulator therapies which are newly initiated within the previous 3 months prior to screening
12. Female participants who are pregnant, lactating, or WOCBP and not using a highly effective method of contraception or abstinence from at least 4 weeks prior to study intervention administration and until at least 6 months after study intervention administration
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Inclusion Criteria:
1. Participant must be ≥ 12 years of age at the time of signing the informed consent/assent
2. Weight ≥ 35 kg
3. Bronchiectasis diagnosed by a physician and confirmed by CT demonstrating abnormal bronchial dilation in ≥ 1 lobe. Note: A historical CT scan within the past 5 years is acceptable. If not available, a CT scan should be conducted at screening to confirm eligibility.
4. Participants who are receiving appropriate standard of care therapy per local guidelines and have a documented history of ≥ 2 moderate exacerbations or ≥ 1 severe exacerbation in the preceding 12 months requiring antibiotics
5. Participants who are clinically stable and free from an exacerbation of bronchiectasis for 4 weeks prior to randomization
6. Participants with pre- or post-bronchodilator FEV1 ≥ 25% predicted value at screening.
7. Presence of positive (PCR or culture) PsA in an airway sample at least once in the last 24 months prior to screening
8. Presence of culture positive PsA in sputum at least within 5 weeks of randomization. Participants who have previously received PsA eradication therapy, as determined appropriate by their treating provider, but remain colonized with PsA are eligible for the study. Participants who experience an exacerbation during the screening period and receive antibiotic therapy remain eligible for the study if the presence of culture-positive PsA is confirmed prior to randomization.
9. Capable of giving signed informed consent/assent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
Exclusion Criteria:
1. Primary lung diagnosis other than bronchiectasis
2. Evidence of active tuberculosis or active nontuberculous mycobacteria being treated or requiring treatment. Participants currently receiving treatment for active tuberculosis or nontuberculous mycobacteria may be considered after completion of an appropriate course of therapy
3. Evidence of an active allergic bronchopulmonary aspergillosis being treated or requiring treatment
4. Need for long term supplemental oxygen. Oxygen use for ambulation and relief of breathlessness after exercise is allowed
5. Malignancy, current or within the previous 5 years, except for stable prostate cancer, adequately treated non-invasive basal cell and squamous cell carcinoma of the skin and cervical carcinoma in situ treated with apparent success more than one year prior to enrolment
6. AIDS or Advanced human immunodeficiency virus disease (CD4 count of \< 200 cells/mm3)
7. History of severe adverse reaction associated with a mAb, and/or history of severe allergic reaction (eg, anaphylaxis that required the use of epinephrine/adrenaline or hospitalization), and/or history of immune complex disease (Type III hypersensitivity reactions) to monoclonal antibody administration
8. Treatment with long term anti-PsA antibiotics, macrolides, or DPP-1 inhibitors, which are newly initiated within the 3 months prior to screening
9. Chronic immunosuppressive therapy (including prednisolone \> 5 mg or equivalent) newly initiated within the last 3 months
10. Receipt of investigational products indicated for the treatment or prevention of bronchiectasis exacerbations or expected receipt during the study
11. Participants with CF on CFTR modulator therapies which are newly initiated within the previous 3 months prior to screening
12. Female participants who are pregnant, lactating, or WOCBP and not using a highly effective method of contraception or abstinence from at least 4 weeks prior to study intervention administration and until at least 6 months after study intervention administration
Inclusion Criteria:
* Histologically or cytologically documented advanced (metastatic and/or unresectable) solid tumor.
* Participants must have received prior anticancer treatment for the disease under study.
* IO monotherapy deemed appropriate by the investigator.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment with no deterioration.
* Minimum life expectancy of ≥ 12 weeks at enrollment.
* Adequate organ and marrow function.
* Body weight ≥ 30 kg.
Exclusion Criteria:
* Any severe or uncontrolled systemic diseases, which makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
* History of organ transplant.
* History of another primary malignancy that was active within past 2 years.
* Persistent toxicities caused by previous anticancer treatment(s) excluding alopecia, not yet improved to Grade ≤ 1 or baseline.
* Unstable, symptomatic brain metastasis or spinal cord compression.
* History of leptomeningeal carcinomatosis.
* Active primary immunodeficiency/active infectious disease including tuberculosis (TB), human immunodeficiency virus (HIV) infection or hepatitis A, B or C infection.
* History of clinically significant arrhythmia, cardiomyopathy of any etiology; symptomatic congestive heart failure, history of myocardial infarction within the past 6 months.
* Uncontrolled intercurrent illness including but not limited to ongoing or active known infection; interstitial lung disease (ILD), serious chronic gastrointestinal conditions associated with diarrhea; active non-infectious skin disease requiring systemic treatment.
* Active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
* Known allergy or hypersensitivity to rilvegostomig, hyaluronidase, or any excipients of the investigational products.
* Participants experienced a toxicity to prior immunotherapy that led to permanent discontinuation of prior immunotherapy.
* Prior anticancer treatment, including immunotherapy, up to 28 days prior to the first dose of study treatment.
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Inclusion Criteria:
* Histologically or cytologically documented advanced (metastatic and/or unresectable) solid tumor.
* Participants must have received prior anticancer treatment for the disease under study: this may include chemotherapy, immunotherapy, or targeted therapy as considered standard of care, where clinically appropriate.
* IO monotherapy considered clinically appropriate and reasonably likely to permit study participation through at least the PK-evaluable period, in the investigator's judgment.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment with no deterioration.
* Minimum life expectancy of ≥ 12 weeks at enrollment.
* Adequate organ and marrow function.
* Body weight ≥ 30 kg.
Exclusion Criteria:
* Any severe or uncontrolled systemic diseases, which makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
* History of organ transplant or allogeneic stem cell transplant.
* History of another primary malignancy that was active within past 2 years.
* Persistent toxicities caused by previous anticancer treatment(s) excluding alopecia, not yet improved to Grade ≤ 1 or baseline.
* Unstable, symptomatic brain metastasis or spinal cord compression.
* History of leptomeningeal carcinomatosis.
* Active primary immunodeficiency/active infectious disease including tuberculosis (TB), human immunodeficiency virus (HIV) infection or hepatitis B or C infection or any other active or uncontrolled infection requiring systemic treatment.
* Clinically significant or uncontrolled cardiovascular disease, including clinically significant arrhythmias, symptomatic heart failure, cardiomyopathy or myocarditis, recent myocardial infarction or unstable angina, or uncontrolled hypertension.
* Active or ongoing interstitial lung disease (ILD)/ pneumonitis, serious chronic gastrointestinal conditions associated with diarrhea; primary immunodeficiency, or non-infectious skin disease requiring systemic treatment.
* Active or prior documented autoimmune or inflammatory disorders requiring chronic systemic treatment with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs.
* Known allergy or hypersensitivity to rilvegostomig, hyaluronidase, or any excipients of the investigational products.
* Participants experienced a toxicity to prior immunotherapy that led to permanent discontinuation of prior immunotherapy.
* Prior anticancer treatment, including immunotherapy, up to 28 days prior to the first dose of study treatment.
Inclusion Criteria:
1. Age ≥18 years at the time of consent.
2. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Able and willing to provide written informed consent.
3. Eastern Cooperative Oncology Group scores ≤ 1 within 28 days prior to registration.
4. Non-muscle-invasive bladder cancer
* Cohort A: CIS +/- high grade papillary urothelial cancer (Ta or T1) after 3-mo evaluation after induction BCG.
* Cohort B: High grade papillary urothelial cancer (Ta or T1) after 3-mo evaluation after induction BCG.
5. Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but pure variant histology is ineligible. NOTE: Pathology report required for documentation purposes.
6. Patients can have BCG-unresponsive or BCG-exposed NMIBC11. Adequate BCG therapy is defined as completing at least induction BCG (≥ 5 doses) and the first round of maintenance or second induction course BCG (≥ 2 doses). The subsequent round of BCG, either maintenance or repeat induction, must be given within 6 months of initial induction BCG.
* BCG-unresponsive is defined as high grade persistent or recurrent NMIBC that has not achieved a disease-free status after an adequate course of BCG therapy. This includes patients with:
* Persistent or recurrent high-grade tumors (Ta/T1) or carcinoma in situ (CIS) within 6 to 12 months of completing adequate BCG therapy.
* Recurrent high-grade papillary disease within 6 months of BCG therapy.
* High-grade T1 disease found at the first evaluation after BCG induction therapy alone.
* BCG-exposed is defined as high grade NMIBC that has recurred after an initial response or is still present after initial treatment, but recurrence is never too late to be considered "BCG-unresponsive". This includes patients with:
* High-grade recurrence between 12 and 24 months after adequate BCG therapy.
* Recurrence within 24 months of inadequate BCG therapy.
* High-risk recurrence at the 3-month mark after an initial BCG induction.
* High grade recurrence (T1, Ta, CIS) while on maintenance therapy would be eligible. The recurrence must be within 6 months of the last BCG dose.
7. Patients may have received up to 2 lines of prior therapy (including chemotherapy or other approved agents) for NMIBC (NOTE: prior PD-1/PD-L1 blockade is prohibited).
8. Patients must be deemed unfit for radical cystectomy by the treating physician or refuse radical cystectomy. NOTE: Reason for being deemed unfit or refusal should be documented in the medical record.
9. All visible tumor must be completely resected within 60 days prior to registration (residual pure CIS is permitted).
* All patients must have had a cystoscopy (or TURBT with complete resection) without papillary tumor and negative urine cytology within 28 days prior to registration (positive cytology is allowed in patients with CIS).
10. All patients with T1 tumors must undergo restaging TURBT within 60 days prior to registration.
* There must be uninvolved muscularis propria in the restaging TURBT specimen.
* The initial TURBT prior to the restaging TURBT may be \> 60 days prior to registration.
11. Patients must have baseline tumor tissue from either initial or repeat TURBTs for submission of a minimum of 2 and up to 10 unstained slides for translational study objectives. If archival tissue is not available, the subject is not eligible.
12. Adequate organ function as defined by ALL of the following within 28 days prior to registration:
* Absolute neutrophil count ≥ 1500/µL
* Platelets ≥ 100,000/µL
* Hemoglobin ≥ 9 g/dL
* Aspartate aminotransferase/alanine aminotransferase ≤ 1.5× upper limit of normal (ULN)
* Total serum bilirubin ≤ 1.5×ULN\*; \*Patients with Gilbert's disease: ≤ 3×ULN
* International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN unless the patient is on therapeutic anticoagulation.
* Creatinine clearance ≥ 40 mL/min by Cockcroft-Gault estimation. The patient's estimated CrCl will be calculated by the local laboratory (for eligibility purposes) using screening/baseline height (m), actual weight (kg), and serum creatinine:
Males: CrCl = ((140 - age in years) × weight (kg)) / (72× serum creatinine (mg/dL)) Females: CrCl = ((140 - age in years) × weight (kg) ×0.85) / (72× serum creatinine (mg/dL))
13. Females of childbearing potential (FOCBP) must have a negative urine or serum pregnancy test within 7 days of registration. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required. FOCBP must agree to use contraception during the study.
14. Men capable of fathering a child must agree to use contraception during the study.
15. Must have a life expectancy of at least 12 weeks.
Exclusion Criteria:
1. Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
2. Prior CIS of the ureters or prostatic urethra within 24 months prior to registration.
3. Evidence of metastatic disease on imaging (CT or MRI) of the abdomen and pelvis within 90 days of registration.
4. Body weight ≤ 30 kg.
5. History of allogeneic organ transplantation.
6. History of another primary malignancy other than muscle-invasive bladder cancer less than 5 years prior to Day 1 of this trial, with the exception of a malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug and of low potential risk for recurrence. Other exceptions include those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer (non-melanoma skin cancer) or lentigo maligna without evidence of disease, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ without evidence of disease treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score ≤ 6, and prostate specific antigen \[PSA\] ≤ 10 mg/mL, etc.)
7. Currently participating in or has participated in a trial of an investigational agent within 4 weeks prior to the first dose of study treatment or 5 half-lives, whichever is longer without recovery of clinically significant toxicities from that therapy.
8. Active or prior autoimmune or inflammatory disorders requiring systemic treatment within 24 months prior to registration. Autoimmune or inflammatory disorders include, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease(colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis),antiphospholipid syndrome, Sarcoidosis syndrome, or Wegener's syndrome (granulomatosis with polyangiitis, Graves' disease, hypophysitis, uveitis, etc), Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. NOTE: The following are exceptions to this criterion: Patients with vitiligo or alopecia, hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement. Any chronic skin condition that does not require systemic therapy. Patients without active disease in the last 5 years may be included but only after consultation with the study physician. Patients with celiac disease controlled by diet alone.
9. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to registration. NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
10. Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
11. Active known tuberculosis.
12. Symptomatic herpes zoster within the past 30 days.
13. Active infection requiring systemic therapy. NOTE: Prophylactic antibiotics are permitted. Treatment for a UTI is allowed but must be deemed adequately treated by the treating physician prior the start of C1D1.
14. History of idiopathic pulmonary fibrosis or organizing pneumonia.
15. History of (non-infectious) pneumonitis that required steroids or have current pneumonitis.
16. Patients known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) are eligible with the following:
* On effective anti-retroviral therapy with undetectable viral load within 6 months of registration.
* HIV-infected participants must not have a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
17. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. NOTE: No testing for Hepatitis B and Hepatitis C is required unless mandated by a local health authority.
18. Participants with a known co-infection with HBV and HCV, or co-infection with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBV DNA); AND HCV positive (presence of anti-HCV antibodies); OR HDV positive (presence of anti-HDV antibodies).
19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
20. Received live vaccines within 30 days of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. COVID-19 vaccinations are permitted.
21. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study drug. Note: Local surgery of isolated lesions for palliative intent is acceptable.
22. Uncontrolled intercurrent illness, including but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
23. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
24. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control.
25. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
* Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
* Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
26. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
27. History of leptomeningeal carcinomatosis
28. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
29. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
* Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
* Systemic corticosteroids at physiologic doses not to exceed \<\<10 mg/day\>\> of prednisone or its equivalent
* Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication
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Inclusion Criteria:
1. Age ≥18 years at the time of consent.
2. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Able and willing to provide written informed consent.
3. Eastern Cooperative Oncology Group scores ≤ 1 within 28 days prior to registration.
4. Non-muscle-invasive bladder cancer
* Cohort A: CIS +/- high grade papillary urothelial cancer (Ta or T1) after 3-mo evaluation after induction BCG.
* Cohort B: High grade papillary urothelial cancer (Ta or T1) after 3-mo evaluation after induction BCG.
5. Mixed variant histology (adenocarcinoma, squamous cell carcinoma) is eligible, but pure variant histology is ineligible. NOTE: Pathology report required for documentation purposes.
6. Patients can have BCG-unresponsive or BCG-exposed NMIBC11. Adequate BCG therapy is defined as completing at least induction BCG (≥ 5 doses) and the first round of maintenance or second induction course BCG (≥ 2 doses). The subsequent round of BCG, either maintenance or repeat induction, must be given within 6 months of initial induction BCG.
* BCG-unresponsive is defined as high grade persistent or recurrent NMIBC that has not achieved a disease-free status after an adequate course of BCG therapy. This includes patients with:
* Persistent or recurrent high-grade tumors (Ta/T1) or carcinoma in situ (CIS) within 6 to 12 months of completing adequate BCG therapy.
* Recurrent high-grade papillary disease within 6 months of BCG therapy.
* High-grade T1 disease found at the first evaluation after BCG induction therapy alone.
* BCG-exposed is defined as high grade NMIBC that has recurred after an initial response or is still present after initial treatment, but recurrence is never too late to be considered "BCG-unresponsive". This includes patients with:
* High-grade recurrence between 12 and 24 months after adequate BCG therapy.
* Recurrence within 24 months of inadequate BCG therapy.
* High-risk recurrence at the 3-month mark after an initial BCG induction.
* High grade recurrence (T1, Ta, CIS) while on maintenance therapy would be eligible. The recurrence must be within 6 months of the last BCG dose.
7. Patients may have received up to 2 lines of prior therapy (including chemotherapy or other approved agents) for NMIBC (NOTE: prior PD-1/PD-L1 blockade is prohibited).
8. Patients must be deemed unfit for radical cystectomy by the treating physician or refuse radical cystectomy. NOTE: Reason for being deemed unfit or refusal should be documented in the medical record.
9. All visible tumor must be completely resected within 60 days prior to registration (residual pure CIS is permitted).
* All patients must have had a cystoscopy (or TURBT with complete resection) without papillary tumor and negative urine cytology within 28 days prior to registration (positive cytology is allowed in patients with CIS).
10. All patients with T1 tumors must undergo restaging TURBT within 60 days prior to registration.
* There must be uninvolved muscularis propria in the restaging TURBT specimen.
* The initial TURBT prior to the restaging TURBT may be \> 60 days prior to registration.
11. Patients must have baseline tumor tissue from either initial or repeat TURBTs for submission of a minimum of 2 and up to 10 unstained slides for translational study objectives. If archival tissue is not available, the subject is not eligible.
12. Adequate organ function as defined by ALL of the following within 28 days prior to registration:
* Absolute neutrophil count ≥ 1500/µL
* Platelets ≥ 100,000/µL
* Hemoglobin ≥ 9 g/dL
* Aspartate aminotransferase/alanine aminotransferase ≤ 1.5× upper limit of normal (ULN)
* Total serum bilirubin ≤ 1.5×ULN\*; \*Patients with Gilbert's disease: ≤ 3×ULN
* International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN unless the patient is on therapeutic anticoagulation.
* Creatinine clearance ≥ 40 mL/min by Cockcroft-Gault estimation. The patient's estimated CrCl will be calculated by the local laboratory (for eligibility purposes) using screening/baseline age, actual weight (kg), and serum creatinine:
Males: CrCl = ((140 - age in years) × weight (kg)) / (72× serum creatinine (mg/dL)) Females: CrCl = ((140 - age in years) × weight (kg) ×0.85) / (72× serum creatinine (mg/dL))
13. Females of childbearing potential (FOCBP) must have a negative urine or serum pregnancy test within 7 days of registration. If a urine test is done and it is positive or cannot be confirmed as negative, a serum pregnancy test will be required. FOCBP must agree to use contraception during the study.
14. Men capable of fathering a child must agree to use contraception during the study.
15. Must have a life expectancy of at least 12 weeks.
Exclusion Criteria:
1. Prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
2. Prior CIS of the ureters or prostatic urethra within 24 months prior to registration.
3. Evidence of metastatic disease on imaging (CT or MRI) of the abdomen and pelvis within 90 days of registration.
4. Body weight ≤ 30 kg.
5. History of allogeneic organ transplantation.
6. History of another primary malignancy other than muscle-invasive bladder cancer less than 5 years prior to Day 1 of this trial, with the exception of a malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug and of low potential risk for recurrence. Other exceptions include those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer (non-melanoma skin cancer) or lentigo maligna without evidence of disease, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ without evidence of disease treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score ≤ 6, and prostate specific antigen \[PSA\] ≤ 10 mg/mL, etc.)
7. Currently participating in or has participated in a trial of an investigational agent within 4 weeks prior to the first dose of study treatment or 5 half-lives, whichever is longer without recovery of clinically significant toxicities from that therapy.
8. Active or prior autoimmune or inflammatory disorders requiring systemic treatment within 24 months prior to registration. Autoimmune or inflammatory disorders include, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease(colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis),antiphospholipid syndrome, Sarcoidosis syndrome, or Wegener's syndrome (granulomatosis with polyangiitis, Graves' disease, hypophysitis, uveitis, etc), Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. NOTE: The following are exceptions to this criterion: Patients with vitiligo or alopecia, hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement. Any chronic skin condition that does not require systemic therapy. Patients without active disease in the last 5 years may be included but only after consultation with the study physician. Patients with celiac disease controlled by diet alone.
9. A diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to registration. NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
10. Known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
11. Active known tuberculosis.
12. Symptomatic herpes zoster within the past 30 days.
13. Active infection requiring systemic therapy. NOTE: Prophylactic antibiotics are permitted. Treatment for a UTI is allowed but must be deemed adequately treated by the treating physician prior the start of C1D1.
14. History of idiopathic pulmonary fibrosis or organizing pneumonia.
15. History of (non-infectious) pneumonitis that required steroids or have current pneumonitis.
16. Patients known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) are eligible with the following:
* On effective anti-retroviral therapy with undetectable viral load within 6 months of registration.
* HIV-infected participants must not have a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
17. Known active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HBsAg) or HBV core antibody (anti-HBc), at screening. Participants with a past or resolved HBV infection (defined as the presence of anti HBc and absence of HBsAg) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. NOTE: No testing for Hepatitis B and Hepatitis C is required unless mandated by a local health authority.
18. Participants with a known co-infection with HBV and HCV, or co-infection with HBV and HDV, namely: HBV positive (presence of HBsAg and/or anti HBcAb with detectable HBV DNA); AND HCV positive (presence of anti-HCV antibodies); OR HDV positive (presence of anti-HDV antibodies).
19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
20. Received live vaccines within 30 days of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. COVID-19 vaccinations are permitted.
21. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of study drug. Note: Local surgery of isolated lesions for palliative intent is acceptable.
22. Uncontrolled intercurrent illness, including but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
23. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
24. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control.
25. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
* Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
* Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
26. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
27. History of leptomeningeal carcinomatosis
28. Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
29. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
* Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
* Systemic corticosteroids at physiologic doses not to exceed \<\<10 mg/day\>\> of prednisone or its equivalent
* Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication
Inclusion Criteria:
* Sign and date the informed consent form (ICF), prior to the start of any study-specific qualification procedures
* Adults ≥18 years of age at the time the ICF is signed (please follow local regulatory requirements if the legal age of consent for study participation is \>18 years old)
* Pathologically documented HER2-expressing or HER2-mutated (activating mutation) solid tumor that is unresectable or metastatic
* Is willing and able to provide tumor tissue
* Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by investigator assessment
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
* Has a left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment
* Has adequate organ and bone marrow function within 14 days before the start of study treatment. Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to Cycle 1 Day 1.
* A woman of childbearing potential (WOCBP) is eligible to participate if she is not pregnant as confirmed by highly sensitive pregnancy test and agrees to adhere to a contraceptive method that is highly effective during the Treatment Period and for at least the time needed to eliminate each study drug after the last dose.
* A male participant capable of producing sperm is eligible to participate if he agrees to adhere to the contraception methods as specified in the protocol and avoids donating sperm during the Treatment Period and for at least the time needed to eliminate each study drug.
* Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions
Dose-escalation Phase:
* Has progressed or was non-responsive to available therapies and for which no standard or available anticancer therapy exists
* Has a pathologically documented HER2-expressing or HER2-mutated solid tumor
Dose-expansion Phase:
* Has pathologically documented specific HER2 altered advanced solid tumor type
* Has received prior therapy as specified in the protocol
Exclusion Criteria:
* Has had prior treatment with an anti-CD47 or anti-signal regulatory protein α (SIRPα) therapy.
* Has an inadequate treatment washout period prior to start of study treatment as specified in the protocol
* Medical history of myocardial infarction (MI) within 6 months before study enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association \[NYHA\] Class II to IV
* Has a QT interval corrected with Fridericia's formula (QTcF) prolongation to \>470 ms (females) or \>450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG)
* Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening
* Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
* Has multiple primary malignancies within 3 years. Exceptions are specified in the protocol.
* Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug products or other monoclonal antibodies
* Has an uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals
* Is requiring concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications during the study
* Has received a live, attenuated vaccine (messenger ribonucleic acid \[mRNA\] and replication-deficient adenoviral vaccines are not considered live, attenuated vaccines) within 30 days prior to first exposure to study drug(s)
* Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the participant's participation in the clinical study or evaluation of the clinical study results.
* Has active or uncontrolled human immunodeficiency virus (HIV) infection as determined by plasma HIV ribonucleic acid (RNA) viral load and CD4 count.
* Has active or uncontrolled HBV or HCV. Hepatitis B and C screening testing is required. Participants are eligible only if they meet criteria as specified in the protocol.
* Has unresolved toxicities from previous anticancer therapy
* Female who is pregnant, breastfeeding, or planning to become pregnant
* Has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder
* Any autoimmune, connective tissue or inflammatory disorders
* Prior complete pneumonectomy
* Any of the following within 6 months of enrollment: Cerebrovascular accident, transient ischemic attack, or other arterial thromboembolism event
* Psychological, social, familial, or geographical factors that would prevent regular follow-up
* Any active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy, or any clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy
* Uncontrolled hypertension (resting systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg) and/or severe arrhythmia within 28 days before enrollment
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Inclusion Criteria:
* Sign and date the informed consent form (ICF), prior to the start of any study-specific qualification procedures
* Adults ≥18 years of age at the time the ICF is signed (please follow local regulatory requirements if the legal age of consent for study participation is \>18 years old)
* Pathologically documented HER2-expressing or HER2-mutated (activating mutation) solid tumor that is unresectable or metastatic
* Is willing and able to provide tumor tissue
* Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by investigator assessment
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
* Has a left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment
* Has adequate organ and bone marrow function within 14 days before the start of study treatment. Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to Cycle 1 Day 1.
* A woman of childbearing potential (WOCBP) is eligible to participate if she is not pregnant as confirmed by highly sensitive pregnancy test and agrees to adhere to a contraceptive method that is highly effective during the Treatment Period and for at least the time needed to eliminate each study drug after the last dose.
* A male participant capable of producing sperm is eligible to participate if he agrees to adhere to the contraception methods as specified in the protocol and avoids donating sperm during the Treatment Period and for at least the time needed to eliminate each study drug.
* Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions
Dose-escalation Phase:
* Has progressed or was non-responsive to available therapies and for which no standard or available anticancer therapy exists
* Has a pathologically documented HER2-expressing or HER2-mutated solid tumor
Dose-expansion Phase:
* Has pathologically documented specific HER2 altered advanced solid tumor type
* Has received prior therapy as specified in the protocol
Exclusion Criteria:
* Has had prior treatment with an anti-CD47 or anti-signal regulatory protein α (SIRPα) therapy.
* Has an inadequate treatment washout period prior to start of study treatment as specified in the protocol
* Medical history of myocardial infarction (MI) within 6 months before study enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association \[NYHA\] Class II to IV
* Has a QT interval corrected with Fridericia's formula (QTcF) prolongation to \>470 ms (females) or \>450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG)
* Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening
* Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
* Has multiple primary malignancies within 3 years. Exceptions are specified in the protocol.
* Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug products or other monoclonal antibodies
* Has an uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals
* Is requiring concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications during the study
* Has received a live, attenuated vaccine (messenger ribonucleic acid \[mRNA\] and replication-deficient adenoviral vaccines are not considered live, attenuated vaccines) within 30 days prior to first exposure to study drug(s)
* Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the participant's participation in the clinical study or evaluation of the clinical study results.
* Has active or uncontrolled human immunodeficiency virus (HIV) infection. Subjects with a positive/reactive HIV antibody and/or known HIV infection at Screening must be tested for HIV RNA viral load and CD4+ T-cell count during the Screening Period (if acceptable by local regulations or IRBs/IECs) and are eligible if certain criteria are met as specified in the protocol.
* Has active or uncontrolled HBV or HCV. Hepatitis B and C screening testing is required. Participants are eligible only if they meet criteria as specified in the protocol.
* Has unresolved toxicities from previous anticancer therapy
* Female who is pregnant, breastfeeding, or planning to become pregnant
* Has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder
* Any autoimmune, connective tissue or inflammatory disorders
* Prior complete pneumonectomy
* Any of the following within 6 months of enrollment: Cerebrovascular accident, transient ischemic attack, or other arterial thromboembolism event
* Psychological, social, familial, or geographical factors that would prevent regular follow-up
* Any active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy, or any clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy
* Uncontrolled hypertension (resting systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg) and/or severe arrhythmia within 28 days before enrollment
Dose Expansion (Phase 2)
* Has had prior treatment with antibody-drug conjugate that consists of an exatecan derivative that is a topoisomerase I inhibitor including prior participation in a study involving an antibody-drug conjugate produced by Daiichi Sankyo and/or AstraZeneca.
Participants of the four RAINBO trials should be eligible according to the inclusion and exclusion criteria of both the overarching RAINBO trials program and the clinical trial that they are assigned to based on the molecular profile.
Inclusion Criteria of the overarching RAINBO program:
* Histologically confirmed diagnosis of endometrial cancer (EC) of the following histotypes: endometrioid endometrial carcinoma, serous endometrial carcinoma, uterine clear cell carcinoma, dedifferentiated and undifferentiated endometrial carcinoma, uterine carcinosarcoma and mixed endometrial carcinomas of the aforementioned histotypes.
* Full molecular classification performed following the diagnostic algorithm described in WHO 2020 (5th Edition, IARC, Lyon, 2020)
* Hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy or sentinel node biopsy, without macroscopic residual disease after surgery
* No distant metastases as determined by pre-surgical or post-surgical imaging (CT scan of chest, abdomen and pelvis or whole-body PET-CT scan)
* WHO performance status 0, 1 or 2
* Expected start of adjuvant treatment (if applicable) within 10 weeks after surgery
* Patients must be accessible for treatment and follow-up
* Written informed consent for participation in one of the RAINBO trials, permission for the contribution of a tissue block for translation research and permission for the use and sharing of data for the overarching research project according to the local Ethics Committee requirements.
Exclusion Criteria overarching RAINBO program:
* History of another primary malignancy, except for non-melanoma skin cancer, in the past 5 years
* Prior pelvic radiation
The p53abn-RED trial
Inclusion criteria:
* p53 abnormal EC
* Histologically confirmed stage I (with invasion) II or III EC
* WHO Performance score 0-1
* Body weight \> 30 kg
* Adequate systemic organ function:
* Creatinine clearance (\> 40 cc/min): Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
* Adequate bone marrow function : hemoglobin \>9.0 g/dl, Absolute neutrophil count (ANC) ≥1.0 x 109/l, platelet count ≥75 x 109/l.
* Adequate liver function: bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician, AND ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN
Exclusion criteria:
* Pathogenic POLE mutation(s)
* Mismatch repair deficiency
* Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of the IP
* History of allogenic organ transplantation
* Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
* Any previous treatment with a PARP inhibitor, including olaparib
* History of active primary immunodeficiency
* History or evidence of hemorrhagic disorders within 6 months prior to randomization
* Patients with myelodysplastic syndrome/acute myeloid leukemia history or with features suggestive of MDS/AML
* Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
* Active infection, including: tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immuno-deficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
* Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
* Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
* Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.
The MMRd-GREEN trial
Inclusion criteria:
* Mismatch repair deficient EC
* Histologically confirmed (FIGO 2009) stage IB/II EC with myometrial or cervical stroma involvement and lympovascular space invasion (LVSI) OR Stage III EC OR Stage IVA with limited pelvic peritoneal involvement
* WHO Performance score 0-1
* Body weight \> 30 kg
* Adequate systemic organ function:
* Creatinine clearance (\> 40 cc/min): Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
* Adequate bone marrow function : hemoglobin \>9.0 g/dl, Absolute neutrophil count (ANC) ≥1.0 x 109/l, platelet count ≥75 x 109/l.
* Adequate liver function: bilirubin ≤1.5 x institutional upper limit of normal (ULN). \<\<This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.\>\> AND ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN
Exclusion criteria:
* Pathogenic POLE mutation(s)
* Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational medicinal product (IMP)
* History of allogenic organ transplantation
* Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
* Any previous treatment with a PD(L)1 inhibitor, including durvalumab.
* Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IMP.
* Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab with the exceptions of:
* Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
* Systemic corticosteroids at physiologic doses not to exceed \<\<10 mg/day\>\> of prednisone or its equivalent.
* Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
* History of active primary immunodeficiency
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome. The following are exceptions to this criterion:
* Patients with vitiligo or alopecia
* Patients with hypothyroidism (e.g., following Hashimoto syndrome)stable on hormone replacement
* Any chronic skin condition that does not require systemic therapy
* Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
* Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immuno-deficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.
The NSMP-ORANGE trial
Inclusion criteria:
* NSMP EC
* Histologically confirmed stage II EC with substantial LVSI or stage III EC
* ER positive EC
* WHO performance status 0-1
Exclusion criteria:
* Pathogenic POLE mutation(s)
* Mismatch repair deficiency
* p53 abnormality
The POLEmut-BLUE trial
Inclusion criteria:
* Pathogenic POLE mutation(s)
* For the main cohort, patients must have one of the following combinations of FIGO stage, grade, and LVSI:
* stage IA (not confined to polyp), grade 3, pN0, with or without LVSI
* stage IB, grade 1 or 2, pNx/N0, with or without LVSI
* stage IB, grade 3, pN0, without substantial LVSI
* stage II (microscopic), grade 1 or 2, pN0, without substantial LVSI
* For the exploratory cohort, patients must have one of the following combinations of FIGO stage, grade, and LVSI:
* stage IA (not confined to polyp), grade 3 - Stage III not included in main cohort
* Multiple molecular classifiers stage IA (not confined to polyp), grade 3 - Stage III
* Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrolment in the trial to document their willingness to participate. A similar process must be followed for sites outside of Canada as per their respective cooperative group's procedures.
* Patient is able (i.e., sufficiently fluent) and willing to complete the QOL and/or health utility questionnaires in either English, French or a validated language. The baseline assessment must be completed within the required timelines, prior to enrolment. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.
* Patients must be accessible for treatment and follow up. Patients enrolled on this trial must be treated and followed at the participating center. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
* Patients must agree to return to their primary care facility for any adverse events which may occur through the course of the trial.
* In accordance with CCTG policy, protocol treatment is to begin within 10 weeks of hysterectomy/bilateral salpingo-oophorectomy.
Exclusion criteria:
* Prior chemotherapy for EC
* Isolated tumor cells identified in lymph node(s) for main study cohort (patient can be included in exploratory cohort)
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Participants of the four RAINBO trials should be eligible according to the inclusion and exclusion criteria of both the overarching RAINBO trials program and the clinical trial that they are assigned to based on the molecular profile.
Inclusion Criteria of the overarching RAINBO program:
* Histologically confirmed diagnosis of endometrial cancer (EC) of the following histotypes: endometrioid endometrial carcinoma, serous endometrial carcinoma, uterine clear cell carcinoma, dedifferentiated and undifferentiated endometrial carcinoma, uterine carcinosarcoma and mixed endometrial carcinomas of the aforementioned histotypes.
* Full molecular classification performed following the diagnostic algorithm described in WHO 2020 (5th Edition, IARC, Lyon, 2020)
* TLH-BSO or TAH-BSO with or without lymphadenectomy or sentinel node biopsy, without macroscopic residual disease after surgery
* No distant metastases as determined by pre-surgical or post-surgical imaging (CT/MRI scan of chest, abdomen and pelvis or PET-CT scan)
* Age ≥ 18 years
* Expected start of adjuvant treatment (if applicable) within 10 weeks after surgery
* Patients must be accessible for treatment and follow-up
* Written informed consent for participation in one of the RAINBO trials, permission for the contribution of a tissue block for translation research and permission for the use and sharing of data for the overarching research project according to the local Ethics Committee requirements.
Exclusion Criteria overarching RAINBO program:
* History of another primary malignancy, except for non-melanoma skin cancer, in the past 5 years
* Prior pelvic radiation
The MMRd-GREEN trial
Inclusion criteria:
* Written informed consent
* WHO Performance score 0-1
* Histologically confirmed FIGO 2009 stage IB/II with LVSI, stage III, or stage IV with limited pelvic peritoneal involvement (FIGO 2023 stage IB with LVSI, stage II with myometrial or cervical stroma involvement and LVSI, or stage III disease)
* Molecular classification: MMRd EC\*
* No prior pelvic radiotherapy
* Body weight \> 30 kg
* Adequate systemic organ function:
* Creatinine clearance (\> 40 cc/min): Measured creatinine clearance (CL) \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
* Adequate bone marrow function : hemoglobin \>9.0 g/dl, Absolute neutrophil count (ANC) ≥1.0 x 109/l, platelet count ≥75 x 109/l.
* Adequate liver function: Bilirubin ≤1.5 x institutional upper limit of normal (ULN). \<\<This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.\>\>
* ALT (SGPT) and/or AST (SGOT) ≤2.5 x ULN
Exclusion criteria:
* Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of Investigational medicinal product (IMP).
* History of allogenic organ transplantation.
* Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
* Any previous treatment with a PD(L)1 inhibitor, including durvalumab.
* Receipt of live attenuated vaccine within 30 days prior to the first dose of durvalumab. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IMP.
* Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab with the exceptions of :
* Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
* Systemic corticosteroids at physiologic doses not to exceed \<\<10 mg/day\>\> of prednisone or its equivalent.
* Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
* History of active primary immunodeficiency
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome. The following are exceptions to this criterion:
* Patients with vitiligo or alopecia
* Patients with hypothyroidism (e.g., following Hashimoto syndrome)stable on hormone replacement
* Any chronic skin condition that does not require systemic therapy
* Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
* Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immuno-deficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
* Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.
Institute Gustave Roussy (sponsor p53abn-RED trial),Leiden University Medical center (sponsor MMRd-GREEN trial),University College London (sponsor NSMP-ORANGE trial),Canadian Clinical Trials Group (sponsor POLEmut-BLUE trial),Dutch Gynaecological Oncology Group,Comprehensive Cancer Centre The Netherlands,Cancer Research UK & UCL Cancer Trials Centre,Dutch Cancer Society,AstraZeneca,National Cancer Institute, France,Canadian Institutes of Health Research (CIHR)
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Dutch Gynaecological Oncology Group,Cancer Research UK & UCL Cancer Trials Centre,Dutch Cancer Society,AstraZeneca,National Cancer Institute, France,Canadian Institutes of Health Research (CIHR),BGOG: Belgian Gynaelogical Onology Group, Belgium,Fondazione Policlinico Universitario Agostino Gemelli IRCCS,Institute Gustave Roussy Paris,Central & Eastern European Gynecologic Oncology Group (CEEGOG),Canadian Cancer Trials Group (CCTG)
Inclusion Criteria:
* Participants with clinical tumour stage T2-T4aN0/1M0 or T1N1M0 with transitional or mixed transitional cell histology
* Patients must be planning to undergo radical cystectomy
* Patients who have not received prior systemic chemotherapy or immunotherapy for treatment of muscle-invasive bladder cancer
* ECOG performance status of 0 or 1
* Minimum life expectancy of 12 weeks at first dose of study medication
Exclusion criteria:
* Evidence of lymph node (N2-N3) or metastatic (M1) disease
* Inoperable tumour(s) with fixation to the pelvic wall on clinical examination
* Prior exposure to immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD 1, anti-PD L1 and anti-PD-L2 antibodies, excluding Bacillus Calmette-Guérin
* Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab
* Any concomitant medication known to be contraindicated to the chemotherapy (ddMVAC or gem/cis).
* Uncontrolled intercurrent illness.
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Inclusion Criteria:
* Participants with clinical tumour stage T2-T4aN0/1M0 or T1N1M0 with transitional or mixed transitional cell histology
* Participants must be planning to undergo radical cystectomy
* Participants who have not received prior systemic chemotherapy or immunotherapy for treatment of muscle-invasive bladder cancer
* ECOG performance status of 0 or 1
* Minimum life expectancy of 12 weeks at first dose of study medication
Exclusion criteria:
* Evidence of lymph node (N2-N3) or metastatic (M1) disease
* Inoperable tumour(s) with fixation to the pelvic wall on clinical examination
* Prior exposure to immune-mediated therapy including, but not limited to, other anti CTLA-4, anti-PD 1, anti-PD L1 and anti-PD-L2 antibodies, excluding Bacillus Calmette-Guérin
* Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab
* Any concomitant medication known to be contraindicated with ddMVAC.
* Uncontrolled intercurrent illness.
Key Inclusion Criteria:
* Male and female patients must be at least 18 years of age at the time of signing the informed consent. Other age restrictions may apply as per local regulations.
* Unresectable, previously untreated, locally advanced or metastatic biliary tract adenocarcinoma. Prior treatment in the perioperative and/or adjuvant setting is permissible provided there is \> 3 months (90 days) between the end of adjuvant treatment and the diagnosis of locally advanced or metastatic disease.
* Histologically confirmed HER2-expressing (IHC 3+ or IHC 2+) BTC.
* Patients must provide an FFPE tumor sample that is no older than 3 years for tissue-based IHC staining to centrally determine HER2 expression, PD-L1 status, and other correlatives.
* Has at least one target lesion assessed by the Investigator based on RECIST v1.1. (Randomized portion only)
* WHO/ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
* Adequate organ and bone marrow function within 14 days before randomization.
* Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential.
* Minimum life expectancy of 12 weeks.
Key Exclusion Criteria:
* Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitors and therapeutic anticancer vaccines.
* Histologically confirmed ampullary carcinoma.
* Any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the Investigator, interfere with the patient's participation in the clinical study or evaluation of the clinical study results.
* Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
* Medical history of myocardial infarction within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (\< 6 months) cardiovascular event including stroke.
* Serious chronic gastrointestinal conditions associated with diarrhea (eg, active inflammatory bowel disease); active non-infectious skin disease (including any grade rash, urticaria, dermatitis, ulceration, or psoriasis) requiring systemic treatment.
* Active autoimmune, connective tissue or inflammatory disorders that has required systemic treatment in the past 2 years, or where there is documented, or a suspicion of pulmonary involvement at the time of screening.
* Corrected QT interval (QTcF) prolongation to \> 470 msec (females) or \> 450 msec (males) based on average of the screening triplicate 12-lead ECG.
* History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
* Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion etc).
* Prior pneumonectomy (complete).
* Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals. Patients with prior cholangitis/biliary tract infections/biliary intervention (eg, stent, external drain) should have completed a full course of antibiotics prior to randomization.
* Active primary immunodeficiency, known uncontrolled active HIV infection or HCV.
* History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected nonmelanoma skin cancer and curatively treated in situ disease. For certain participant populations, exceptions could also include carcinomas in-situ or Ta tumors treated with curative intent.
* Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (Drainage and Cell free and Concentrated Ascites Reinfusion Therapy are not allowed within 2 weeks prior to screening assessment).
* Any concurrent anticancer treatment without an adequate washout period prior to randomization. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is allowed.
* History of organ transplants or allogenic stem cell transplant.
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Key Inclusion Criteria:
* Male and female patients must be at least 18 years of age at the time of signing the informed consent. Other age restrictions may apply as per local regulations.
* Unresectable, previously untreated, locally advanced or metastatic biliary tract adenocarcinoma. Prior treatment in the perioperative and/or adjuvant setting is permissible provided there is \> 3 months (90 days) between the end of adjuvant treatment (or surgery or radiation with curative intent) and the diagnosis of locally advanced or metastatic disease.
* Histologically confirmed HER2-expressing (IHC 3+ or IHC 2+) BTC.
* Patients must provide an FFPE tumor sample that is no older than 3 years.
* Has at least one target lesion assessed by the Investigator based on RECIST v1.1. (Randomized portion only)
* WHO/ECOG performance status of 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
* Adequate organ and bone marrow function within 14 days before randomization.
* Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential.
* Minimum life expectancy of 12 weeks.
Key Exclusion Criteria:
* Prior exposure to other HER2 targeting therapies, ADCs, immune checkpoint inhibitors and therapeutic anticancer vaccines.
* Histologically confirmed ampullary carcinoma.
* Any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the Investigator, interfere with the patient's participation in the clinical study or evaluation of the clinical study results.
* Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
* Medical history of myocardial infarction within 6 months before randomization/enrollment, symptomatic congestive heart failure (New York Heart Association Class II to IV), unstable angina pectoris, cardiomyopathy of any etiology, history of myocarditis, clinically important cardiac arrhythmias, or a recent (\< 6 months) cardiovascular event including stroke.
* Active autoimmune, connective tissue or inflammatory disorders that has required systemic treatment in the past 2 years, or where there is documented, or a suspicion of pulmonary involvement at the time of screening.
* Corrected QT interval (QTcF) prolongation to \> 470 msec (females) or \> 450 msec (males) based on average of the screening triplicate 12-lead ECG.
* History of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
* Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion etc).
* Prior pneumonectomy (complete).
* Active primary immunodeficiency and/or active uncontrolled infectious disease(s).
* History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected nonmelanoma skin cancer and curatively treated in situ disease. For certain participant populations, exceptions could also include carcinomas in-situ or Ta tumors treated with curative intent.
* Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (Drainage and Cell free and Concentrated Ascites Reinfusion Therapy are not allowed within 2 weeks prior to screening assessment).
* Any concurrent anticancer treatment without an adequate washout period prior to randomization. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is allowed.
* History of organ transplants or allogenic stem cell transplant.
Inclusion Criteria:
* 1\. Age:
* 16 years old in Module 1 (US only: ≥18year)
* 12 years old in Module 2
2\. Diagnosis: Known Diagnosis of CD22-positive B-ALL based on criteria established by WHO (Alaggio et al. 2022).
* Participants must have relapsed or refractory B-ALL ('relapsed' defined as bone marrow blasts \> 5% or reappearance of blasts in PB)
* Module 1 (DE): Ph(-) B-ALL and Ph(+) B-ALL - R/R
* Backfill of Module 1 and Module 2 (DO): R/R Ph(-) B-ALL
3\. Performance status (ECOG ≤ 2; KPS ≥ 50; LPS ≥ 50)
4\. Peripheral lymphoblast count \< 10,000/µL (may receive cytoreduction prior to C1D1 per protocol-specified criteria)
5\. At least 2 prior therapies with refractoriness or relapse, or 1 prior therapy with refractoriness or relapse and no standard options available. Participants who have received prior CD22 targeted therapies are eligible.
* Ph+ B-ALL (Module 1 DE only): intolerant to or have contraindications to TKI therapy or R/R disease despite treatment with at least 2 prior TKIs or at least one 3rd generation TKI
6\. Prior DLI \>4 weeks, prior cell therapy or autoHSCT \>8 weeks, alloHSCT \>12 weeks
Exclusion Criteria:
1. Burkitt lymphoma and leukemia
2. Isolated extramedullary disease; Active testicular or CNS (\> CNS1) involvement
3. Unresolved non-heme toxicities Grade ≥ 2 (except alopecia, stable Grade ≤ 2 neuropathy, vitiligo, endocrine disorders controlled with therapy)
4. History of drug-induced non-infectious ILD/pneumonitis requiring oral or IV steroids or supplemental oxygen or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
5. Prior/concomitant therapy
* Cytotoxic treatment within 14 days (except ALL maintenance medications or cytoreduction)
* Biologic (immuno-oncology) treatment within 28 days or 5 half-lives (whichever is shorter)
* Non-CNS radiation within 2 weeks \& CNS radiation within 4 weeks
* Medications known to prolong QTc and/or associated with Torsades de Pointes within 5 half-lives
* Strong inhibitors of CYP 3A4 within 14 days or 5 half-lives (whichever is longer)
* Investigational agents or study interventions in the last 30 days or 5 half-lives prior to the first dose of AZD4512 whichever is longer. If the investigational product is an agent to treat B-ALL and meets the modality criteria, then a specific washout period must be adhered to instead.
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Inclusion Criteria:
* 1\. Age:
* 16 years old in Module 1 (US only: ≥18year)
* 12 years old in Module 2
2\. Diagnosis: Known Diagnosis of CD22-positive B-ALL based on criteria established by WHO (Alaggio et al. 2022).
* All Participants must have relapsed or refractory B-ALL ('relapsed' defined as bone marrow blasts \> 5% or reappearance of blasts in PB)
* Module 1 (DE): R/R B-ALL \[Ph(-) and Ph(+)\]
* Backfill of Module 1 and Module 2 (DO): R/R B-ALL \[Ph(-)\] with demonstration of CD22 expression by local assessment in screening.
3\. Performance status (ECOG ≤ 2; KPS ≥ 50; LPS ≥ 50)
4\. Peripheral lymphoblast count \< 10,000/µL (may receive cytoreduction prior to C1D1 per protocol-specified criteria)
5\. Prior therapies:
* Module 1 (DE): At least 2 prior therapies with refractoriness or relapse, or 1 prior therapy with refractoriness or relapse and no standard options available. For Ph+ B-ALL: intolerant to or have contraindications to TKI therapy or R/R disease despite treatment with at least 2 prior TKIs or at least one 3rd generation TKI
* Backfill of Module 1 (backfills) and Module 2 (DO): at least one prior line of therapy (SOC or clinical trial) to which the participant has been either refractory or has subsequently relapsed.
* Participants who have received prior CD22 targeted therapies and were not refractory to these therapies are eligible
6\. Prior DLI \>4 weeks, prior cell therapy or autoHSCT \>8 weeks, alloHSCT \>12 weeks
Exclusion Criteria:
1. Burkitt lymphoma and leukemia
2. Isolated extramedullary disease; Active testicular or CNS (\> CNS1) involvement
3. Unresolved non-heme toxicities Grade ≥ 2 (except alopecia, stable Grade ≤ 2 neuropathy, vitiligo, endocrine disorders controlled with therapy)
4. History of drug-induced non-infectious ILD/pneumonitis requiring oral or IV steroids or supplemental oxygen or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
5. Prior/concomitant therapy
* Cytotoxic treatment within 14 days (except ALL maintenance medications or cytoreduction)
* Biologic (immuno-oncology) treatment within 28 days or 5 half-lives (whichever is shorter)
* Non-CNS radiation within 2 weeks \& CNS radiation within 4 weeks
* Medications known to prolong QTc and/or associated with Torsades de Pointes within 5 half-lives
* Strong inhibitors of CYP 3A4 within 14 days or 5 half-lives (whichever is longer)
* Investigational agents or study interventions in the last 30 days or 5 half-lives prior to the first dose of AZD4512 whichever is longer.
If the investigational product is an agent to treat B-ALL and meets the modality criteria, then a specific washout period must be adhered to instead.
Inclusion Criteria:
* Histologically or cytologically confirmed non-squamous NSCLC.
* Must have evidence of documented pre-existing EGFRm information (EGFRm known to be associated with (epidermal growth factor receptor \[EGFR\] tyrosine kinase inhibitor \[TKis\] sensitivity \[Ex19del, L858R, G719X, S768I, or L861Q\], either alone or in combination with other EGFR mutations, which may include T790M).
* Documented extra-cranial radiologic progression on prior osimertinib monotherapy (as most recent line of treatment) in the adjuvant, locally advanced, or metastatic setting.
* Less than or equal to (\<=2) prior lines of EGFR TKIs (osimertinib is the only permitted prior third generation EGFR TKI).
* At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 TL at baseline and can be accurately measured at baseline.
* World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate bone marrow reserve and organ function within 7 days before randomization.
Exclusion Criteria:
* Use of chemotherapy, vascular endothelial growth factor inhibitor, immunotherapy or any anti-cancer therapy in the metastatic setting. Platinum-based chemotherapy in non-metastatic setting within 12 months prior to randomization.
* History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention.
* Any evidence of severe or uncontrolled systemic diseases, including, but not limited to active bleeding diseases, active infection, active ILD/pneumonitis, cardiac disease.
* Has significant third-space fluid retention (example \[eg.\], ascites or pleural effusion) as judged by the investigator and is not amenable for required repeated drainage.
* History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids or drug-induced ILD, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
* Has severe pulmonary function compromise resulting from intercurrent pulmonary illnesses.
* Unstable spinal cord compression and/or unstable brain metastases.
* Participants with symptomatic brain metastases (including leptomeningeal involvement).
* Clinically significant corneal disease.
* Uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals, suspected infections or inability to rule out infections. Use of systemic antibiotics within 14 days of randomization.
* Has known human immunodeficiency virus (HIV) infection that is not well controlled.
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Inclusion Criteria:
* \- Histologically or cytologically confirmed non-squamous NSCLC.
* \- Must have evidence of documented pre-existing EGFRm information (EGFRm known to be associated with (epidermal growth factor receptor \[EGFR\] tyrosine kinase inhibitor \[TKis\] sensitivity \[Ex19del, L858R, G719X, S768I, or L861Q\], either alone or in combination with other EGFR mutations, which may include T790M).
* \- Documented extra-cranial radiologic progression on prior osimertinib monotherapy (as most recent line of treatment) in the adjuvant, locally advanced, or metastatic setting.
* \- Less than or equal to (\<=2) prior lines of EGFR TKIs (osimertinib is the only permitted prior third generation EGFR TKI).
* \- At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 TL at baseline and can be accurately measured at baseline.
* \- World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* \- Adequate bone marrow reserve and organ function within 7 days before randomization.
Exclusion Criteria:
* \- Use of chemotherapy, vascular endothelial growth factor inhibitor, immunotherapy or any anti-cancer therapy in the metastatic setting. Platinum-based chemotherapy in non-metastatic setting within 12 months prior to randomization.
* \- History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention.
* \- Any evidence of severe or uncontrolled systemic diseases, including, but not limited to active bleeding diseases, active infection, active ILD/pneumonitis, cardiac disease.
* \- Has significant third-space fluid retention (example \[eg.\], ascites or pleural effusion) as judged by the investigator and is not amenable for required repeated drainage.
* \- History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids or drug-induced ILD, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
* \- Has severe pulmonary function compromise resulting from intercurrent pulmonary illnesses.
* -Unstable spinal cord compression and/or unstable brain metastases.
* \- Participants with symptomatic brain metastases (including leptomeningeal involvement).
* \- Clinically significant corneal disease.
* \- Uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals, suspected infections or inability to rule out infections. Use of systemic antibiotics within 14 days of randomization.
* \- Has known human immunodeficiency virus (HIV) infection that is not well controlled.
Inclusion Criteria:
* Male or female participants must be ≥ 18 years of age
* Participants with a documented diagnosis of PA that fulfils the criteria defined in the 2016 or 2025 Endocrine Society Guidelines.
* Participants willing and able to cease dosing of MRA or potassium sparing diuretics per study requirement for participants taking an MRA or potassium sparing diuretic at Screening.
* eGFR ≥ 45 mL/min/1.73m2 at Screening
* Serum potassium level ≥ 3.0 and \< 5.0 mmol/L at Screening determined as per the central laboratory.
* Have a stable regimen of antihypertensive medications for at least 4 weeks prior to randomisation
* Mean seated SBP on AOBPM of ≥ 135 mmHg and ≤ 170 mmHg and mean DBP of
≤ 105 mmHg.
* Serum potassium (local lab) \> 3.0 mmol/L at randomization.
Exclusion Criteria:
\- If not taking an MRA or potassium sparing diuretic at Screening: Mean seated SBP \> 170 mmHg or mean seated DBP \>105 mmHg (on AOBPM).
If taking an MRA or potassium sparing diuretic at Screening: Mean seated SBP \> 160 mmHg or mean seated DBP ≥ 100 mmHg.
* Previous surgical intervention for an adrenal adenoma or have a planned adrenalectomy, renal nerve denervation, or adrenal ablative procedure during the course of the study.
* Has the following known secondary causes of HTN: renal artery stenosis, uncontrolled or untreated hyperthyroidism, uncontrolled or untreated hypothyroidism, pheochromocytoma, Cushing's syndrome, aortic coarctation.
* Serum sodium level \< 135 mmol/L at Screening, determined as per central laboratory.
* New York Heart Association functional HF class IV at Screening.
* Persistent atrial fibrillation.
* Treatment with any MRA or potassium-sparing diuretic within 2 weeks prior to Randomisation.
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Parent study
Inclusion Criteria:
* Male or female participants must be ≥ 18 years of age
* Participants with a documented diagnosis of PA that fulfils the criteria defined in the 2016 or 2025 Endocrine Society Guidelines.
* Participants willing and able to cease dosing of MRA or potassium sparing diuretics per study requirement for participants taking an MRA or potassium sparing diuretic at Screening.
* eGFR ≥ 45 mL/min/1.73m2 at Screening
* Serum potassium level ≥ 3.0 and \< 5.0 mmol/L at Screening determined as per the central laboratory.
* Have a stable regimen of antihypertensive medications for at least 4 weeks prior to randomisation
* Mean seated SBP on AOBPM of ≥ 135 mmHg and ≤ 170 mmHg and mean DBP of
≤ 105 mmHg.
* Serum potassium (local lab) \> 3.0 mmol/L at randomization.
Exclusion Criteria:
\- If not taking an MRA or potassium sparing diuretic at Screening: Mean seated SBP \> 170 mmHg or mean seated DBP \>105 mmHg (on AOBPM).
If taking an MRA or potassium sparing diuretic at Screening: Mean seated SBP \> 160 mmHg or mean seated DBP ≥ 100 mmHg.
* Previous surgical intervention for an adrenal adenoma or have a planned adrenalectomy, renal nerve denervation, or adrenal ablative procedure during the course of the study.
* Has the following known secondary causes of HTN: renal artery stenosis, uncontrolled or untreated hyperthyroidism, uncontrolled or untreated hypothyroidism, pheochromocytoma, Cushing's syndrome, aortic coarctation.
* Serum sodium level \< 135 mmol/L at Screening, determined as per central laboratory.
* New York Heart Association functional HF class IV at Screening.
* Persistent atrial fibrillation.
* Treatment with any MRA or potassium-sparing diuretic within 2 weeks prior to Randomisation.
Substudy
Inclusion Criteria:
Completed the BaxPA main study through the End of Study visit and was randomised and treated during the Randomised Withdrawal period.
Exclusion Criteria:
Not applicable
Main Inclusion Criteria:
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
* Histologically confirmed diagnosis of adenocarcinoma of the prostate without strong clinical suspicion of majority neuroendocrine differentiation.
* Must have had prior bilateral orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L).
* At least one metastatic lesion present on baseline Computed Tomography (CT), Magnetic Resonance Imaging (MRI), or bone scan obtained ≤ 28 days prior to the first dose of Investigational Medicinal Product (IMP). Participants may have non-measurable lesions including bone only metastases.
* Adequate organ function
* Part A only: Metastatic prostate cancer considered to be stable or progressing metastatic castration resistant prostate cancer (mCRPC).
* Part B only: Progressing mCRPC defined as meeting at least one of following documented criteria -
1. Serum/plasma PSA progression
2. Soft-tissue progression
3. Progression of bone disease
* Part B Dose Escalation: Previously treated with at least 2 prior lines of systemic anti-cancer therapy for mCRPC. Prior lines must include:
1. At least 1 androgen receptor pathway inhibitor (ARPI)
2. A poly (adp-ribose) polymerase (PARP) inhibitor for participants with known BRCA mutation
3. A checkpoint inhibitor for participants with known microsatellite instability-high (MSI-H), deficient mismatch pair (dMMR), or tumor mutational burden (TMB) ≥ 10 mut/Mb
* Part B Dose Expansion: Previously treated with at least 1 prior line of systemic anti-cancer therapy for mCRPC. Prior lines must include:
1. At least 1 ARPI
2. A PARP inhibitor for participants with known BRCA mutation per local practice, unless ineligible per Investigator decision.
3. A checkpoint inhibitor for participants with known MSI-H, dMMR, or TMB ≥ 10 mut/Mb.
4. No previous cytotoxic chemotherapy for CRPC. Taxanes for metastatic hormone sensitive prostate cancer (mHSPC) is acceptable if the last cycle Day 1 was \> 12 months before first study treatment.
5. Previous treatment with prostate specific membrane antigen radioligand therapy (PSMA-RLT) or Radium-223 is allowed but not required. Participants who have had prior radiation therapy, including therapeutic radiopharmaceuticals, external bean radiation therapy (EBRT), and/or brachytherapy are eligible, subject to satisfying all other inclusion/exclusion criteria. Therapeutic radiopharmaceuticals will be considered a prior line of systemic therapy.
Main Exclusion Criteria:
* Treatment with any radiopharmaceutical within 6 weeks of the first dose of Investigational Medicinal Product (IMP).
* Radiation therapy (RT) or external beam radiation therapy (EBRT) within 28 days prior to the first dose and all RT-related events have not recovered to Grade ≤ 1.
* Administration of any systemic cytotoxic or investigational therapy ≤ 28 days of the first dose of IMP or 5 half-lives, whichever is shorter.
* All prior treatment-related adverse events must have resolved to Grade ≤ 1.
* Concurrent severe and/or uncontrolled illness not related to cancer and/or social situation that would limit compliance with study requirements.
* Known or suspected allergies or contraindications to any of the investigational drugs or any component of the investigational drug formulation.
* Clinically relevant proteinuria
* Diffuse and intense osseous radiotracer uptake on bone scintigraphy or PSMA imaging characteristic of a superscan.
* Chronic corticosteroid use greater than 10 mg prednisone equivalent daily.
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Inclusion Criteria:
* eria:
* • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
* • Histologically confirmed diagnosis of adenocarcinoma of the prostate without strong clinical suspicion of majority neuroendocrine differentiation.
* • Must have had prior bilateral orchiectomy and/or ongoing androgen-deprivation therapy and a castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L).
* • At least one metastatic lesion present on baseline Computed Tomography (CT), Magnetic Resonance Imaging (MRI), or bone scan obtained ≤ 28 days prior to the first dose of Investigational Medicinal Product (IMP). Participants may have non-measurable lesions including bone only metastases.
* • Adequate organ function
* • Part A only: Metastatic prostate cancer considered to be stable or progressing metastatic castration resistant prostate cancer (mCRPC).
* • Part B only: Progressing mCRPC defined as meeting at least one of following documented criteria -
* a)Serum/plasma PSA progression
* b)Soft-tissue progression
* c)Progression of bone disease
* • Part B Dose Escalation: Previously treated with at least 2 prior lines of systemic anti-cancer therapy for mCRPC. Prior lines must include:
* a)At least 1 androgen receptor pathway inhibitor (ARPI)
* b)A poly (adp-ribose) polymerase (PARP) inhibitor for participants with known BRCA mutation
* c)A checkpoint inhibitor for participants with known microsatellite instability-high (MSI-H), deficient mismatch pair (dMMR), or tumor mutational burden (TMB) ≥ 10 mut/Mb
* • Part B Dose Expansion: Previously treated with at least 1 prior line of systemic anti-cancer therapy for mCRPC. Prior lines must include:
* (a)At least 1 ARPI
* (b)A PARP inhibitor for participants with known BRCA mutation per local practice, unless ineligible per Investigator decision.
* (c)A checkpoint inhibitor for participants with known MSI-H, dMMR, or TMB ≥ 10 mut/Mb.
* (d)No previous cytotoxic chemotherapy for CRPC. Taxanes for metastatic hormone sensitive prostate cancer (mHSPC) is acceptable if the last cycle Day 1 was \> 12 months before first study treatment.
* (e)Previous treatment with prostate specific membrane antigen radioligand therapy (PSMA-RLT) or Radium-223 is allowed but not required. Participants who have had prior radiation therapy, including therapeutic radiopharmaceuticals, external bean radiation therapy (EBRT), and/or brachytherapy are eligible, subject to satisfying all other inclusion/exclusion criteria. Therapeutic radiopharmaceuticals will be considered a prior line of systemic therapy.
* Main
Exclusion Criteria:
* • Treatment with any radiopharmaceutical within 6 weeks of the first dose of Investigational Medicinal Product (IMP).
* • Radiation therapy (RT) or external beam radiation therapy (EBRT) within 28 days prior to the first dose and all RT-related events have not recovered to Grade ≤ 1.
* • Administration of any systemic cytotoxic or investigational therapy ≤ 28 days of the first dose of IMP or 5 half-lives, whichever is shorter.
* • All prior treatment-related adverse events must have resolved to Grade ≤ 1.
* • Concurrent severe and/or uncontrolled illness not related to cancer and/or social situation that would limit compliance with study requirements.
* • Known or suspected allergies or contraindications to any of the investigational drugs or any component of the investigational drug formulation.
* • Clinically relevant proteinuria
* • Diffuse and intense osseous radiotracer uptake on bone scintigraphy or PSMA imaging characteristic of a superscan.
* • Chronic corticosteroid use greater than 10 mg prednisone equivalent daily.
Inclusion Criteria:
* Participants with confirmed histology of high-grade epithelial serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer.
* Provision of an archival FFPE tumour sample
* Participants who received at least one, and no more than 2 lines of prior systemic anticancer therapy.
* Participants with radiologically confirmed disease relapse ≥ 6 months after their last platinum chemotherapy infusion in the previous line of treatment
* Participants who received at least 6 cycles of PBC during the induction phase of their current line of treatment.
* Participants assigned to bevacizumab must have received a minimum of 3 cycles of bevacizumab with 3 cycles of PBC prior to randomisation.
* Participants with non-progressive disease upon completion of PBC in their current line of treatment.
* Participants with documented BRCA mutation 1/2 must have received prior PARP inhibitor (unless ineligible due to contraindications, precautions, or intolerance).
Exclusion Criteria:
* Participants with tumours of non-epithelial origin, borderline tumours, clear cell OC, mucinous OC, carcinosarcoma, or low-grade epithelial tumours.
* Participants with history of (non-infectious) ILD/pneumonitis that required steroids, or supplemental oxygen, or has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening
* Participants with non-healing wound, active ulcer, or bone fracture (not applicable if not receiving bevacizumab)
* Participants with evidence of active or ongoing bowel obstruction (not applicable if not receiving bevacizumab)
* Participants with prior exposure to any FRα-targeted therapy, including MIRV, or any TOP1i Antibody-drug Conjugate (ADC)
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Inclusion Criteria:
* Participants with confirmed histology of high-grade epithelial serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer.
* Provision of an archival FFPE tumour sample
* Participants who received at least one, and no more than 2 lines of prior systemic anticancer therapy.
* Participants with radiologically confirmed disease relapse ≥ 6 months after their last platinum chemotherapy infusion in the previous line of treatment
* Participants who received 4-6 cycles of PBC during the induction phase of their current line of treatment.
* Participants assigned to bevacizumab must have received a minimum of 3 cycles of bevacizumab with 3 cycles of PBC prior to randomisation.
* Participants with non-progressive disease upon completion of PBC in their current line of treatment.
* Participants with documented BRCA mutation 1/2 must have received prior PARP inhibitor (unless ineligible due to contraindications, precautions, or intolerance).
Exclusion Criteria:
* Participants with tumours of non-epithelial origin, borderline tumours, clear cell OC, mucinous OC, carcinosarcoma, or low-grade epithelial tumours.
* Participants with history of (non-infectious) ILD/pneumonitis that required steroids, or supplemental oxygen, or has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening
* Participants with non-healing wound, active ulcer, or bone fracture (not applicable if not receiving bevacizumab)
* Participants with evidence of active or ongoing bowel obstruction (not applicable if not receiving bevacizumab)
* Participants with prior exposure to any FRα-targeted therapy, including MIRV, or any TOP1i Antibody-drug Conjugate (ADC)
Inclusion Criteria:
Clinicians will be eligible if they:
1. are practicing primary care or specialty care physicians at a recruiting site within the University of Pennsylvania Health System;
2. care for patients who completed LCS via LDCT in 2019-2023; and
3. do not opt-out of study participation.
Patients will be eligible if they:
1. are eligible for LCS based on 2021 US Preventive Services Task Force (USPSTF) population guidelines (aged 50-80; smoking history of 20-pack years; smoked within the last 15 years)
2. completed LCS via LDCT in 2019-2023;
3. have not been diagnosed with lung cancer;
4. meet criteria for non-adherence;
5. remain eligible for LCS during the trial enrollment period; and
6. receive LCS care from a clinician that has not opted-out of study participation
Exclusion Criteria:
Patients will be excluded if they:
a) have a highly suspicious baseline LDCT (Lung-RADS 4B/X) given the presence of existing clinical pathways to ensure adherence in this group
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Inclusion Criteria:
Clinicians will be eligible if they:
1. are practicing primary care or specialty care physicians at a recruiting site within the University of Pennsylvania Health System;
2. care for patients who completed LCS via LDCT in 2019-2023; and
3. do not opt-out of study participation.
Patients will be eligible if they:
1. are eligible for LCS based on 2021 US Preventive Services Task Force (USPSTF) population guidelines (aged 50-80; smoking history of 20-pack years; smoked within the last 15 years)
2. completed LCS via LDCT in 2019-2023;
3. have not been diagnosed with lung cancer at the time of randomization;
4. meet criteria for non-adherence;
5. remain eligible for LCS during the trial enrollment period; and
6. receive LCS care from a clinician that has not opted-out of study participation
Exclusion Criteria:
Patients will be excluded if they:
a) have a highly suspicious baseline LDCT (Lung-RADS 4B/X) given the presence of existing clinical pathways to ensure adherence in this group
Inclusion Criteria:
1. Male patients aged ≥ 18 years old;
2. Signed ICF, including consent for blood samples ctDNA and ctDNA-based HRRm testing;
3. Metastatic hormone-sensitive prostate cancer (mHSPC) (de novo or progressed from earlier stages);
4. High-aggressive disease (Gleason 8-10);
5. High-volume disease (according to CHAARTED trial criteria: presence of 4 and more (≥4) bone metastases (including at least one (≥1) outside the vertebral column/pelvis) and/or 1 and more (≥1) visceral metastasis);
6. Availability of source medical documentation;
7. Known HRRm status based on tumour sample evaluation performed in routine practice.
Exclusion Criteria:
1. Participation in any interventional trial since the mPC diagnosis.
2. Progression to mCRPC.
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Inclusion Criteria:
1. Male patients aged ≥ 18 years old;
2. Signed ICF, including consent for blood samples ctDNA and ctDNA-based HRRm testing;
3. Metastatic hormone-sensitive prostate cancer (mHSPC) (de novo or progressed from earlier stages);
4. High-aggressive disease (Gleason 8-10);
5. High-volume disease (according to CHAARTED trial criteria: presence of 4 and more (≥4) bone metastases (including at least one (≥1) outside the vertebral column/pelvis) and/or 1 and more (≥1) visceral metastasis);
6. Availability of source medical documentation;
7. Known HRRm status based on routine tumour sample analysis.
Exclusion Criteria:
1. Participation in any interventional trial since the mPC diagnosis.
2. Progression to mCRPC.
Overall Inclusion Criteria:
* Histopathologically confirmed colorectal adenocarcinoma.
* Provision of FFPE tumor sample collected as per SoC.
* Presence of measurable disease by RECIST 1.1 criteria.
* ECOG performance status of 0 or 1.
* Life expectancy ≥ 12 weeks at the time of screening.
Substudy Inclusion Criteria:
* No radiological evidence of liver metastasis.
* No prior systemic therapy for mCRC, except for neoadjuvant/adjuvant chemotherapy where, \> 6 months have elapsed between completion of therapy and documented date of diagnosis of recurrent or metastatic disease.
* Known pMMR/MSS status (only pMMR/MSS mCRC allowed).
* Adequate organ and bone marrow function
* Body weight \> 35 kg at screening and at randomization.
* Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Overall Exclusion Criteria:
* Central nervous system metastases or spinal cord compression
* Known history of severe allergy to any monoclonal antibody or study intervention.
* Any unresolved toxicity CTCAE Grade ≥ 2 from a previous anticancer therapy.
* History of another primary malignancy.
Substudy Exclusion Criteria:
* Potentially resectable disease with multidisciplinary plan for radical surgery.
* Active or prior documented autoimmune or inflammatory disorders or cardiac conditions.
* Participants with a prior history of hypertensive crisis or hypertensive encephalopathy or bleeding risks.
* Deep venous thrombosis, pulmonary embolism, arterial thrombosis, transient ischemic attack or cerebrovascular accident.
* History of abdominal or tracheoesophageal fistula, GI perforation and/or fistulae, or intraabdominal abscess within 6 months prior to randomization.
* Prior exposure to immune mediated therapy.
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Overall Inclusion Criteria:
* Histopathologically confirmed colorectal adenocarcinoma.
* Provision of FFPE tumor sample collected as per SoC.
* Presence of measurable disease by RECIST 1.1 criteria.
* ECOG performance status of 0 or 1.
* Life expectancy ≥ 12 weeks at the time of screening.
Substudy Inclusion Criteria:
* No radiological evidence of liver metastasis.
* No prior systemic therapy for mCRC, prior neoadjuvant/adjuvant chemotherapy is permitted only when given for resected (M0) disease and only after at least 6 months have elapsed since completion of that therapy and diagnosis of recurrent or metastatic disease.
* Known pMMR/MSS status (only pMMR/MSS mCRC allowed).
* Adequate organ and bone marrow function
* Body weight \> 35 kg at screening and at randomization.
* Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Overall Exclusion Criteria:
* Central nervous system metastases or spinal cord compression
* Known history of severe allergy to any monoclonal antibody or study intervention.
* Any unresolved toxicity CTCAE Grade ≥ 2 from a previous anticancer therapy.
* History of another primary malignancy.
Substudy Exclusion Criteria:
* Potentially resectable disease with multidisciplinary plan for radical surgery.
* Active or prior documented autoimmune or inflammatory disorders or cardiac conditions.
* Participants with a prior history of hypertensive crisis or hypertensive encephalopathy or bleeding risks.
* Deep venous thrombosis, pulmonary embolism, arterial thrombosis, transient ischemic attack or cerebrovascular accident.
* History of abdominal or tracheoesophageal fistula, GI perforation and/or fistulae, or intraabdominal abscess within 6 months prior to randomization.
* Prior exposure to immune mediated therapy.
* History of active primary immunodeficiency.
Main Inclusion Criteria:
1. Participant must be ≥ 18 years at the time of signing informed consent.
2. Diagnosis of CLL/SLL according to iwCLL guidelines 2018 (Hallek et al. 2018)
3. Participants must have received first line treatment with fixed duration covalent BTKi plus BCL2i therapy (± obinutuzumab) with a response ≥ PR (i.e., CR, CRi, nPR, or PR) with a minimum of 2 years since the end of the prior 1L treatment.
4. The following data must be available or at least the appropriate samples drawn/acquired prior to dosing:
1. IGHV (mutated vs. unmutated)
2. del(17p) (present or absent)
3. TP53 mutation (present or absent)
5. ECOG performance status 0, 1 or 2
6. Adequate organ and bone marrow (BM) function.
Main Exclusion Criteria:
1. Any evidence of diseases that, in the investigator's opinion, makes it undesirable for patient to participate in the study.
2. Significant cardiovascular or cerebrovascular disease.
3. Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
4. Child-Pugh B/C liver cirrhosis.
5. History of prior or current malignancy.
6. HIV positive
7. History of progressive multifocal leukoencephalopathy (PML).
8. Active hepatitis B or C infection:
9. Corticosteroid use \> 20 mg within 1 week before the first dose of study intervention.
10. History of hypersensitivity or anaphylaxis to study intervention(s).
11. Requires treatment with a strong CYP3A4 inhibitor/inducer.
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
13. Major surgical procedure within 30 days of the first dose of study intervention.
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Main Inclusion Criteria:
1. Participant must be ≥ 18 years at the time of signing informed consent.
2. Diagnosis of relapsed CLL/SLL according to iwCLL guidelines 2018 (Hallek et al. 2018) in need of treatment.
3. Participants must have received only one prior first line treatment with fixed duration covalent BTKi plus BCL2i therapy (± obinutuzumab) with a response ≥ PR (i.e., CR, CRi, nPR, or PR) for a minimum of 2 years since the end of the prior 1L treatment.
4. The following data must be available or at least the appropriate samples drawn/acquired prior to dosing:
1. IGHV (mutated vs. unmutated)
2. del(17p) (present or absent)
3. TP53 mutation (present or absent)
5. ECOG performance status 0, 1 or 2
6. Adequate organ and bone marrow (BM) function.
Main Exclusion Criteria:
1. Any evidence of diseases that, in the investigator's opinion, makes it undesirable for patient to participate in the study.
2. Significant cardiovascular or cerebrovascular disease.
3. Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand disease).
4. Child-Pugh B/C liver cirrhosis.
5. History of prior or current malignancy.
6. HIV positive
7. History of progressive multifocal leukoencephalopathy (PML).
8. Active hepatitis B or C infection:
9. Corticosteroid use \> 20 mg within 1 week before the first dose of study intervention.
10. History of hypersensitivity or anaphylaxis to study intervention(s).
11. Requires treatment with a strong CYP3A4 inhibitor/inducer.
12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists.
13. Major surgical procedure within 30 days of the first dose of study intervention.
Inclusion Criteria:
1. Patient\* has given written informed consent.
2. Patient is ≥ 18 years of age at time of signing the written informed consent.
3. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
4. Patient has been diagnosed with histologically or cytologically confirmed
1. histologically or cytologically confirmed cholangiocarcinoma as adenocarcinoma of pancreatobiliary type
2. unresectable perihilar and/or ductal cholangiocarcinoma with indication for bile duct stenting and palliative systemic therapy as determined by the local multidisciplinary team (MDT) and already resolved cholestasis due to RFA + stent
5. Patient tolerated RFA prior to inclusion and is eligible for repeat RFA during the study (does not have any contraindications) as determined by investigator.
6. Patient is eligible for palliative systemic therapy based on clinical and laboratory parameters (except hyperbilirubinemia) as determined by the local MDT
7. Patient has a ECOG ≤ 1.
8. Patient has life expectancy of ≥ 12 weeks
9. Patient has body weight \> 30 kg
10. Adequate blood count, liver-enzymes, and renal function:
1. ANC \> 1,500 cells/μL without the use of hematopoietic growth factors
2. Platelet count ≥ 100 x 109/L (\>100,000 per mm3)
3. Hemoglobin ≥ 9 g/dL
4. Serum total bilirubin ≤ 3x upper normal limit (ULN) (biliary drainage is allowed for biliary obstruction; elevated bilirubin should be caused by obstruction not impaired liver function as assessed by albumin and INR values)
5. Albumin levels ≥ 2.8 g/dL
6. Patients not receiving therapeutic anticoagulation must have an INR\< 2.0 ULN and PTT \< 1.5 ULN within 7 days prior to randomization. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of inclusion
7. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN unless liver metastases are present, in which case it must be ≤ 5x ULN
8. Serum Creatinine ≤ 1.5 x ULN and a calculated creatinine clearance rate ≥ 60 mL /min
11. Female patients defined as women of childbearing potential (WOCBP) or male patients with WOCBP partners must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least 6 months after the last dose of chemotherapy or for at least 3 months after last dose of durvalumab, whatever happens last. Male patients must refrain from donating sperm during this same period. Male patients with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy.
Exclusion Criteria:
1. Patient received previous or simultaneous endobiliary treatment other than RFA (e.g. PDT or brachytherapy)
2. Patient received previous systemic therapy with a PD-1, PD-L1 inhibitor (including durvalumab) or CTLA4 inhibitor or classical chemotherapy agents like platinum, fluoropyrimidine or gemcitabine-based regimens.
3. Patient receives any concurrent chemotherapy, investigational product or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g., hormone replace therapy) is acceptable.
4. Patient has known hypersensitivity to any component of the durvalumab formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to gemcitabine or cisplatin.
5. Patient has history of primary immunodeficiency
6. Patient has stage B cirrhosis according to Child-Pugh criteria (or worse) or cirrhosis (of any grade) with a history of hepatic encephalopathy or clinically significant ascites resulting from cirrhosis. Clinically significant ascites is defined as ascites resulting from cirrhosis requiring diuretics or paracentesis.
7. Patient has any unresolved NCI CTCAE grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and laboratory values defined in the inclusion criteria
1. Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Lead Investigator
2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Lead Investigator.
8. Patient had a prior allogeneic bone marrow transplantation or prior solid organ transplantation.
9. Patient has active or history of autoimmune or inflammatory disorders (including, but not limited to, inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis\]) . The following are exceptions:
1. Patients with vitiligo or alopecia
2. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
3. Patients with any chronic skin condition that does not require systemic therapy
4. Patients with celiac disease controlled by diet alone
5. Patients without active disease in the last 5 years may be included but only after consultation with the Lead Investigator
10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
→
Inclusion Criteria:
1. Patient\* has given written informed consent.
2. Patient is ≥ 18 years of age at time of signing the written informed consent.
3. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
4. Patient has been diagnosed with histologically or cytologically confirmed
1. histologically or cytologically confirmed cholangiocarcinoma as adenocarcinoma of pancreatobiliary type
2. unresectable perihilar and/or ductal extrahepatic cholangiocarcinoma or intrahepatic CCA with perihilar stricture according to Bismuth-Corlette classification with indication for bile duct stenting and palliative systemic therapy as determined by the local multidisciplinary team (MDT) and already resolved cholestasis due to RFA + stent
5. Patient tolerated RFA prior to inclusion and is eligible for repeat RFA during the study (does not have any contraindications) as determined by investigator.
6. Patient is eligible for palliative systemic therapy based on clinical and laboratory parameters (except hyperbilirubinemia) as determined by the local MDT
7. Patient has a ECOG ≤ 1.
8. Patient has life expectancy of ≥ 12 weeks
9. Patient has body weight \> 30 kg
10. Adequate blood count, liver-enzymes, and renal function:
1. ANC \> 1,500 cells/μL without the use of hematopoietic growth factors
2. Platelet count ≥ 100 x 109/L (\>100,000 per mm3)
3. Hemoglobin ≥ 9 g/dL
4. Serum total bilirubin ≤ 3x upper normal limit (ULN) (biliary drainage is allowed for biliary obstruction; elevated bilirubin should be caused by obstruction not impaired liver function as assessed by albumin and INR values)
5. Albumin levels ≥ 2.8 g/dL
6. Patients not receiving therapeutic anticoagulation must have an INR\< 2.0 ULN and PTT \< 1.5 ULN within 7 days prior to randomization. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of inclusion
7. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN unless liver metastases are present, in which case it must be ≤ 5x ULN
8. Serum Creatinine ≤ 1.5 x ULN and a calculated creatinine clearance rate ≥ 60 mL /min
11. Female patients defined as women of childbearing potential (WOCBP) or male patients with WOCBP partners must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least 6 months after the last dose of chemotherapy or for at least 3 months after last dose of durvalumab, whatever happens last. Male patients must refrain from donating sperm during this same period. Male patients with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy.
Exclusion Criteria:
1. Patient received previous or simultaneous endobiliary treatment other than RFA (e.g. PDT or brachytherapy)
2. Patient received previous systemic therapy with a PD-1, PD-L1 inhibitor (including durvalumab) or CTLA4 inhibitor or classical chemotherapy agents like platinum, fluoropyrimidine or gemcitabine-based regimens.
3. Patient receives any concurrent chemotherapy, investigational product or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g., hormone replace therapy) is acceptable.
4. Patient has known hypersensitivity to any component of the durvalumab formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to gemcitabine or cisplatin.
5. Patient has history of primary immunodeficiency
6. Patient has stage B cirrhosis according to Child-Pugh criteria (or worse) or cirrhosis (of any grade) with a history of hepatic encephalopathy or clinically significant ascites resulting from cirrhosis. Clinically significant ascites is defined as ascites resulting from cirrhosis requiring diuretics or paracentesis.
7. Patient has any unresolved NCI CTCAE grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and laboratory values defined in the inclusion criteria
1. Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Lead Investigator
2. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Lead Investigator.
8. Patient had a prior allogeneic bone marrow transplantation or prior solid organ transplantation.
9. Patient has active or history of autoimmune or inflammatory disorders (including, but not limited to, inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis\]) . The following are exceptions:
1. Patients with vitiligo or alopecia
2. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement
3. Patients with any chronic skin condition that does not require systemic therapy
4. Patients with celiac disease controlled by diet alone
5. Patients without active disease in the last 5 years may be included but only after consultation with the Lead Investigator
10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
Inclusion Criteria:
* Men and women \>= 18 years of age.
* Diagnosis of CLL or small lymphocytic lymphoma (SLL) that meets the published diagnostic criteria.
* Active disease per IWCLL 2018 criteria that require treatment. At least one of the following:
* Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
* Massive (\> 6 cm below left costal margin), progressive, or symptomatic splenomegaly
* Massive nodes (\> 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy
* Progressive lymphocytosis with an increase of \> 50% over a 2-month period or lymphocyte-doubling time of \< 6 months. Lymphocyte-doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of \< 30 x 109/L lymphocyte-doubling time should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (e.g., infection) should be excluded.
* Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs
* Unintentional weight loss of \> 10% within the previous 6 months
* Significant fatigue
* Fevers \> 100.5 degrees Fahrenheit (F) or 38 degrees Celsius (C) for 2 weeks without other evidence of infection
* Night sweats for \> 1 month without evidence of infection
* Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. A line of therapy is defined as completing at least 2 cycles of treatment of standard regimen according to current National Comprehensive Cancer Network (NCCN) guidelines, or of an investigational regimen on a clinical trial.
* Absolute neutrophil count (ANC) \>= 750 cells/microliter (0.75 x 10\^9/L); ANC \>= 500 cells/microliter (0.50 x 10\^9/L) in subjects with documented bone marrow involvement of CLL (independent of growth factor or transfusion support within 1 week of screening).
* Hemoglobin \>= 10 g/dL (independent of growth factor or transfusion support within 1 week of screening).
* Platelet count \>= 50,000 cells/microliter (50 x 10\^9/L); platelet count \>= 25,000 cells/microliter (25 x 10\^9/L) in subjects with documented bone marrow involvement of CLL (independent of growth factor or transfusion support within 1 week of screening).
* Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal (ULN)
* Total bilirubin =\< 2 x ULN, unless directly attributable to Gilbert's syndrome
* Estimated creatinine clearance of \>= 50 mL/min
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Women of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 30 days after the last dose of acalabrutinib or venetoclax, whichever occurs later
* Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules or tablets without difficulty
* Ability to understand the purpose and the risks of the study and provide signed and dated informed consent and authorization to use protected health information
Exclusion Criteria:
* Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation (biopsy based on clinical suspicion may be needed to rule out transformation)
* Prior disease progression while on a BTK inhibitor
* Prior disease progression while on venetoclax
* Prior intolerance to acalabrutinib or venetoclax
* Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, low-grade prostate carcinoma (Gleason grade =\< 6) or other cancer from which the subject has been disease free for \>= 2 years or which will not limit survival to \< 3 years
* Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac diseases as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study.
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. Patients with history of such operations are eligible if in treating physician's opinion they have no absorption issues.
* Known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib or venetoclax
* Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease), or requires/is receiving anticoagulation with warfarin or equivalent vitamin K antagonists
* Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastic time (aPTT) (in the absence of lupus anticoagulant) \> 2 x ULN
* Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP)
* Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening
* Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducers. The use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first dose of study drug is prohibited.
* For patients receiving capsule formulation of acalabrutinib only: Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) at the time of enrollment. Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
* History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug
* Major surgical procedure within 7 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug
* Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded.
* Breastfeeding or pregnant
* Concurrent participation in another therapeutic clinical trial
* Known history of infection with human immunodeficiency virus (HIV) or any active significant infection (e.g,. bacterial, viral, or fungal)
* History of or ongoing confirmed central nervous system (CNS) CLL
* History of confirmed progressive multifocal leukoencephalopathy (PML)
→
Inclusion Criteria:
* Men and women \>= 18 years of age.
* Diagnosis of CLL or small lymphocytic lymphoma (SLL) that meets the published diagnostic criteria.
* Active disease per IWCLL 2018 criteria that require treatment. At least one of the following:
* Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia
* Massive (\> 6 cm below left costal margin), progressive, or symptomatic splenomegaly
* Massive nodes (\> 10 cm in longest diameter), or progressive or symptomatic lymphadenopathy
* Progressive lymphocytosis with an increase of \> 50% over a 2-month period or lymphocyte-doubling time of \< 6 months. Lymphocyte-doubling time may be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In patients with initial blood lymphocyte counts of \< 30 x 109/L lymphocyte-doubling time should not be used as a single parameter to define treatment indication. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL/SLL (e.g., infection) should be excluded.
* Constitutional symptoms, defined as any 1 or more of the following disease-related symptoms or signs
* Unintentional weight loss of \> 10% within the previous 6 months
* Significant fatigue
* Fevers \> 100.5 degrees Fahrenheit (F) or 38 degrees Celsius (C) for 2 weeks without other evidence of infection
* Night sweats for \> 1 month without evidence of infection
* Relapsed or refractory to at least 1 prior systemic therapy for CLL/SLL. A line of therapy is defined as completing at least 2 cycles of treatment of standard regimen according to current National Comprehensive Cancer Network (NCCN) guidelines, or of an investigational regimen on a clinical trial.
* Absolute neutrophil count (ANC) \>= 750 cells/microliter (0.75 x 10\^9/L); ANC \>= 500 cells/microliter (0.50 x 10\^9/L) in subjects with documented bone marrow involvement of CLL (independent of growth factor or transfusion support within 1 week of screening).
* Hemoglobin \>= 10 g/dL (independent of growth factor or transfusion support within 1 week of screening).
* Platelet count \>= 50,000 cells/microliter (50 x 10\^9/L); platelet count \>= 25,000 cells/microliter (25 x 10\^9/L) in subjects with documented bone marrow involvement of CLL (independent of growth factor or transfusion support within 1 week of screening).
* Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal (ULN)
* Total bilirubin =\< 2 x ULN, unless directly attributable to Gilbert's syndrome
* Estimated creatinine clearance of \>= 50 mL/min
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Women of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 30 days after the last dose of acalabrutinib or venetoclax, whichever occurs later
* Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing tablets without difficulty
* Ability to understand the purpose and the risks of the study and provide signed and dated informed consent and authorization to use protected health information
Exclusion Criteria:
* Known prolymphocytic leukemia or history of, or currently suspected, Richter's transformation (biopsy based on clinical suspicion may be needed to rule out transformation)
* Prior disease progression while on a BTK inhibitor
* Prior disease progression while on venetoclax
* Prior intolerance to acalabrutinib or venetoclax
* Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, low-grade prostate carcinoma (Gleason grade =\< 6) or other cancer from which the subject has been disease free for \>= 2 years or which will not limit survival to \< 3 years
* Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 or 4 cardiac diseases as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study.
* Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. Patients with history of such operations are eligible if in treating physician's opinion they have no absorption issues.
* Known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib or venetoclax
* Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease), or requires/is receiving anticoagulation with warfarin or equivalent vitamin K antagonists
* Prothrombin time (PT)/international normalized ratio (INR) or activated partial thromboplastic time (aPTT) (in the absence of lupus anticoagulant) \> 2 x ULN
* Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP)
* Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening
* Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor or inducers. The use of strong or moderate CYP3A inhibitors or inducers within 7 days of the first dose of study drug is prohibited.
* History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug
* Major surgical procedure within 7 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug
* Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded.
* Breastfeeding or pregnant
* Concurrent participation in another therapeutic clinical trial
* Known history of infection with human immunodeficiency virus (HIV) or any active significant infection (e.g,. bacterial, viral, or fungal)
* History of or ongoing confirmed central nervous system (CNS) CLL
* History of confirmed progressive multifocal leukoencephalopathy (PML)
Inclusion Criteria:
* Signed informed consent form, prior to the start of any study-specific qualification procedures and willing to comply with all study requirements.
* Currently enrolled in a DS or DS/AZ-sponsored parent study that has met EOS definition.
* No evidence of progressive disease and determined to have investigator-assessed clinical benefit from continued treatment with a DS or DS/AZ alliance study drug(s).
Exclusion Criteria:
* Participants with any unresolved/ongoing AE(s) that meets the study drug discontinuation criteria
* Participant who has been off T-DXd therapy for \>18 weeks (126 days) between the last dose from the parent study and the initiation of study drug administration on this study
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Inclusion Criteria:
Participants must meet all of the following criteria to be eligible for enrollment into the study:
1. Currently enrolled in a DS or DS/AZ-sponsored parent study that has met EOS definition.
2. No evidence of progressive disease at screening and determined to have investigator-assessed clinical benefit from continued treatment with a DS or DS/AZ alliance study drug(s).
3. Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 months for females and 4 months for males after the last dose of study drug.
a. If the participant is a female of childbearing potential, she must have a negative urine pregnancy test at Screening, during the Treatment Period, and for 7 months, following the last dose of study drug.
4. Male subjects must not freeze or donate sperm starting at Screening, throughout the study period, and at least 4 months after the final study drug administration.
5. Female subjects must not donate, or retrieve for their own use, ova from the time of Screening, and throughout the Treatment Period in the compound-specific sub-protocol and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time.
Exclusion Criteria:
Participants who meet any of the following criteria will be disqualified from entering the study:
1. Participants who permanently discontinued from the study drug in the parent study.
2. Any AE, laboratory abnormality, or intercurrent illness that, in the opinion of the investigator, indicates study participation is not in the best interest of the subject.
3. Local access to commercially available drug at no cost to the subject as permitted by local/country regulation.
Key Inclusion Criteria
* Adults ≥18 years at the time the ICF is signed (Please follow local regulatory requirements if the legal age of consent for trial participation is \>18 years old)
* Has histologically confirmed diagnosis of epithelial endometrial carcinoma. All histology's are allowed except for sarcomas (carcinosarcomas are allowed).
* Is newly diagnosed FIGO 2023 Stage IIC (including Stage IICmp53abn) or Stage III Note: FIGO 2023 Stage IIC includes disease with aggressive histological types (aggressive histological types are composed of high-grade EECs (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, and carcinosarcomas) with any myometrial involvement. FIGO 2023 Stage III includes disease with local and/or regional spread of the tumor of any histological subtype.
* Has HER2-expression (IHC 3+/2+) per 2016 ASCO-CAP gastric cancer IHC scoring guidelines as confirmed by central laboratory testing.
* Has adequate archived tumor tissue sample (sample from surgery is strongly recommended) available for assessment of HER2 status by central laboratory.
Key Exclusion Criteria
* Has uterine mesenchymal tumor such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas. Adenosarcomas are also not allowed.
* Has recurrent or FIGO 2023 Stage IV
* Has measurable residual tumor after surgery as determined by BICR assessment.
* Is known to have a POLE mutation from an approved and/or validated local test, according to local regulations, if available
* Has a medical history of MI within 6 months before randomization/enrollment, symptomatic CHF (NYHA Class II to IV). Participants with troponin levels above ULN at SCR (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation during SCR Period to rule out MI.
* Has a QTcF prolongation to \> 480 msec based on average of the SCR triplicate12-lead ECG. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months of the trial enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.) and any autoimmune, connective tissue, or inflammatory disorder with potential pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
* Has a history of (noninfectious) ILD/pneumonitis that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at SCR.
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Key Inclusion Criteria
* Adults ≥18 years at the time the ICF is signed (Please follow local regulatory requirements if the legal age of consent for trial participation is \>18 years old)
* Has histologically confirmed diagnosis of epithelial endometrial carcinoma. All histology's are allowed except for sarcomas (carcinosarcomas are allowed).
* Is newly diagnosed FIGO 2023 Stage IIC (including Stage IICmp53abn) or Stage III Note: FIGO 2023 Stage IIC includes disease with aggressive histological types (aggressive histological types are composed of high-grade EECs (grade 3), serous, clear cell, undifferentiated, mixed, mesonephric-like, gastrointestinal mucinous type carcinomas, and carcinosarcomas) with any myometrial involvement. FIGO 2023 Stage III includes disease with local and/or regional spread of the tumor of any histological subtype.
* Has HER2-expression (IHC 3+/2+).
* Has adequate archived tumor tissue sample available for assessment of HER2 status by central laboratory.
Key Exclusion Criteria
* Has uterine mesenchymal tumor such as an endometrial stromal sarcoma, leiomyosarcoma, or other types of pure sarcomas. Adenosarcomas are also not allowed.
* Has recurrent or FIGO 2023 Stage IV
* Has residual tumor after surgery as determined by BICR assessment.
* Is known to have a POLE mutation from an approved and/or validated local test, according to local regulations, if available
* Has a medical history of MI within 6 months before randomization/enrollment, symptomatic CHF (NYHA Class II to IV). Participants with troponin levels above ULN at SCR (as defined by the manufacturer), and without any MI related symptoms should have a cardiologic consultation during SCR Period to rule out MI.
* Has a QTcF prolongation to \> 480 msec based on average of the SCR triplicate12-lead ECG.
* Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months of the trial enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.) and any autoimmune, connective tissue, or inflammatory disorder with potential pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy.
* Has a history of (noninfectious) ILD/pneumonitis that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at SCR.
Inclusion criteria:
The following patients will be eligible for inclusion in the AQUALIS study :
* Patient enrolled in the PLATON database
* Patient ≥18 years old
* Treatment naïve CLL patient treated with acalabrutinib in a real life setting. Treatment pattern is Acala mono or Acala + Obinutuzumab
* Patient who do not object to his health data collected in PLATON study being re-use for analysis/research purpose
* Patients who started Acala but discontinued before 12 months are also included.
Exclusion criteria:
* Pregnant women
* Patients under protection of justice
* Patients over the age of 18 and unable to express their non-opposition
* Patients with prior CLL treatments
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Inclusion Criteria:
* The following patients will be eligible for inclusion in the AQUALIS study :
* -Patient enrolled in the PLATON database
* -Patient ≥18 years old
* -Treatment naïve CLL patient treated with acalabrutinib in a real life setting. Treatment pattern is Acala mono or Acala + Obinutuzumab
* -Patient who do not object to his health data collected in PLATON study being re-use for analysis/research purpose
* -Patients who started Acala but discontinued before 12 months are also included.
* Exclusion criteria:
* -Pregnant women
* -Patients under protection of justice
* -Patients over the age of 18 and unable to express their non-opposition
* -Patients with prior CLL treatments
Exclusion Criteria:
Inclusion Criteria:
1. Participant must be ≥ 18 years or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent form.
2. Participants with histologically documented NSCLC of predominantly nonsquamous, squamous, and adenosquamous pathology who present with locally advanced, unresectable (Stage III, according to Version 8 of the IASLC Staging Manual in Thoracic Oncology) disease. It is recommended but not required that except for overt cT4 disease, nodal status N2, or N3 should have been proven by biopsy, via endobronchial ultrasound, mediastinoscopy, thoracoscopy, or in absence of biopsy, should have been confirmed with whole body contrast-enhanced CT.
3. Participants who had recurred from Stage I/II/III after complete surgery or had gross incomplete resections can be included if they didn't receive treatment with any chemotherapy, radiation therapy, immunotherapy, targeted therapy, or investigational agents.
4. Participants with availability of the EGFRm test results confirming that the tumor harbors 1 of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including de novo T790M
5. WHO performance status of 0, 1 or 2 with no deterioration over the previous 2 weeks prior to baseline at screening and prior to first dose.
6. Participants who are eligible for and planning to undergo RT treatment per physician assessment.
7. Participant refusal or ineligible for chemotherapy per physician assessment.
8. Minimum life expectancy of \> 12 weeks at Day 1.
9. At least one lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements.
10. Capable of giving signed informed consent as described which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion Criteria
1. Any presence of small cell and mixed small-cell and non-small cell histology.
2. Past medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD.
3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the participant to participate in the trial or which would jeopardize compliance with the protocol, or active infection.
4. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
5. History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease. Patients who have received RT with overlapping fields (eg, cured breast cancer) should be excluded.
6. Patient meets any of the following cardiac criteria: Mean resting QTc \> 470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value.
7. Inadequate bone marrow reserve or organ function.
8. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum-therapy related neuropathy. Prior treatment with any chemotherapy, radiation therapy, immunotherapy, targeted therapy, or investigational agents for locally advanced, unresectable Stage III NSCLC. Prior surgical resection (ie, Stage I, II, or III) with no systemic treatment with residual disease or a recurrence is permitted.
11 Prior exposure to EGFR-TKI therapy. 12 Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
13 Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks.
14 History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
15 History of hypersensitivity to active or inactive excipients of RT. 16 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
17 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
18 Previous enrolment in the present study. Rescreening of individuals who were screen failures is allowed.
19 For females only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
20 Patients should refrain from breastfeeding from enrolment throughout the study and until 6 weeks after last dose of study intervention.
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Inclusion Criteria:
1. Participant must be ≥ 18 years or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent form.
2. Participants with histologically documented NSCLC of predominantly nonsquamous, squamous, and adenosquamous pathology who present with locally advanced, unresectable (Stage III, according to Version 8 of the IASLC Staging Manual in Thoracic Oncology) disease. It is recommended but not required that except for overt cT4 disease, nodal status N2, or N3 should have been proven by biopsy, via endobronchial ultrasound, mediastinoscopy, thoracoscopy, or in absence of biopsy, should have been confirmed with whole body contrast-enhanced CT.
3. Participants who had recurred from Stage I/II/III after complete surgery or had gross incomplete resections can be included if they didn't receive treatment with any chemotherapy, radiation therapy, immunotherapy, targeted therapy, or investigational agents.
4. Participants with availability of the EGFRm test results confirming that the tumor harbors 1 of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including de novo T790M
5. WHO performance status of 0, 1 or 2 with no deterioration over the previous 2 weeks prior to baseline at screening and prior to first dose.
6. Participants who are eligible for and planning to undergo RT treatment per physician assessment.
7. Participant refusal or ineligible for chemotherapy per physician assessment.
8. Minimum life expectancy of \> 12 weeks at Day 1.
9. At least one lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or MRI and is suitable for accurate repeated measurements.
10. Capable of giving signed informed consent as described which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion Criteria
1. Any presence of small cell and mixed small-cell and non-small cell histology.
2. Past medical history of ILD/pneumonitis, including radiation pneumonitis (apart from radiation pneumonitis that did not require steroids), or drug-induced ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the participant to participate in the trial or which would jeopardize compliance with the protocol, or active infection.
4. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
5. History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include adequately resected non-melanoma skin cancer and curatively treated in situ disease. Patients who have received RT with overlapping fields (eg, cured breast cancer) should be excluded.
6. Patient meets any of the following cardiac criteria: Mean resting QTc \> 470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value. Hypomagnesaemia and hypocalcaemia are acceptable at screening if ≤ CTCAE Grade 1. Values \> Grade 1 for magnesium or calcium should be corrected to ≤ Grade 1 prior to first dose, with documentation of the correction attempt.
7. Inadequate bone marrow reserve or organ function.
8. Patients who are currently taking strong CYP3A4 inducers and cannot discontinue them at least 3 weeks before the first study dose must be excluded. This is because strong CYP3A4 inducers can decrease the exposure of osimertinib.
9. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum-therapy related neuropathy.
10. Prior treatment with any chemotherapy, radiation therapy, immunotherapy, targeted therapy, or investigational agents for locally advanced, unresectable Stage III NSCLC. Prior surgical resection (ie, Stage I, II, or III) with no systemic treatment with residual disease or a recurrence is permitted.
11. Prior exposure to EGFR-TKI therapy.
12. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
13. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks.
14. History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib.
15. History of hypersensitivity to active or inactive excipients of RT.
16. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
17. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
18. Previous enrolment in the present study. Rescreening of individuals who were screen failures is allowed.
19. For females only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
20. Patients should refrain from breastfeeding from enrolment throughout the study and until 6 weeks after last dose of study intervention.
Inclusion Criteria:
1. Patients must be at least 18 years of age
2. Male and female patients must have a histological confirmed diagnosis of NSCLC, BTC, GYN cancers, or UC between Jan 01, 2023 and Sep 30, 2025.
* For GYN cancers, only cervical cancer, endometrial cancer and ovarian cancer should be included. For each gynecological cancer listed above, at least 5 cases need to be enrolled at each expression level (i.e., IHC 0/1+/2+/3+).
3. Patients must have sufficient archived tumor tissue available, with at least 15 slides suitable for HER2 status determination. Both resection or biopsy samples are acceptable. The age limit of archived tissue blocks is 5 years.
Exclusion Criteria:
1. Have a history of other cancers besides NSCLC, BTC, GYN cancers and UC.
2. Specimens of patients that may affect interpretation evaluated by the researcher (e.g., frozen specimens, decalcified specimens, specimens with limited tumor content, etc.)
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Inclusion Criteria:
* 1\. Patients must be at least 18 years of age
* 2\. Male and female patients must have a histological confirmed diagnosis of NSCLC, BTC, GYN cancers, or UC between Jan 01, 2023 and Sep 30, 2025.
* --For GYN cancers, only cervical cancer, endometrial cancer and ovarian cancer should be included. For each gynecological cancer listed above, at least 5 cases need to be enrolled at each expression level (i.e., IHC 0/1+/2+/3+).
* 3\. Patients must have sufficient archived tumor tissue available, with at least 15 slides suitable for HER2 status determination. Both resection or biopsy samples are acceptable. The age limit of archived tissue blocks is 5 years.
Exclusion Criteria:
* 1\. Have a history of other cancers besides NSCLC, BTC, GYN cancers and UC.
* 2\. Specimens of patients that may affect interpretation evaluated by the researcher (e.g., frozen specimens, decalcified specimens, specimens with limited tumor content, etc.)
Inclusion Criteria:
* Patients must have histologically confirmed MIBC (T2-T4a, N0, M0 per American Joint Commission on Cancer \[AJCC\]) pure or mixed histology urothelial carcinoma.
* Patients must be ineligible for cisplatin-based chemotherapy due to any of the following: Creatinine clearance (CrCl) \< 60 mL/min by the Cockcroft-Gault formula; Hearing impaired ≥ Grade 2 by CTCAE criteria; Neuropathy ≥ Grade 2 by CTCAE criteria; Heart failure NYHA ≥ III; ECOG ≥ 2.
* Patients must be medically fit for TURBT and radical cystectomy (RC
* Age ≥ 18 years
* Body weight \>30 kg
* Ability to understand and willingness to sign IRB-approved informed consent.
* Willing to provide tumor tissue, blood, and urine samples for research.
* ECOG performance status 0 or 1 (Karnofsky ≥80%).
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Participants must have adequate organ and marrow function as defined below: Hemoglobin ≥ 9.0 g/dL; Absolute neutrophil count (ANC) ≥ 1500/mcL; Platelet count ≥100,000/mcL; Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN); total bilirubin must be \< 3 x ULN for patients with Gilberts syndrome; AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal; Measured creatinine CL \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance.
* Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients.
* Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥120 days after the last dose of durvalumab.
* Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
* Patient must have a life expectancy of at least 12 weeks
Exclusion Criteria:
* Patients with active or prior documented autoimmune disease within the past 2 years prior to Screening or other immunosuppressive agent within 14 days of study treatment. NOTE: Patients with well controlled type 1 diabetes mellitus, vitiligo, Graves' disease, Hashimoto's disease, eczema, lichen simplex chronicus, or psoriasis not requiring systemic treatment (within the past 2 years prior to Screening) are not excluded.
* Patients who have concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma. Patients with history of non-invasive (Ta, T1, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.
* Patients who have another malignancy that could interfere with the evaluation of safety or efficacy of the study drugs. Patients with a prior malignancy will be allowed without Principal Investigator approval in the following circumstances: Not currently active and diagnosed at least 5 years prior to the date of registration; Non-invasive diseases such as low risk cervical cancer or any cancer in situ; Localized (early stage) cancer treated with curative intent (without evidence of recurrence and intent for further therapy), and in which no chemotherapy was indicated (e.g. low/intermediate risk prostate cancer, etc.). Patients with other malignancies not meeting these criteria must be discussed prior to registration.
* Patients who have received any prior immune checkpoint inhibitor (i.e. anti-KIR, anti-PD-1, anti- PD-L1, (including durvalumab) anti-CTLA4 or other).
* Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury or specific anti-cancer treatment ≤ 4 weeks prior to starting study drug, or patients who have had placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury.
* Patients who have clinically significant cardiac diseases deemed not fit for radical cystectomy, including any of the following: History or presence of serious uncontrolled ventricular arrhythmias; Clinically significant resting bradycardia; Any of the following within 3 months prior to starting study drug: severe/unstable angina, Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA); Uncontrolled hypertension defined by a SBP ≥ 180 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s).
* Patients who have history of chronic active liver disease or evidence of acute or chronic Hepatitis B Virus (HBV) or Hepatitis C (HCV).
* Patients who have known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not required in absence of clinical suspicion.
* Patients who have known diagnosis of any condition (e.g. post-hematopoietic or solid organ transplant, pneumonitis, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy which cannot be stopped for the duration of the clinical trial. Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted.
* Patients with any serious and/or uncontrolled concurrent medical conditions.
* Patients who have used any live viral vaccine for prevention of infectious diseases within 4 weeks prior to study drug(s). Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. COVID vaccination is allowed.
* Patients unwilling or unable to comply with the protocol.
* Patients with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
* Patients who participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial throughout the duration of this study.
* Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference.
* Patients with local symptoms from bladder cancer, (e.g. gross hematuria, dysuria, etc.) who are deemed to be unable to complete the treatment protocol per PI.
* Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
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Inclusion Criteria:
* Patients must have histologically confirmed MIBC (T2-T4a, N0, M0 per American Joint Commission on Cancer \[AJCC\]) pure or mixed histology urothelial carcinoma.
* Patients must be ineligible for cisplatin-based chemotherapy due to any of the following: Creatinine clearance (CrCl) \< 60 mL/min by the Cockcroft-Gault formula; Hearing impaired ≥ Grade 2 by CTCAE criteria; Neuropathy ≥ Grade 2 by CTCAE criteria; Heart failure NYHA ≥ III
* Patients must be medically fit for TURBT and radical cystectomy (RC
* Age ≥ 18 years
* Body weight \>30 kg
* Ability to understand and willingness to sign IRB-approved informed consent.
* Willing to provide tumor tissue, blood, and urine samples for research.
* ECOG performance status 0 or 1 (Karnofsky ≥80%) for patients planning consolidative radical cystectomy. For patients planning consolidative chemoradiation, ECOG performance status 0, 1, or 2 (Karnofsky ≥60%) is permitted.
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Participants must have adequate organ and marrow function as defined below: Hemoglobin ≥ 9.0 g/dL; Absolute neutrophil count (ANC) ≥ 1500/mcL; Platelet count ≥100,000/mcL; Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN); total bilirubin must be \< 3 x ULN for patients with Gilberts syndrome; AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal; Measured creatinine CL \>40 mL/min or Calculated creatinine CL\>40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance.
* Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients.
* Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥120 days after the last dose of durvalumab.
* Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
* Patient must have a life expectancy of at least 12 weeks
Exclusion Criteria:
* Patients with active or prior documented autoimmune disease within the past 2 years prior to Screening or other immunosuppressive agent within 14 days of study treatment. NOTE: Patients with well controlled type 1 diabetes mellitus, vitiligo, Graves' disease, Hashimoto's disease, eczema, lichen simplex chronicus, or psoriasis not requiring systemic treatment (within the past 2 years prior to Screening) are not excluded.
* Patients who have concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma. Patients with history of non-invasive (Ta, T1, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.
* Patients who have another malignancy that could interfere with the evaluation of safety or efficacy of the study drugs. Patients with a prior malignancy will be allowed without Principal Investigator approval in the following circumstances: Not currently active and diagnosed at least 5 years prior to the date of registration; Non-invasive diseases such as low risk cervical cancer or any cancer in situ; Localized (early stage) cancer treated with curative intent (without evidence of recurrence and intent for further therapy), and in which no chemotherapy was indicated (e.g. low/intermediate risk prostate cancer, etc.). Patients with other malignancies not meeting these criteria must be discussed prior to registration.
* Patients who have received any prior immune checkpoint inhibitor (i.e. anti-KIR, anti-PD-1, anti- PD-L1, (including durvalumab) anti-CTLA4 or other).
* Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury or specific anti-cancer treatment ≤ 4 weeks prior to starting study drug, or patients who have had placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury.
* Patients planning consolidative radical cystectomy who have clinically significant cardiac disease deemed not fit for radical cystectomy, including any of the following: History or presence of serious uncontrolled ventricular arrhythmias; Clinically significant resting bradycardia; Any of the following within 3 months prior to starting study drug: severe/unstable angina, Congestive Heart Failure (CHF), Cerebrovascular Accident (CVA), Transient Ischemic Attack (TIA); Uncontrolled hypertension defined by a SBP ≥ 180 mm Hg and/or DBP ≥ 100 mm Hg, with or without anti-hypertensive medication(s).
* Patients who have history of chronic active liver disease or evidence of acute or chronic Hepatitis B Virus (HBV) or Hepatitis C (HCV).
* Patients who have known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not required in absence of clinical suspicion.
* Patients who have known diagnosis of any condition (e.g. post-hematopoietic or solid organ transplant, pneumonitis, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy which cannot be stopped for the duration of the clinical trial. Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted.
* Patients with any serious and/or uncontrolled concurrent medical conditions.
* Patients who have used any live viral vaccine for prevention of infectious diseases within 4 weeks prior to study drug(s). Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. COVID vaccination is allowed.
* Patients unwilling or unable to comply with the protocol.
* Patients with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
* Patients who participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial throughout the duration of this study.
* Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference.
* Patients with local symptoms from bladder cancer, (e.g. gross hematuria, dysuria, etc.) who are deemed to be unable to complete the treatment protocol per PI.
* Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
Key Inclusion Criteria:
* Participants must be at least 18 years of age or the legal age of consent in the jurisdiction
* in which the study is taking place;
* Eastern Cooperative Oncology Group performance status of ≤ 2 in module 1, or 0 or 1 in modules 2 and 3;
* Documentation of Multiple Myeloma (MM) as defined by International Myeloma Working Group (IMWG) Diagnostic Criteria for Multiple Myeloma. Site should ensure that Multiple Myeloma diagnosis is confirmed in accordance with the IMWG Diagnostic Criteria;
* Participants must have one or more measurable disease criteria for Serum M-Protein, Urine M-protein, and Serum immunoglobulin free light chains as specified in the relevant module of the CSP;
* Adequate organ and bone marrow function assessment at screening according to the hematological, hepatic, and renal parameters listed in the CSP as relevant to each module;
* Participants must have received at least 3 prior lines of treatment in module 1, or 1-3 prior lines in modules 2 and 3, with additional module-specific requirements related to prior lines of therapy
The above is a summary of key criteria, other inclusion criteria details may apply
Key Exclusion Criteria:
* Amyloidosis, plasma cell leukemia, Waldenstrom Macroglobulinemia, Polyneuropathy Organomegaly Endocrinopathy M-protein and Skin Syndrome, or Smoldering Multiple Myeloma (compliant with WHO criteria);
* Participants exhibiting clinical signs of central nervous system involvement of MM;
* Participants with known COPD, or previous history of ILD/pneumonitis;
* Participants with known moderate or severe persistent asthma within the past 5 years, or uncontrolled asthma of any classification;
* Participants who have severe cardiovascular disease which is not adequately controlled;
* Participants who have a history of immunodeficiency disease;
* Participants with peripheral neuropathy ≥ Grade 2;
* Primary refractory MM;
* Participants who have previously received anti-GPRC5D or MMAE-containing treatment;
* Participants who have previously received allogenic stem cell transplant, or participant has received autologous stem cell transplant within 3 months before the first dose of study intervention;
* Participants with a history of prior malignancy other than MM within 3 years prior to first dose of study intervention. some exceptions apply;
* Participants with previous history of active JC virus infection resulting in PML;
* Participants with a known hypersensitivity to AZD0305 or any of the excipients of the product or to any of the drugs included in the respective modules or who experienced Grade 3 or higher hypersensitivity to prior monoclonal antibody therapy;
* Participants who have uncontrolled severe illness including but not limited to ongoing active infection requiring therapeutic antibiotics and/or other administration
The above is a summary of key criteria, other exclusion criteria details may apply
→
Key Inclusion Criteria:
* Participants must be at least 18 years of age or the legal age of consent in the jurisdiction in which the study is taking place.
* Eastern Cooperative Oncology Group performance status of ≤ 2 in module 1, or 0 or 1 in modules 2 and 3
* Documentation of Multiple Myeloma (MM) as defined by International Myeloma Working Group (IMWG) Diagnostic Criteria for Multiple Myeloma. Site should ensure that Multiple Myeloma diagnosis is confirmed in accordance with the IMWG Diagnostic Criteria
* Participants must have one or more measurable disease criteria for Serum M-Protein, Urine M-protein, and Serum immunoglobulin free light chains as specified in the relevant module of the CSP;
* Adequate organ and bone marrow function assessment at screening according to the hematological, hepatic, and renal parameters listed in the CSP as relevant to each module.
* Participants must have received at least 3 prior lines of treatment in module 1. In modules 2 and 3, participants must meet the phase-specific requirements for the number of prior lines of therapy.
* The above is a summary of key criteria, other module specific inclusion criteria details may apply
Key Exclusion Criteria:
* Amyloidosis, plasma cell leukemia, Waldenstrom Macroglobulinemia, Polyneuropathy Organomegaly Endocrinopathy M-protein and Skin Syndrome, or Smoldering Multiple Myeloma(compliant with WHO criteria);
* Participants who have previously received anti-GPRC5D or MMAE-containing treatment
* Participants with a history of prior malignancy other than MM within 3 years prior to first dose of study intervention. some exceptions apply Participants with previous history of active John Cunningham virus infection resulting in PML
* Participants with a known hypersensitivity toAZD0305 or any of the excipients of the productor to any of the drugs included in the respective modules or who experienced Grade 3 or higher hypersensitivity to prior mono clonal antibody therapy
* Participants who have uncontrolled severe illness including but not limited to ongoing active infection requiring therapeutic antibiotics and/or other administration
* Participants who have previously received allogenic stem cell transplant, or participant has received autologous stem cell transplant within 3months before the first dose of study intervention
* Participants exhibiting clinical signs of central nervous system involvement of MM;
* Participants with known history of severe or very severe COPD, or previous history of non-infectious ILD/pneumonitis that has required oral or IV steroids of supplemental oxygen, or where suspected suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
* Participants with known severe persistent asthma within the past 5 years, or uncontrolled asthma of any classification;
* Participants who have severe cardio vascular disease which is not adequately controlled.
* Participants who have a history of immunodeficiency disease.
* Participants with peripheral neuropathy ≥ Grade2.
* Primary refractory MM.
* The above is a summary of key criteria, other exclusion criteria details may apply
Inclusion Criteria:
* Capable of giving signed informed consent.
* Adequate physiological function and reserve at screening.
* Able to comply with recommended medication washout period.
* Participants who are suitable for the study as determined by medical evaluation and at the discretion of the investigator.
* Willingness to remain on/start appropriate, highly effective methods of birth control or other acceptable criteria.
Exclusion Criteria:
* BMI at screening \< 18 or \> 35kg/m2.
* Any prior CAR T exposure.
* Unable or unwilling to remain within proximity (\~2 hours travel time) of the administering investigational site for the first 28 days post study drug administration.
* Received a bone marrow or solid organ transplant at any time or on an active transplant waiting list.
* Received any investigational drug within ≥ 5 half-lives or 4 weeks, whichever is longer, prior to screening.
* Has certain heart conditions that could make it unsafe or unsuitable to take part in the study.
* Requirement for supplemental oxygen at rest (except at night for sleep apnea) or mechanical ventilation.
* Uncontrolled hypertension (\> 160/100 mmHg) or symptomatic hypertension.
* Any central nervous system disease that may impact participants safety in the investigator's opinion.
* Other concurrent autoimmune or autoinflammatory disease. Certain autoimmune/autoinflammatory diseases may be included after discussion with the medical monitor.
* Evidence of clinically significant bleeding or active bleeding conditions within 90 days before screening
* History of malignancy or ongoing treatment for prior malignancy. Certain malignancies may be excepted.
* Known genetic inborn error of immunity and/or primary immunodeficiency.
* Active viral, bacterial, or fungal infection, or any ongoing infection that requires systemic antimicrobial therapy in the 4 weeks prior to screening.
* Seropositive for HIV.
* Active viral hepatitis are excluded.
* Active syphilis, positive for Treponema pallidum antibody.
* Vaccinated with live, attenuated vaccine within 4 weeks prior to apheresis or lymphodepletion.
* Not up-to-date on vaccinations per local/national health authority or institutional guidelines for immune-compromised individuals.
* Known life threatening allergies, hypersensitivity, or intolerance to AZD0120 or its excipients, including dimethyl sulfoxide.
* Contraindications or hypersensitivity to fludarabine and cyclophosphamide.
* Major surgery, or has surgery planned during the study.
* Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 1 year after receiving study treatment (whichever is later).
* Plans to father a child while enrolled in this study or within 1 year after receiving study treatment (whichever is later).
* Any issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to provide informed consent or any condition in the opinion of the investigator, participation would not be in the best interest of the participant.
Other protocol-defined eligibility criteria may apply.
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Inclusion Criteria:
* Capable of giving signed informed consent.
* Adequate physiological function and reserve at screening.
* Able to comply with recommended medication washout period.
* Participants who are suitable for the study as determined by medical evaluation and at the discretion of the investigator.
* Willingness to remain on/start appropriate, highly effective methods of birth control or other acceptable criteria.
* Particpant musy be 18-years-old to ≤ 75-years-old inclusive at the time of signing the informed consent
* Others as described in Clinical Study Protocol
Exclusion Criteria:
* Any prior CAR T exposure.
* Unable or unwilling to remain within proximity (2 hours travel time) of the administering investigational site post discharge for the first 28 days post AZD0120 administration.
* Received a bone marrow or solid organ transplant at any time or on an active transplant waiting list.
* Received any investigational drug within ≥ 5 half-lives or 4 weeks, whichever is longer, prior to screening.
* Has certain cardiac conditions that could make it unsafe or unsuitable to take part in the study.
* Requirement for supplemental oxygen at rest (except at night for sleep apnea) or mechanical ventilation.
* Uncontrolled hypertension (\> 160/100 mmHg) or symptomatic hypertension.
* Any central nervous system disease that may impact participants safety in the investigator's opinion.
* Other concurrent autoimmune or autoinflammatory disease. Certain autoimmune/autoinflammatory diseases may be included after discussion with the medical monitor.
* Evidence of clinically significant bleeding or active bleeding conditions within 90 days before screening
* History of malignancy or ongoing treatment for prior malignancy. Certain malignancies may be excepted.
* Known genetic inborn error of immunity and/or primary immunodeficiency.
* Active viral, bacterial, or fungal infection, or any ongoing infection that requires systemic antimicrobial therapy in the 4 weeks prior to screening.
* Seropositive for HIV or HTLV.
* Active viral hepatitis are excluded.
* Active syphilis, positive for Treponema pallidum antibody.
* Vaccinated with live, attenuated vaccine within 4 weeks prior to apheresis or lymphodepletion.
* Not up-to-date on vaccinations per local/national health authority or institutional guidelines for immune-compromised individuals.
* Known life threatening allergies, hypersensitivity, or intolerance to AZD0120 or its excipients, including dimethyl sulfoxide.
* Contraindications or hypersensitivity to fludarabine and cyclophosphamide.
* \- Major surgery within 8 weeks prior to apheresis or has surgery planned during the study.
* Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 1 year after receiving study treatment (whichever is later).
* Plans to father a child while enrolled in this study or within 1 year after receiving study treatment (whichever is later).
* Any issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to provide informed consent or any condition in the opinion of the investigator, participation would not be in the best interest of the participant.
* Other protocol-defined eligibility criteria may apply.
Inclusion Criteria:
All Parts:
* Participants with plasminogen level (concentration) within normal range at the Screening Visit.
* All females must have a negative pregnancy test at the Screening Visit and on admission to the study site.
* Females of childbearing potential must not be lactating and if heterosexually active must agree to use an approved method of highly effective contraception.
* Females of non-childbearing potential must be confirmed at the Screening Visit.
* Sexually active fertile male participants with partners of childbearing potential must adhere to the study specific contraception methods from the time of first administration of study intervention until 3 months after the study Follow-up Visit.
Parts A and B (Healthy Participants):
* Male and female participants aged 18 to 65 years with suitable veins for cannulation or repeated venipuncture.
* Have a body mass index (BMI) between 18 and 35 kg/m² inclusive.
* For Japanese and Chinese participants (Parts A and B):
1. A Japanese participant is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan.
2. A Chinese participant is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.
Part B (Healthy Participants):
* Participants must have elevated Lp(a) ≥ 30 mg/dL at the Screening Visit.
Part B (Participants with Dyslipidemia):
* Male and female participants aged 18 to 70 years with suitable veins for cannulation or repeated venipuncture.
* Have a BMI \> 18 kg/m².
* Participants must have elevated Lp(a) ≥ 70 mg/dL at the Screening Visit.
* Participants with a fasting LDL-C ≥ 70 mg/dL and \< 190 mg/L at the Screening Visit.
* Participants should be receiving moderate or high-intensity statin therapy for ≥ 2 months prior to the Screening Visit, according to the American College of Cardiology/American Heart Association guidelines on blood cholesterol management.
* Participants with documented coronary artery disease, stroke, or peripheral artery disease or at moderate or high risk for an atherosclerotic cardiovascular disease event.
* There should be no planned medication or dose change during study participation.
Exclusion Criteria:
All Parts:
* History of any clinically important disease or disorder.
* History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
* Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
* Participants with known bleeding or coagulation disorders.
* Participants who have an elevated high-sensitivity C-reactive protein (\> 3 mg/L) or have a prothrombin time/international normalized ratio (PT/INR) or activated partial thromboplastin time (aPTT) \> 1.25 times × upper limit normal (ULN).
* Any clinically important abnormalities in hematology, coagulation, clinical chemistry, urinalysis, abnormal vital signs or abnormal laboratory values.
* Any positive result on Screening for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C virus (HCV) or human immunodeficiency virus (HIV).
* Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead electrocardiogram (ECG) at Screening.
* Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of study intervention.
Parts A and B (Healthy Participants):
* Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, intake of \> 3 × daily recommended levels of vitamins and minerals during the 2 weeks prior to the first administration of study intervention or longer if the medication has a long half-life.
* Current smokers or those who have smoked or used nicotine products.
Part B (Participants with Dyslipidemia):
* Acute ischemic cardiovascular event in the last 12 months prior to randomization.
* Poorly controlled diabetes.
* Previous administration of Lp(a) inhibitor.
* Have uncontrolled hypertension.
* Abnormal vital heart rate.
→
Inclusion Criteria:
All Parts:
* Participants with plasminogen level (concentration) within normal range at the Screening Visit.
* All females must have a negative pregnancy test at the Screening Visit and on admission to the study site.
* Females of childbearing potential must not be lactating and if heterosexually active must agree to use an approved method of highly effective contraception.
* Females of non-childbearing potential must be confirmed at the Screening Visit.
* Sexually active fertile male participants with partners of childbearing potential must adhere to the study specific contraception methods from the time of first administration of study intervention until 3 months after the study Follow-up Visit.
Parts A and B (Healthy Participants):
* Male and female participants aged 18 to 65 years with suitable veins for cannulation or repeated venipuncture.
* Have a body mass index (BMI) between 18 and 35 kg/m² inclusive.
* For Japanese and Chinese participants (Parts A and B):
1. A Japanese participant is defined as having both parents and 4 grandparents who are ethnically Japanese. This includes second and third generation Japanese whose parents or grandparents are living in a country other than Japan.
2. A Chinese participant is defined as having both parents and 4 grandparents who are ethnically Chinese. This includes second and third generation Chinese whose parents or grandparents are living in a country other than China.
Part B (Healthy Participants):
* Participants must have elevated Lp(a) ≥ 30 mg/dL (62 nmol/L) at the Screening Visit.
Part B (Participants with Dyslipidemia):
* Male and female participants aged 18 to 70 years with suitable veins for cannulation or repeated venipuncture.
* Have a BMI \> 18 kg/m².
* Participants must have elevated Lp(a) ≥ 70 mg/dL (150 nmol/L) at the Screening Visit.
* Participants with a fasting LDL-C ≥ 70 mg/dL and \< 190 mg/L at the Screening Visit.
* Participants should be receiving moderate or high-intensity statin therapy for ≥ 2 months prior to the Screening Visit, according to the American College of Cardiology/American Heart Association guidelines on blood cholesterol management.
* Participants with documented coronary artery disease, stroke, or peripheral artery disease or at moderate or high risk for an atherosclerotic cardiovascular disease event.
* There should be no planned medication or dose change during study participation.
Exclusion Criteria:
All Parts:
* History of any clinically important disease or disorder.
* History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
* Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study intervention.
* Participants with known bleeding or coagulation disorders.
* Participants who have an elevated high-sensitivity C-reactive protein (\> 3 mg/L) or have a prothrombin time/international normalized ratio (PT/INR) or activated partial thromboplastin time (aPTT) \> 1.25 times × upper limit normal (ULN).
* Any clinically important abnormalities in hematology, coagulation, clinical chemistry, urinalysis, abnormal vital signs or abnormal laboratory values.
* Any positive result on Screening for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C virus (HCV) or human immunodeficiency virus (HIV).
* Any clinically important abnormalities in rhythm, conduction, or morphology of the resting 12-lead electrocardiogram (ECG) at Screening.
* Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks prior to the first administration of study intervention.
Parts A and B (Healthy Participants):
* Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, intake of \> 3 × daily recommended levels of vitamins and minerals during the 2 weeks prior to the first administration of study intervention or longer if the medication has a long half-life.
* Current smokers or those who have smoked or used nicotine products.
Part B (Participants with Dyslipidemia):
* Acute ischemic cardiovascular event in the last 12 months prior to randomization.
* Poorly controlled diabetes.
* Previous administration of Lp(a) inhibitor.
* Have uncontrolled hypertension.
* Abnormal vital heart rate.
Inclusion criteria:
* Patients must be ≥18 years of age (≥20 years of age in Japan). All genders are permitted.
* Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity and permitted in the osimertinib national label (such as either exon 19 deletion and/or L858R) which is not amenable to curative therapy.
* Documented radiologic disease progression on 1L osimertinib.
* MET amplification and/or overexpression (FISH10+ and/or IHC90+) as determined by FISH (central) and IHC (central) testing on tumour sample collected following progression on 1L osimertinib treatment.
* Available tumour sample for central MET FISH and IHC analysis or willingness to collect additional sample for central testing which fulfils the following requirements:
Obtained following progression on previous osimertinib therapy;
obtained within 2 years of submission for MET analysis;
sufficient tissue to meet the minimum tissue requirement defined in the current Laboratory Manual.
* At least 1 lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or MRI which is suitable for accurate repeated measurements. If only 1 measurable lesion exists, it is acceptable to be used as long as baseline tumour assessment scans are done at least 14 days after the screening tumour sample collection is performed.
* Prior lines of therapy in locally advanced/metastatic setting: Only prior 1L osimertinib treatment in metastatic setting is permitted.
* Adequate haematological function defined as:
* Absolute neutrophil count ≥1500/μL
* Haemoglobin ≥9 g/dL (no transfusion in the past 2 weeks)
* Platelets ≥100,000/μL (no transfusion in the past 10 days)
* Adequate liver function
* ALT, AST ≤2.5 x ULN with TBL ≤ ULN OR
* TBL \>ULN to ≤1.5x ULN with ALT and AST ≤ ULN
* Adequate renal function - defined as a serum creatinine \<1.5 times the institutional ULN OR a glomerular filtration rate ≥50 mL/min. Confirmation of creatinine clearance is only required when creatinine is only required when creatinine is \>1.5 times ULN.
* Adequate coagulation parameters: INR \<1.5 and activated partial thromboplastin time \<1.5 x ULN unless patients are receiving therapeutic anti coagulation which affects these parameters.
* Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for ≥2 weeks. The use of direct oral anticoagulants such as apixaban/rivaroxaban will be accepted as treatment for cancer related thromboembolism treatment. The use of warfarin for oral anticoagulation is not recommended.
* ECOG/WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
* Females must be using highly effective contraceptive measures, should not be breast feeding and must have a negative pregnancy test if of childbearing potential, or must have evidence of non-childbearing potential.
* Males with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study drug.
Exclusion Criteria:
* Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum therapy related neuropathy.
* As judged by the investigator, active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥2, malabsorption syndrome or previous significant bowel resection).
* Any of the following cardiac diseases currently or within the last 6 months:
Unstable angina pectoris
Congestive heart failure (New York Heart Association \[NYHA\] ≥Grade 2)
Acute myocardial infarction
Stroke or transient ischemic attack
Uncontrolled hypertension (blood pressure \[BP\] ≥150/95 mmHg despite medical therapy).
Mean resting correct QT interval (QTcF) \>470 msec for women and \>450 msec for men at Screening, obtained from 3 ECGs using the screening clinic ECG machine derived QTcF value.
Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events such as heart failure, chronic hypokalaemia not correctable with supplements, congenital or familial long QT syndrome, family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs, eg, complete left bundle branch block, third degree heart block, second degree heart block, P-R interval \>250 msec.
Acute coronary syndrome
* Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy.
* Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days
* Evidence of severe or uncontrolled systemic diseases, including renal transplant, active bleeding diatheses or uncontrolled hypertension, which in the investigator's opinion makes it undesirable for the patient to participate
* Active hepatitis B or C or known serious active infection e.g. tuberculosis or human immunodeficiency virus. Viral testing is not required for assessment of eligibility for the study.
* Known serious active infection including, but not limited to, tuberculosis, or human immunodeficiency virus (positive human immunodeficiency virus 1/2 antibodies).
* Presence of other active cancers, or history of treatment for invasive cancer, within the last 5 years. Patients with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.
* Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study treatment.
* Past medical history of interstitial lung disease(ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
* History of liver cirrhosis of any origin and clinical stage; or history of other serious liver disease or chronic disease with relevant liver involvement, with or without normal LFTs,
* Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib
* Prior or current treatment with savolitinib or another MET inhibitor (eg, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib).
* Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days prior to the first dose of study treatment with the exception of monotherapy osimertinib which may continue uninterrupted during screening.
* Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4, strong inhibitors of CYP1A2 within 3 weeks of the first dose of study treatment (including St John's Wort).
* Participation in another clinical study with a cytotoxic, investigational product (IP), or other anticancer drug for the treatment of advanced NSCLC if received IP from that study within 14 days of the first dose of study treatment.
* Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class.
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Inclusion criteria:
* Participants must be ≥18 years of age (≥20 years of age in Japan). All genders are permitted.
* Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity and permitted in the osimertinib national label (such as either exon 19 deletion and/or L858R) which is not amenable to curative therapy.
* Documented radiologic disease progression on first-line (1L) osimertinib.
* MET amplification and/or overexpression (FISH10+ and/or IHC90+) as determined by FISH (central) and IHC (central) testing on tumour sample collected following progression on 1L osimertinib treatment.
* Available tumour sample for central MET FISH and IHC analysis or willingness to collect additional sample for central testing which fulfils the following requirements:
Obtained following progression on previous osimertinib therapy;
obtained within 2 years of submission for MET analysis;
sufficient tissue to meet the minimum tissue requirement defined in the current Laboratory Manual.
* At least 1 lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements. If only 1 measurable lesion exists, it is acceptable to be used as long as baseline tumour assessment scans are done at least 14 days after the screening tumour sample collection is performed.
* Prior lines of therapy in locally advanced/metastatic setting: Only prior 1L osimertinib treatment in metastatic setting is permitted.
* Adequate haematological function defined as:
* Absolute neutrophil count ≥1500/μL
* Haemoglobin ≥9 g/dL (no transfusion in the past 2 weeks)
* Platelets ≥100,000/μL (no transfusion in the past 10 days)
* Adequate liver function
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN) with total bilirubin (TBL) ≤ ULN OR
* TBL \> ULN to ≤1.5x ULN with ALT and AST ≤ ULN
* Adequate renal function - defined as a serum creatinine \<1.5 times the institutional ULN OR a glomerular filtration rate ≥50 mL/min. Confirmation of creatinine clearance is only required when creatinine is only required when creatinine is \>1.5 times ULN.
* Adequate coagulation parameters: INR \<1.5 and activated partial thromboplastin time \<1.5 x ULN unless participants are receiving therapeutic anti coagulation which affects these parameters.
* Participants with known tumour thrombus or deep vein thrombosis are eligible if clinically stable on low molecular weight heparin for ≥2 weeks. The use of direct oral anticoagulants such as apixaban/rivaroxaban will be accepted as treatment for cancer related thromboembolism treatment. The use of warfarin for oral anticoagulation is not recommended.
* Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
* Females must be using highly effective contraceptive measures, should not be breast feeding and must have a negative pregnancy test if of childbearing potential, or must have evidence of non-childbearing potential.
* Males with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study drug.
Exclusion Criteria:
* Unresolved toxicities from any prior therapy greater than common terminology criteria for adverse events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2 prior platinum therapy related neuropathy.
* As judged by the investigator, active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥2, malabsorption syndrome or previous significant bowel resection).
* Any of the following cardiac diseases currently or within the last 6 months:
Unstable angina pectoris
Congestive heart failure (New York Heart Association \[NYHA\] ≥Grade 2)
Acute myocardial infarction
Stroke or transient ischemic attack
Uncontrolled hypertension (blood pressure \[BP\] ≥150/95 mmHg despite medical therapy).
Mean resting correct QT interval (QTcF) \>470 msec for women and \>450 msec for men at Screening, obtained from 3 ECGs using the screening clinic ECG machine derived QTcF value.
Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events such as heart failure, chronic hypokalaemia not correctable with supplements, congenital or familial long QT syndrome, family history of unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval and cause Torsade de Pointes.
Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs, eg, complete left bundle branch block, third degree heart block, second degree heart block, P-R interval \>250 msec.
Acute coronary syndrome
* Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy.
* Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days
* Evidence of severe or uncontrolled systemic diseases, including renal transplant, active bleeding diatheses or uncontrolled hypertension, which in the investigator's opinion makes it undesirable for the participant to participate
* Active hepatitis B or C or known serious active infection e.g. tuberculosis or human immunodeficiency virus. Viral testing is not required for assessment of eligibility for the study.
* Known serious active infection including, but not limited to, tuberculosis, or human immunodeficiency virus (positive human immunodeficiency virus 1/2 antibodies).
* Presence of other active cancers, or history of treatment for invasive cancer, within the last 5 years. Participants with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All participants with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are participants with history of non-melanoma skin cancer.
* Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study treatment.
* Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
* History of liver cirrhosis of any origin and clinical stage; or history of other serious liver disease or chronic disease with relevant liver involvement, with or without normal liver function tests (LFTs),
* Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib
* Prior or current treatment with savolitinib or another MET inhibitor (eg, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib).
* Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days prior to the first dose of study treatment with the exception of monotherapy osimertinib which may continue uninterrupted during screening.
* Participants currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be strong inducers of CYP3A4, strong inhibitors of CYP1A2 within 3 weeks of the first dose of study treatment (including St John's Wort).
* Participation in another clinical study with a cytotoxic, investigational product (IP), or other anticancer drug for the treatment of advanced NSCLC if received IP from that study within 14 days of the first dose of study treatment.
* Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class.
Key Inclusion Criteria:
* Eligible patients must be adults (≥18 years)
* Documented histologically confirmed diagnosis of B-cell non-Hodgkin lymphoma (B-NHL) as per World Health Organization (WHO) 2022 classification. In the dose escalation phase, any B-NHL subtype is allowed (excluding some subtypes), while the backfill phase restricts inclusion to defined subtypes: large B-cell lymphomas (as defined as Diffuse large B-cell lymphoma (DLBCL), Grade 3b Follicular lymphoma (FL), high-grade B-cell lymphoma (HGBCL) NOS, DLBCL/HGBCL with MYC and BCL2 rearrangements, primary mediastinal Large B-cell lymphoma, T-cell/histiocyte-rich LBCL, and transformed indolent lymphoma) and mantle cell lymphoma.
* Patients must have relapsed or refractory disease after at least two prior lines of systemic therapy and lack additional standard options with established benefit:
A)LBCL patients must have progressed after both anti-CD20 and at least one systemic chemotherapy regimen, and have considered-or be ineligible for-CAR-T, T cell engager, and stem cell transplant modalities.
B) Mantle cell lymphoma (MCL) patients must have had anti-CD20 and Bruton's Tyrosine Kinase (BTK) inhibitor.
Additional criteria include measurable disease by Lugano 2014, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and adequate organ and bone marrow function (as specified by blood counts, cardiac ejection fraction, renal and hepatic parameters, and coagulation indices).
Key Exclusion criteria
* Patients are excluded if they have a diagnosis of post-transplant lymphoproliferative disease, Richter's transformation, Burkitt's lymphoma, or chronic lymphocytic leukemia (CLL)/ Small lymphocytic lymphoma (SLL), Waldenstrom Macroglobulinemia/ Lymphoplasmacytic Lymphoma, or if they have active Central nervous system (CNS) involvement from their B-NHL. Exclusion also applies to those who have received Chimeric antigen receptor-T (CAR-T) or T cell engager therapies within 90 days prior to Cycle 1 Day 1 (C1D1), any investigational drug or other systemic anticancer therapies (except low-dose corticosteroids) within 21 days or 5 half-lives, and curative radiation within 14 days (localized palliative radiotherapy is allowed).
* Other exclusions include allogeneic Hematopoietic stem cell transplantation (HSCT) within 180 days (unless stable without active (graft-versus-host disease) GVHD for ≥2 months), autologous HSCT within 90 days (unless resolved toxicities), major surgery within 28 days, use of strong CYP3A inhibitors within 14 days or 5 half-lives before the dosing date, use of QTc-prolonging agents within 5 half-lives before the dosing date, or other malignancies within two years. Patients with unresolved ≥ Grade 2 AEs from prior therapy (except specified tolerable conditions), serious uncontrolled medical conditions, active infection within 14 days, or history/suspicion of significant interstitial lung disease/pneumonitis are also excluded.
* Females who are pregnant or breastfeeding are not eligible.
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Core Inclusion Criteria
* Eligible patients must be adults (≥18 years)
* Additional criteria include measurable disease by Lugano 2014, ECOG performance status ≤2, and adequate organ and bone marrow function (as specified by blood counts, cardiac ejection fraction, renal and hepatic parameters, and coagulation indices).
Module 1 Monotherapy Inclusion criteria
* Documented histologically confirmed diagnosis of B-cell non-Hodgkin lymphoma (B-NHL) as per World Health Organization (WHO) 2022 classification. In the dose escalation phase, any B-NHL subtype is allowed (excluding some subtypes), while the backfill phase restricts inclusion to defined subtypes: large B-cell lymphomas (as defined as Diffuse large B-cell lymphoma (DLBCL), Grade 3b Follicular lymphoma (FL), high-grade B-cell lymphoma (HGBCL) NOS, DLBCL/HGBCL with MYC and BCL2 rearrangements, primary mediastinal Large B-cell lymphoma, T-cell/histiocyte-rich LBCL, and transformed indolent lymphoma) and mantle cell lymphoma.
* Patients with LBCL must have relapsed or refractory disease after at least two prior lines of systemic therapy and lack additional standard options with established benefit. Additionally patients must have progressed after both anti CD20 and at least one systemic chemotherapy regimen, and have considered-or be ineligible for-CAR-T, T cell engager, and stem cell transplant modalities Participants with MCL must have previously received an anti-CD20 based therapy, and BTKi
Module 2 Surovatamig Combination Inclusion criteria
* Documented histologically confirmed diagnosis of LBCL as defined as: DLBCL ( not otherwise specified), Grade 3b FL, DLBCL/high grade B-cell lymphoma with MYC and BCL2 rearrangements, High grade B-cell lymphoma (not other specified), Primary mediastinal LBCL, T-cell/histiocyte-rich LBCL, Transformations of indolent B-cell lymphoma.
* Participants who have received previous CD19-directed therapy must have locally assessed confirmation (after completion of the CD19-directed therapy) to demonstrate presence of CD19 expression by immunohistochemistry or flow cytometry.
* Patients must have relapsed or refractory disease after at least two prior lines of systemic therapy and lack additional standard options with established benefit. Additionally patients must have progressed after both anti-CD20 and at least one systemic chemotherapy regimen, and have considered-or be ineligible for-CAR-T, T cell engager, and stem cell transplant modalities
Core Exclusion Criteria
* Active CNS involvement from their B-NHL. Exclusion also applies to those who have received CAR-T , within 6 months or T cell engager therapies within 90 days prior to C1D1, any investigational drug or other systemic anticancer therapies (except low-dose corticosteroids, ≤10mg prednisone/day) within 21 days or 5 half-lives, and curative radiation within 14 days (localized palliative radiotherapy is allowed).
* Other exclusions include: allogeneic HSCT within 180 days (unless stable without active GVHD for ≥2 months), autologous HSCT within 90 days (unless resolved toxicities), major surgery within 28 days, use of strong CYP3A inhibitors within 14 days or 5 half-lives before the dosing date, use of QTc-prolonging agents within 5 half-lives before the dosing date, or other malignancies within two years. Patients with unresolved ≥ Grade 2 AEs from prior therapy (except specified tolerable conditions), serious uncontrolled medical conditions, active infection within 14 days, or history/suspicion of significant ILD/pneumonitis are also excluded.
* Females who are pregnant or breastfeeding are not eligible.
* Previous dosing with AZD4512
Module 1 Exclusion Criteria Patients are excluded if they have a diagnosis of post transplant lymphoproliferative disease, Richter's transformation, Burkitt's lymphoma, CLL/SLL, Waldenstrom Macroglobulinemia/ Lymphoplasmacytic Lymphoma
Module 2 Exclusion Criteria
Participants will be excluded if they have:
* Clinically significant central nervous system (CNS) pathologies, including neurological, neurodegenerative, psychiatric, or other severe mental health conditions.
* Active or prior CNS involvement related to autoimmune disease.
* Leukemic presentation of non-Hodgkin lymphoma (NHL), with circulating malignant lymphoid cells in peripheral blood.
* A history of hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). • Prior Grade ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) following CAR T-cell or T-cell engager (TCE) therapy, or any unresolved CRS/ICANS.
* Prior exposure to surovatamig.
* Diagnosis of Richter's transformation