Inclusion Criteria:
STEP 1 REGISTRATION
* Aged \>= 18 years
* Histologically confirmed diagnosis of WHO grade 1-3 meningioma
* Presence of measurable contrast-enhancing disease on gadolinium-enhanced MRI brain scan defined as at least one lesion with two perpendicular diameters measuring ≥10 mm on two or more axial slices (≤ 5 mm interslice thickness, ≤ 1 mm interslice gap) per current RANO meningioma criteria
* Progression of disease determined by local radiology review per current RANO meningioma criteria, defined as
* ≥ 15% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 6 months, or
* ≥ 25% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 12 months, or
* Development of a new measurable lesion
* The following scans must be available for submission for central radiology review:
* Pre-progression gadolinium-enhanced MRI brain scan
* Progression gadolinium-enhanced MRI brain scan
STEP 2 REGISTRATION
* Progression of disease determined by central radiology review per current RANO meningioma criteria, defined as
* ≥ 15% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 6 months, or
* ≥ 25% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 12 months, or
* Development of a new measurable lesion.
* \[68Ga\]Ga-DOTATATE uptake on PET-CT. Positive uptake is defined as uptake at least as high as liver, based on the uptake in at least one target lesion.
* If randomized to the control (standard of care) arm, both the patient and investigator must agree NOT to receive SSTR2-targeted therapy, surgical resection, or radiation therapy.
* Patients must be willing and able to undergo regular MRI scans of the brain and \[68Ga\]Ga-DOTATATE PET-CT imaging during the study.
* Patients must have recovered to CTCAE grade ≤1 or pretreatment baseline from clinically significant adverse events related to prior therapy (exclusions include alopecia, lymphopenia, sensory neuropathy ≤ grade 2, or other ≤ grade 2 not constituting a safety risk based on the investigator's judgment).
* Adequate organ and bone marrow function as defined below (within 28 days prior to step 2 registration):
* Absolute neutrophil count (ANC) ≥ 1500/mm3
* Platelet count ≥ 75,000/mm3
* Hemoglobin ≥ 8 g/dL
* Creatinine clearance (calculated by the Cockroft-Gault method) ≥40mL/min
* Total serum bilirubin ≤ 3 x ULN (except participants with Gilbert's Syndrome, who can have a total bilirubin ≤ 5 x ULN)
* Potassium within normal limits.
Exclusion Criteria:
* Patients with a clinical diagnosis of NF2-related schwannomatosis or with a known molecular diagnosis of NF2-related schwannomatosis.
* Patients with radiation-associated meningiomas.
* Patients with known intraspinal meningiomas or meningioma metastases outside the skull/spinal column.
* Prior SSTR2-targeted therapy, e.g. Somatostatin LAR or short-acting Octreotide.
* Unstable neurological symptoms requiring steroids to control symptoms at a dose of \>2 mg of dexamethasone (or equivalent) daily within 28 days prior to step 2 registration.
* Patients requiring immediate local therapy (e.g. surgical resection).
* Surgical procedure within the timeframes listed below, prior to step 2 registration.
* 28 days from any prior craniotomy
* 7 days from stereotactic biopsy Note: There is no limit to the number of prior surgical interventions
* Treatment within the timeframes specified below, prior to step 2 registration.
* 28 days (or 5 half-lives, whichever is longer) for cytotoxic chemotherapy, biologic agent, investigational agent or any other systemic agent prescribed for the purpose of treating meningioma
* 6 weeks from nitrosoureas Note: There is no limit to the number of prior systemically administered therapeutic agents.
* Prior external beam radiation, interstitial brachytherapy or stereotactic radiosurgery cumulative radiation dose of \> 70 Gy or the last dose of radiotherapy \< 24 weeks (6 months) prior to step 2 registration
* Peptide receptor radionuclide therapy at any time prior to registration.
* Known hypersensitivity to somatostatin analogues or any component of the \[68Ga\]Ga- DOTATATE or \[177Lu\]Lu-DOTATATE formulations.
* Active infection requiring current use of intravenous therapy with antibiotics.
* Active cardiovascular disease: cerebral vascular accident/stroke (≤ 6 months prior to registration), myocardial infarction (≤ 6 months prior to registration), congestive heart failure (≥ NYHA class II), unstable angina pectoris, or serious cardiac arrhythmia requiring medication.
* An active malignancy ≤ 3 years. Note: Patients with a malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Pregnant and/or breastfeeding patients who are unwilling to discontinue breast feeding.
* Participants of childbearing potential must have a negative pregnancy test within 14 days of study entry.
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Inclusion Criteria:
STEP 1 REGISTRATION
* Aged \>= 18 years
* Histologically confirmed diagnosis of WHO grade 1-3 meningioma
* Disease progression following at least one prior surgical intervention (biopsy or resection) and at least one prior course of radiation.
* The patient is not considered a candidate for additional surgery and/or radiation or the patient has declined additional surgery and/or radiation.
* Presence of measurable contrast-enhancing disease on gadolinium-enhanced MRI brain scan defined as at least one lesion with two perpendicular diameters measuring ≥10 mm on two or more axial slices (≤ 5 mm interslice thickness, ≤ 1 mm interslice gap) per current RANO meningioma criteria
* Progression of disease determined by local radiology review per current RANO meningioma criteria, defined as:
* ≥ 15% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 6 months (196 days), or
* ≥ 25% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 12 months (379 days), or
* Development of a new measurable lesion
* The following scans must be available for submission for central radiology review:
* Pre-progression gadolinium-enhanced MRI brain scan no older than 12 months (379 days) that serves as a reference for evaluation of radiographic disease progression
* Progression gadolinium-enhanced MRI brain scan
STEP 2 REGISTRATION
* Progression of disease determined by central radiology review per current RANO meningioma criteria, defined as:
* ≥ 15% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 6 months (196 days), or
* ≥ 25% increase in sum of product of perpendicular measurements of up to 5 measurable target lesions within the last 12 months (379 days), or
* Development of a new measurable lesion.
* \[68Ga\]Ga-DOTATATE uptake on PET-CT. Positive uptake is defined as uptake at least as high as liver, based on the uptake in at least one target lesion.
* Both the patient and investigator must agree that the patient will NOT receive SSTR2-targeted therapy, surgical resection, or radiation therapy until progression of disease while on study treatment.
* Patients must be willing and able to undergo regular MRI scans of the brain and \[68Ga\]Ga-DOTATATE PET-CT imaging during the study.
* Patients must have recovered to CTCAE grade ≤1 or pretreatment baseline from clinically significant adverse events related to prior therapy (exclusions include alopecia, lymphopenia, sensory neuropathy ≤ grade 2, or other ≤ grade 2 not constituting a safety risk based on the investigator's judgment).
* Adequate organ and bone marrow function as defined below (within 28 days prior to step 2 registration):
* Absolute neutrophil count (ANC) ≥ 1500/mm3
* Platelet count ≥ 75,000/mm3
* Hemoglobin ≥ 8 g/dL
* Creatinine clearance (calculated by the Cockroft-Gault method) ≥40mL/min
* AST (SGOT) and ALT (SGPT) ≤ 3 x the laboratory upper limit of normal (ULN)
* Total serum bilirubin ≤ 3 x ULN (except participants with Gilbert's Syndrome, who can have a total bilirubin ≤ 5 x ULN)
* Potassium within normal limits.
Exclusion Criteria:
* Patients with a clinical diagnosis of NF2-related schwannomatosis or with a known molecular diagnosis of NF2-related schwannomatosis.
* Patients with radiation-associated meningiomas.
* Patients with known intraspinal meningiomas or meningioma metastases outside the skull/spinal column. Meningiomas invading the skull base or orbits are not excluded.
* Prior SSTR2-targeted therapy, e.g. Somatostatin LAR or short-acting Octreotide. No limit on number of prior non-SSTR2-tartgeted systemic therapies.
* Unstable neurological symptoms requiring steroids to control symptoms at a dose of \>2 mg of dexamethasone (or equivalent) daily within 28 days prior to step 2 registration.
* Patients requiring immediate local therapy (e.g. surgical resection).
* Surgical procedure within the timeframes listed below, prior to step 2 registration.
* 28 days from any prior craniotomy
* 7 days from stereotactic biopsy Note: There is no limit to the number of prior surgical interventions
* Treatment within the timeframes specified below, prior to step 2 registration.
* 28 days (or 5 half-lives, whichever is longer) for cytotoxic chemotherapy, biologic agent, investigational agent or any other systemic agent prescribed for the purpose of treating meningioma
* 6 weeks from nitrosoureas Note: There is no limit to the number of prior systemically administered therapeutic agents.
* A target lesion is excluded if it has received any of the following:
* More than 2 total prior courses of radiation
* More than 1 prior course of standard fractionated external beam radiation therapy (EBRT)
* Radiation treatment to the target lesion completed \<24 weeks (168 days) before Step 2 registration.
For purposes of this criterion, one course of EBRT counts as one course regardless of duration, and each course of stereotactic radiation (1-5 fractions) counts as one course. Accordingly, a target lesion may have received at most one prior course of EBRT plus one prior course of stereotactic radiation, or two prior courses of stereotactic radiation. Prior radiation history must be evaluated on a lesion-by-lesion basis, including radiation delivered before any subsequent surgical resection.
* All types of radioligand therapy at any time prior to registration. Radioligands received for diagnostic purposes are not exclusionary.
* Known hypersensitivity to somatostatin analogues or any component of the \[68Ga\]Ga- DOTATATE or \[177Lu\]Lu-DOTATATE formulations.
* Active infection requiring current use of intravenous therapy with antibiotics.
* Active cardiovascular disease: cerebral vascular accident/stroke (≤ 6 months prior to registration), myocardial infarction (≤ 6 months prior to registration), congestive heart failure (≥ NYHA class II), unstable angina pectoris, or serious cardiac arrhythmia requiring medication.
* An active malignancy ≤ 3 years. Note: Patients with a malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Pregnant and/or breastfeeding patients who are unwilling to discontinue breast feeding.
* Participants of childbearing potential must have a negative pregnancy test within 14 days of study entry.
Small Cell Lung Carcinoma,Large Cell Neuroendocrine Carcinoma of the Lung,Neuroendocrine Prostate Cancer,Gastroenteropancreatic Neuroendocrine Carcinoma
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Small Cell Lung Carcinoma,Large Cell Neuroendocrine Carcinoma of the Lung,Neuroendocrine Prostate Cancer,Gastroenteropancreatic Neuroendocrine Carcinoma,Non-prostate Extrapulmonary Neuroendocrine Carcinoma,Cervical Neuroendocrine Carcinoma,Thymic Neuroendocrine Carcinoma,Genitourinary Neuroendocrine Carcinoma,Unknown Primary Neuroendocrine Carcinomas,Merkel Cell Carcinoma,Medullary Thyroid Carcinoma
Inclusion Criteria:
* Age ≥ 18 years old
* Patients with one of the following indications:
* Locally advanced, unresectable, or metastatic SCLC with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy, unless patient was ineligible to receive such therapy. Prior DLL3-targeted therapy is allowed. For dose expansion, patients should have received no more than 2 prior lines of systemic therapy.
* Dose escalation only: LCNEC of the lung with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy, unless patient was ineligible to receive such therapy.
* Dose expansion only: Locally advanced, unresectable, or metastatic de novo or castration-resistant, treatment-emergent NEPC with neuroendocrine differentiation confirmed by local histology and NEPC marker expression (e.g., chromogranin, synaptophysin) confirmed by local IHC. Prior PSMA-targeted, Lu-177-based RLT is allowed. Patients must have at least one measurable lesion (per RECIST 1.1) that shows 111In-ETN029 uptake higher than surrounding tissues on SPECT/CT as assessed by the Investigator.
* Dose expansion only: Locally advanced, unresectable, or metastatic GEP-NEC with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy, unless patient was ineligible to receive such therapy. Patients must have at least one measurable lesion (per RECIST 1.1) that shows 111In-ETN029 uptake higher than surrounding tissues on SPECT/CT as assessed by the Investigator.
Exclusion Criteria:
* Absolute neutrophil count (ANC) \< 1.0 x 109/L, hemoglobin \< 9 g/dL, or platelet count \< 75 x 109/L
* QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec
* eGFR \< 60 mL/min (\<0.835 mL/s), calculated using the CKD-EPI 2021 formula or measured
* Unmanageable urinary tract obstruction or urinary incontinence
* Presence of leptomeningeal disease, of symptomatic CNS metastases or of CNS metastases that require local CNS-directed therapy
* History of or current interstitial lung disease or pneumonitis ≥ Grade 2
* Any prior DLL3-targeted therapy (except for SCLC) and any prior RLT (except for NEPC)
Other protocol-defined inclusion/exclusion criteria may apply.
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Inclusion Criteria:
* Age ≥ 18 years old
* Patients with one of the following indications:
Dose Escalation Only:
* Locally advanced, unresectable, or metastatic SCLC with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy (prior DLL3-targeted therapy allowed).
* LCNEC of the lung with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy.
* Metastatic de novo or treatment-emergent neuroendocrine prostate cancer (NEPC) confirmed by local histopathology, for whom no standard therapy is available, tolerated, or appropriate, in the investigator's judgment. Prior RLT is not allowed, though exceptions can be made following discussion with Novartis Medical Monitor.
* Locally advanced, unresectable, or metastatic GEP-NEC, cervical NEC, genitourinary NEC, thymic NEC, Merkel cell carcinoma, or unknown primary NEC with disease progression following, or intolerance to, at least one line of systemic therapy (including platinum-containing chemotherapy for non-MCC indications, or PD-1 or PD-L1 inhibition for MCC, unless patient was ineligible to receive such therapy), and for whom no standard therapy is available, tolerated, or appropriate, in the investigator's judgment.
* Locally advanced, unresectable, or metastatic medullary thyroid cancer with disease progression following, or intolerance to, at least 1 line of systemic therapy (unless patient was ineligible to receive such therapy), and for whom no standard therapy is available, tolerated, or appropriate, in the investigator's judgment.
Dose expansion only:
* Locally advanced, unresectable, or metastatic SCLC with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum-containing chemotherapy (prior DLL3-targeted therapy allowed). Patients should have received no more than 2 prior lines of systemic therapy.
* Locally advanced, unresectable, or metastatic GEP-NEC, with disease progression following, or intolerance to, at least 1 line of systemic therapy, including platinum containing chemotherapy. Patients must have at least one measurable lesion (per RECIST 1.1) that shows 111In-ETN029 uptake higher than surrounding tissues on SPECT/CT as assessed by the Investigator.
* Locally advanced, unresectable, or metastatic de novo or castration-resistant, treatment emergent NEPC with neuroendocrine differentiation confirmed by local histology and NEPC marker expression (e.g., chromogranin, synaptophysin) confirmed by local IHC. Prior PSMA-targeted, Lu-177-based RLT is allowed. Patients must have at least one measurable lesion (per RECIST 1.1) that shows 111In-ETN029 uptake higher than surrounding tissues on SPECT/CT as assessed by the Investigator.
Exclusion Criteria:
* Absolute neutrophil count (ANC) \< 1.0 x 10\^9/L, hemoglobin \< 9 g/dL, or platelet count \< 75 x 10\^9/L
* QT interval corrected by Fridericia's formula (QTcF) ≥ 470 msec
* eGFR \< 60 mL/min/1.73m2 calculated using the CKD-EPI 2021 formula or measured
* Unmanageable urinary tract obstruction or urinary incontinence
* Presence of leptomeningeal disease, of symptomatic CNS metastases or of CNS metastases that require local CNS-directed therapy
* History of or current interstitial lung disease or pneumonitis ≥ Grade 2
* Any prior DLL3-targeted therapy (except for SCLC)
* Any prior RLT (except for NEPC patients in expansion)
Other protocol-defined inclusion/exclusion criteria may apply.
Inclusion Criteria:
Participant eligible for inclusion in this study must meet all the following criteria:
At Screening:
1. Signed informed consent must be obtained prior to participation in the study.
2. Males and females, ≥18 years of age at the time of providing written informed consent.
3. Ability to understand study's requirements and provide informed consent and comply with all required study procedures.
4. Hospitalization for a ACS event (STEMI or NSTEMI).
5. Receiving treatment for the qualifying ACS event, according to clinical judgement, by means of medical treatment alone or percutaneous coronary revascularization.
6. Had a successful PCI (with or without stent) for the qualifying event if a PCI was required.
7. LDL-C value at the Screening visit measured by the local lab of:
* LDL-C ≥70 mg/dL in participant previously treated with high-intensity statin (atorvastatin ≥40 mg/day or rosuvastatin ≥20 mg/day) or equivalent as per national guidelines and local regulation for at least 4 weeks before screening or
* LDL-C ≥100 mg/dL in participant previously treated with low/moderate-intensity statin for at least 4 weeks before screening or
* LDL-C ≥125 mg/dL in participant previously not treated with statins for at least 4 weeks before screening, or who never received statins (including statin intolerant participants).
At Randomization:
8. The participant must have a Baseline fasting LDL-C ≥70 mg/dL (local lab assessment) to be eligible for randomization.
9. Randomization within 7 days (≤ 7 days) following hospital admission for the qualifying ACS event and before/at discharge.
Exclusion Criteria:
Participant meeting any of the following criteria is not eligible for inclusion in this study.
Only for Japan: For exclusion criteria 6, investigator judgment should be documented in the source data document.
1. Participant who is clinically unstable during hospitalization for the qualifying ACS event, defined by any of the following events within 24 hours prior to randomization:
* Hemodynamic instability: hypotension, defined as sustained systolic blood pressure of \<90 mmHg due to cardiac failure with associated symptoms requiring inotropes
* Arrhythmic events: Ventricular storm (e.g., torsade, ventricular tachycardia, ventricular flutter)
* Cardiogenic shock or mechanical complication of myocardial infarction
* New York Heart Association (NYHA) class IV heart failure
* Left ventricular ejection fraction \<20% at randomization (after all treatment procedures, based on the latest assessment of the LVEF using invasive or non-invasive assessment modalities)
* Uncontrolled severe hypertension: systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg prior to randomization despite antihypertensive therapy.
2. Participant who has undergone or is scheduled to undergo CABG for treatment of the qualifying ACS event.
3. Active liver disease defined as: (i) any known current infectious, neoplastic, or metabolic pathology of the liver or (ii) alanine aminotransferase (ALT) elevation \>3x ULN or aspartate aminotransferase (AST) elevation \>3x ULN, or total bilirubin elevation \>2x ULN (except participant with Gilbert's syndrome) at the Screening visit, in the context of an ACS, and assessed as related to the index event and/or treatment procedures (such as PCI). Eligibility will be based on Investigator's judgement for participant who will be randomized.
4. Renal insufficiency (eGFR \<30 mL/min/1.73m2) at the Screening visit.
5. Fasting triglycerides value \>400 mg/dL (4.52 mmol/L; assessed by local labs) at randomization visit.
6. Participant, who based on the Investigator's judgement, could reach the LDL-C target value of \<55 mg/dL after 4 weeks on statin treatment only.
7. Secondary hypercholesterolemia (based on medical history).
8. Homozygous familial hypercholesterolemia (based on medical history).
9. Participant on apheresis at the Screening visit.
10. Ongoing or medical history of myopathy at the Screening visit.
11. CK values ≥5x ULN at Screening visit and confirmed by repeat test during Screening (local lab) , in the context of an ACS, and assessed as related to the index event and/or treatment procedures (such as PCI) eligibility will be based on Investigator's judgement for participant who will be randomized (who will be switched to or initiated on the protocol-specified dose of high-intensity statin of atorvastatin ≥40 mg QD or rosuvastatin ≥20 mg QD). Unless a more stringent CK value threshold is mandated by a local regulatory authority (e.g., ≥3x ULN in Korea according to MFDS internal guideline).
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Inclusion Criteria:
Participant eligible for inclusion in this study must meet all the following criteria:
At Screening:
1. Signed informed consent must be obtained prior to participation in the study.
2. Males and females, ≥18 years of age at the time of providing written informed consent.
3. Ability to understand study's requirements and provide informed consent and comply with all required study procedures.
4. Hospitalization for a ACS event (STEMI or NSTEMI).
5. Receiving treatment for the qualifying ACS event, according to clinical judgement, by means of medical treatment alone or percutaneous coronary revascularization.
6. Had a successful PCI (with or without stent) for the qualifying event if a PCI was required.
7. LDL-C values measured by the local lab either at the Screening visit or results from local lab tests performed prior to ICF signature, strictly as part of the routine clinical practice in this emergency ACS setting and not older than 2 days of:
* LDL-C ≥70 mg/dL in participant previously treated with high-intensity statin (atorvastatin ≥40 mg/day or rosuvastatin ≥20 mg/day) or equivalent as per national guidelines and local regulation for at least 4 weeks before screening or
* LDL-C ≥80 mg/dL in participant previously treated with low/moderate-intensity statin for at least 4 weeks before screening or
* LDL-C ≥100 mg/dL in participant previously not treated with statins for at least 4 weeks before screening, or who never received statins (including statin intolerant participants).
At Randomization:
8. The participant must have a Baseline fasting LDL-C ≥70 mg/dL (local lab assessment) to be eligible for randomization.
9. Randomization within 7 days (≤ 7 days) following hospital admission for the qualifying ACS event and before/at discharge.
Exclusion Criteria:
Participant meeting any of the following criteria is not eligible for inclusion in this study.
Only for Japan: For exclusion criteria 6, investigator judgment should be documented in the source data document.
1. Participant who is clinically unstable during hospitalization for the qualifying ACS event, defined by any of the following events within 24 hours prior to randomization:
* Hemodynamic instability: hypotension, defined as sustained systolic blood pressure of \<90 mmHg due to cardiac failure with associated symptoms requiring inotropes
* Sustained arrhythmic events such as: ventricular storm (e.g., torsade, ventricular tachycardia, ventricular flutter) not resolved before randomization
* Cardiogenic shock or mechanical complication of myocardial infarction
* New York Heart Association (NYHA) class IV heart failure
* Left ventricular ejection fraction \<20% at randomization (after all treatment procedures, based on the latest assessment of the LVEF using invasive or non-invasive assessment modalities)
* Uncontrolled severe hypertension: systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg prior to randomization despite antihypertensive therapy.
2. Participant who has undergone or is scheduled to undergo CABG for treatment of the qualifying ACS event.
3. Active liver disease defined as: (i) any known current infectious, neoplastic, or metabolic pathology of the liver or (ii) alanine aminotransferase (ALT) elevation \>3x ULN or aspartate aminotransferase (AST) elevation \>3x ULN, or total bilirubin elevation \>2x ULN (except participant with Gilbert's syndrome) at the Screening visit, in the context of an ACS, and assessed as related to the index event and/or treatment procedures (such as PCI). Eligibility will be based on Investigator's judgement for participant who will be randomized.
4. Renal insufficiency (eGFR \<30 mL/min/1.73m2) at the Screening visit.
5. Fasting triglycerides value \>400 mg/dL (4.52 mmol/L; assessed by local labs) at randomization visit.
6. Participant, who based on the Investigator's judgement, could reach the LDL-C target value of \<55 mg/dL after 4 weeks on statin treatment only.
7. Secondary hypercholesterolemia (based on medical history).
8. Homozygous familial hypercholesterolemia (based on medical history).
9. Participant on apheresis at the Screening visit or for whom an apheresis is planned during study (from Day 1 to EOS).
10. Ongoing or medical history of myopathy at the Screening visit.
11. CK values ≥5x ULN at Screening visit and confirmed by repeat test during Screening (local lab) , in the context of an ACS, and assessed as related to the index event and/or treatment procedures (such as PCI) eligibility will be based on Investigator's judgement for participant who will be randomized (who will be switched to or initiated on the protocol-specified dose of high-intensity statin of atorvastatin ≥40 mg QD or rosuvastatin ≥20 mg QD). Unless a more stringent CK value threshold is mandated by a local regulatory authority (e.g., ≥3x ULN in Korea according to MFDS internal guideline).
Inclusion Criteria: ∙
* adults ≥ 18 years of age.
* ECOG performance status of 0 to 2.
* histopathological and/or cytological confirmation of adenocarcinoma of the prostate.
* PSMA-positive disease as assessed by PSMA PET/CT scan using an approved PSMA imaging agent as protocol instructed,
* castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L).
* Prior treatments with an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy, and progressed on or after \[177Lu\]Lu-PSMA targeted therapy.
* ≥ 1 metastatic lesion that is present on screening/baseline CT, MRI, or bone scan imaging obtained ≤ 28 days prior to randomization
* eGFR as requested by the sponsor
Exclusion Criteria:
* Any investigational agents within 28 days prior to the day of randomization.
* Any 225Ac-based investigational compound used prior to the day of randomization.
* Participants with a history of CNS metastases who are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity.
* Concurrent acute kidney injury (renal failure developed between 48 hours to 7 days) or chronic kidney disease (at least 3 months of ongoing renal injury)
* Baseline xerostomia ≥ Grade 2 by CTCAE v.5
* History of uncontrolled hypertension, myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature and/or clinically active significant cardiac disease
* History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 5 years (except for basal cell carcinoma or actinic keratosis that have been treated with no evidence of recurrence in the past 3 months, non-invasive malignant colon polyps that have been removed).
Other protocol-defined inclusion/exclusion criteria may apply.
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Inclusion Criteria: ∙
* adults ≥ 18 years of age.
* ECOG performance status of 0 to 2.
* histopathological and/or cytological confirmation of adenocarcinoma of the prostate.
* PSMA-positive disease as assessed by PSMA PET/CT scan using an approved PSMA imaging agent as protocol instructed,
* castrate level of serum/plasma testosterone (\< 50 ng/dL or \< 1.7 nmol/L).
* Prior treatments with an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy, and progressed on or after \[177Lu\]Lu-PSMA targeted therapy.
* ≥ 1 metastatic lesion that is present on screening/baseline CT, MRI, or bone scan imaging obtained ≤ 28 days prior to randomization
* eGFR as requested by the sponsor
Exclusion Criteria:
* Any investigational agents within 28 days prior to the day of randomization.
* Any 225Ac-based investigational compound used prior to the day of randomization.
* Participants with a history of CNS metastases who are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity.
* Concurrent acute kidney injury (renal failure developed between 48 hours to 7 days) or chronic kidney disease (at least 3 months of ongoing renal injury)
* Baseline xerostomia ≥ Grade 2 by CTCAE v.5
* History of uncontrolled hypertension, myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature and/or clinically active significant cardiac disease
* History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system within the past 2 years (except for basal cell carcinoma or actinic keratosis that have been treated with no evidence of recurrence in the past 3 months, non-invasive malignant colon polyps that have been removed).
Other protocol-defined inclusion/exclusion criteria may apply.
Inclusion Criteria:
1. Patients who provide written informed consent to participate in the study
2. Male or female patients ≥ 18 years of age
3. Oral LLT Cohort: Patients with documented ASCVD newly initiated on an oral lipid lowering treatment on top of a statin (e.g. ezetimibe, bempedoic acid, cholestyraimin) or new oral LLT alone in case of statin intolerance or contraindication
4. Inclisiran Cohort: Patients newly initiated on Inclisiran fulfilling the restricted reimbursement criteria or individual access requirements who are not at LDL-C goal as per their CV risk as recommended in the 2019 EAS/ESC guidelines (Mach et al., 2020). At least 60% of the documented patients must be PCSK9-inhibitor naive
5. Apheresis plus Inclisiran Cohort: Patients with Inclisiran on top of regular weekly or bi-weekly lipoprotein apheresis (LDL-c or LP(a)).
Exclusion Criteria:
1. Oral LLT Cohort: Patients who receive a PCSK9-mAB or other PCSK9-targeted therapy
2. Inclisiran 1 Cohort: current or previous PCSK9-targeted treatment
3. Contraindication for Inclisiran according to the SmPC
4. Patients who have received Inclisiran previously
5. Patients with homozygous FH
6. Any underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate) might interfere with interpretation of the clinical study results.
7. Simultaneous or planned participation in an interventional research study
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Inclusion Criteria:
1. Patients who provide written informed consent to participate in the study
2. Male or female patients ≥ 18 years of age
3. Oral LLT Cohort: Patients with documented ASCVD newly initiated on an oral lipid lowering treatment on top of a statin (e.g. ezetimibe, bempedoic acid, cholestyraimin) or new oral LLT alone in case of statin intolerance or contraindication
4. Inclisiran Cohort: Patients newly initiated on Inclisiran fulfilling the restricted reimbursement criteria or individual access requirements who are not at LDL-C goal as per their CV risk as recommended in the 2019 EAS/ESC guidelines (Mach et al., 2020). At least 60% of the documented patients must be PCSK9-inhibitor naive
5. Apheresis plus Inclisiran Cohort: Patients with Inclisiran on top of regular weekly or bi-weekly lipoprotein apheresis (LDL-C or LP(a)).
Exclusion Criteria:
1. Oral LLT Cohort: Patients who receive a PCSK9-mAB or other PCSK9-targeted therapy
2. Inclisiran Cohort: current or previous PCSK9-targeted treatment
3. Contraindication for Inclisiran according to the SmPC
4. Patients who have received Inclisiran previously
5. Patients with homozygous FH
6. Any underlying known disease, or surgical, physical, or medical condition that, in the opinion of the investigator (or delegate) might interfere with interpretation of the clinical study results.
7. Simultaneous or planned participation in an interventional research study
Key Inclusion Criteria:
* Adult men ≥ 18 years old with de novo or recurrent mHSPC (without neuroendocrine or small cell features). The tumor lesion(s) may be located in the bone, soft tissue/visceral region, or both.
* Participants must have castrate levels of testosterone, i.e., ≤ 50 ng/dL (≤ 1.7 nM).
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
* Adequate bone marrow and organ function
* Prior ADT: Participants must have started ADT at least 1 month (at least 28 days) but no more than 12 months before study entry and be willing to continue ADT during treatment
* Prior taxane use for mHSPC is permitted:
\~ Phase I and II: Participants may have received, but not progressed on, one prior taxane-based therapy. Phase II: Limited to 25% participants with prior taxane use.
* Prior ARPI is allowed in both Phase I and Phase II:
1. Prior ARPI use in biochemical recurrence (BCR) or curative treatment is allowed for any duration, provided therapy was discontinued and participant had no evidence of conventional imaging positive metastatic disease at that time
2. Prior ARPI use in mHSPC is permitted but not mandated. - If participants meet all study eligibility criteria, they are required to stop their prior ARPI after providing informed consent and remain off ARPI until Cycle 1 Day 1, when study treatment is initiated.
* Phase I: Allowed for any duration.
* Phase II: Allowed prior exposure to ARPI is ≤4 months.
* Phase II: Participants with ongoing use of darolutamide are not eligible. Participants with ongoing ARPI are eligible for a switch from their ongoing ARPI therapy if they have not progressed to CRPC disease, and meet any of the criteria, indicative of suboptimal biochemical response, or intolerability, as assessed by the Investigator.
* Other permitted prior local therapy for mHSPC:
* Phase I and II: Prior prostate-directed radiation or surgical intervention. Radiation must be completed before study entry; surgery at least 2 weeks prior.
Key Exclusion Criteria:
* Participants with evidence of mCRPC or biochemical recurrence / PSA only disease or asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy and with normal PSA for ≥ 1 year prior to the start of study treatment.
* Participants who have not received ARPI treatment for mHSPC and present with PSA levels of ≤0.5 ng/mL or those with prior/ongoing ARPI treatment presenting with PSA levels of ≤ 0.2 ng/mL prior to treatment assignment/randomization.
* Participants with CNS metastases are excluded unless:
* they have received prior therapy (e.g. surgery, radiotherapy, gamma knife), are neurologically stable and asymptomatic.
* they are not receiving corticosteroid for the purpose of maintaining neurologic integrity and have baseline and subsequent radiological imaging of the brain.
* Concurrent use of first-generation anti-androgens (like bicalutamide). Prior use of a first-generation anti-androgen drug in the context of ADT initiation with a GNRH analog is allowed, provided it was administered for ≤14 days and the last dose was administered ≥7 days from the study entry.
* Systemic ketoconazole is used as antineoplastic treatment for prostate cancer.
* Previous exposure to radioligand therapy.
* Treatment with any investigational agent within 28 days (or 5 half-lives, whichever is longer) prior to study entry.
* Previous treatment with any Polycomb Repressive Complex 2 (PRC2) inhibitor, including but not limited to Enhancer of Zeste Homolog 2 (EZH2) inhibitors, EZH2/1 inhibitors, or embryonic ectoderm development (EED) inhibitors.
* Herbal products that may decrease PSA levels within 4 weeks prior to the start of study drug treatment and while on study.
* Participants taking prohibited medication(s) (e.g., strong CYP3A4 inducers or strong or moderate CYP3A4 inhibitors that cannot be stopped within 7 days or 5 half-lives (whichever is longer) prior to study treatment and for the duration of the study treatment or prohibited herbal product(s) that cannot be stopped 7 days prior to study treatment.
Other inclusion/exclusion criteria may apply
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Key Inclusion Criteria:
* Adult men ≥ 18 years old with de novo or recurrent mHSPC (without neuroendocrine or small cell features). The tumor lesion(s) may be located in the bone, soft tissue/visceral region, or both.
* Participants must have castrate levels of testosterone, i.e., ≤ 50 ng/dL (≤ 1.7 nM).
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
* Adequate bone marrow and organ function
* Prior ADT: Participants must have started ADT at least 1 month (at least 28 days) but no more than 12 months before study entry and be willing to continue ADT during treatment
* Prior taxane use for mHSPC is permitted:
* Phase I and II: Participants may have received, but not progressed on, one prior taxane-based therapy.
* Phase II: Limited to 25% participants with prior taxane use.
* Prior ARPI is allowed in both Phase I and Phase II:
* Prior ARPI use in biochemical recurrence (BCR) or curative treatment is allowed for any duration, provided therapy was discontinued and participant had no evidence of conventional imaging positive metastatic disease at that time
* Prior ARPI use in mHSPC is permitted but not mandated. If participants meet all study eligibility criteria, they are required to stop their prior ARPI after providing informed consent and remain off ARPI until Cycle 1 Day 1, when study treatment is initiated.
* Phase I: Allowed for any duration.
* Phase II: Allowed prior exposure to ARPI is ≤4 months. Participants with ongoing use of darolutamide are not eligible.
Participants with ongoing ARPI are eligible for a switch from their ongoing ARPI therapy if they have not progressed to CRPC disease, and meet any of the criteria, indicative of suboptimal biochemical response, or intolerability, as assessed by the Investigator:
* Evidence of insufficient PSA control or suboptimal PSA response, defined as PSA ≥ 0.2 ng/mL after 6-12 months ADT and no more than 4 months of current ARPI therapy in mHSPC with declining or stable PSA trend. Eligibility based on biochemical progression should be supported by objective evidence (e.g. PSA results).
* Intolerance and non-compliance: Participant's inability to tolerate or comply with the prescribed ARPI. The site should maintain documentation to support the appropriateness of therapy changes resulting from intolerance or non-compliance.
• Other permitted prior local therapy for mHSPC:
* Phase I and II: Prior prostate-directed radiation or surgical intervention. Radiation must be completed before study entry; surgery at least 2 weeks prior.
Key Exclusion Criteria:
* Participants with evidence of mCRPC or biochemical recurrence / PSA only disease or asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy and with normal PSA for ≥ 1 year prior to the start of study treatment.
* Participants who have not received ARPI treatment for mHSPC and present with PSA levels of ≤0.5 ng/mL or those with prior/ongoing ARPI treatment presenting with PSA levels of ≤ 0.2 ng/mL prior to treatment assignment/randomization.
* Participants with CNS metastases are excluded unless:
* they have received prior therapy (e.g. surgery, radiotherapy, gamma knife), are neurologically stable and asymptomatic.
* they are not receiving corticosteroid for the purpose of maintaining neurologic integrity and have baseline and subsequent radiological imaging of the brain.
* Concurrent use of first-generation anti-androgens (like bicalutamide). Prior use of a first-generation anti-androgen drug in the context of ADT initiation with a GNRH analog is allowed, provided it was administered for ≤14 days and the last dose was administered ≥7 days from the study entry.
* Systemic ketoconazole is used as antineoplastic treatment for prostate cancer.
* Previous exposure to radioligand therapy.
* Treatment with any investigational agent within 28 days (or 5 half-lives, whichever is longer) prior to study entry.
* Previous treatment with any Polycomb Repressive Complex 2 (PRC2) inhibitor, including but not limited to Enhancer of Zeste Homolog 2 (EZH2) inhibitors, EZH2/1 inhibitors, or embryonic ectoderm development (EED) inhibitors.
* Herbal products that may decrease PSA levels within 4 weeks prior to the start of study drug treatment and while on study.
* Participants taking prohibited medication(s) (e.g., strong CYP3A4 inducers or strong or moderate CYP3A4 inhibitors that cannot be stopped within 7 days or 5 half-lives (whichever is longer) prior to study treatment and for the duration of the study treatment or prohibited herbal product(s) that cannot be stopped 7 days prior to study treatment.
* Have a history of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ≥ 3 years. Participants with a history of leukemia/lymphoma and/or MDS are not eligible.
Other inclusion/exclusion criteria may apply
Key Inclusion Criteria:
* Signed informed consent prior to participation in the extension study. Parent or legal guardian's signed informed consent and child's assent, if appropriate, are required before any assessment is performed for participants \<18 years of age. Of note, if the participant reaches age of consent (age as per local law) during the study, they will also need to sign the corresponding study Informed Consent Form (ICF) at the next study visit.
* Participants must have participated in either one of the two SIRIUS-SLE core studies, CVAY736F12301 or CVAY736F12302, and have completed the treatment period through Week 60 without treatment discontinuation.
* In the judgement of the investigator, participants must be expected to clinically benefit from continued study treatment.
Key Exclusion Criteria:
* Use of prohibited therapies.
* Active viral, bacterial or other infections requiring intravenous or intramuscular treatment for clinically significant infection which in the opinion of the investigator will place the participant at risk for participation.
* Plans for administration of live vaccines during the study period.
* Pregnant or nursing (lactating) women.
* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, refusing or unable to use highly effective methods of contraception while on study treatment and for 6 months after stopping of study drug (or longer if required by concomitant medications).
* United States (and other countries, if locally required): sexually active males, unless they agree to use barrier protection during intercourse with women of child-bearing potential while taking study treatment.
Other protocol-defined inclusion/exclusion criteria may apply.
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Key Inclusion Criteria:
* Signed informed consent prior to participation in the extension study. Parent or legal guardian's signed informed consent and child's assent, if appropriate, are required before any assessment is performed for participants \<18 years of age. Of note, if the participant reaches age of consent (age as per local law) during the study, they will also need to sign the corresponding study Informed Consent Form (ICF) at the next study visit.
* Participants must have participated in either one of the two SIRIUS-SLE core studies, CVAY736F12301 or CVAY736F12302, and have completed the treatment period through Week 60 without treatment discontinuation.
* In the judgement of the investigator, participants must be expected to clinically benefit from continued study treatment.
Key Exclusion Criteria:
* Use of prohibited therapies.
* Active viral, bacterial or other infections requiring intravenous or intramuscular treatment for clinically significant infection which in the opinion of the investigator will place the participant at risk for participation.
* Plans for administration of live vaccines during the study period.
* Pregnant or nursing (lactating) women.
Other protocol-defined inclusion/exclusion criteria may apply.
Inclusion Criteria:
Participants eligible for inclusion in this study must meet all of the following criteria:
* Men and women aged 18 years or older
* Stable NYHA functional class II-III
* LVEF \<50%
* NT-proBNP ≥600 pg/ml if in sinus rhythm or ≥900 pg/ml if in atrial fibrillation at screening
* On stable standard of care therapy with sacubitril/valsartan with a dose of at least 49/51 mg BID for at least 4 weeks before screening.
Exclusion Criteria:
Participants will be deemed ineligible for inclusion if they meet any of the following exclusion criteria:
* Acute decompensated heart failure within 3 months prior to screening
* SBP \<105 mmHg at screening or baseline.
* Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major cardiovascular surgery, PCI, or carotid angioplasty within the 6 months prior to screening
* Hemodynamically significant mitral and/or aortic valve disease, or any prior valve replacement, except mitral regurgitation secondary to LV dilation at screening
* eGFR \<30 ml/min/1.73m2 at screening, as measured by the CKD-EPI formula
* BMI \>40 kg/m2
* Strong CYP3A4 inhibitors or inducers, sGC activators (vericiguat), PDE5 inhibitors, and nitroglycerin products
* Women of childbearing potential
Further eligibility criteria might apply in alignment with the trial protocol.
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Inclusion Criteria:
Participants eligible for inclusion in this study must meet all of the following criteria:
* Men and women aged 18 years or older
* Stable NYHA functional class II-III
* LVEF \<50%
* NT-proBNP ≥600 pg/ml if in sinus rhythm or ≥900 pg/ml if in atrial fibrillation at screening
* On stable standard of care therapy with sacubitril/valsartan for at least 4 weeks before screening.
Exclusion Criteria:
Participants will be deemed ineligible for inclusion if they meet any of the following exclusion criteria:
* Acute decompensated heart failure within 3 months prior to screening
* SBP \<105 mmHg at screening or baseline.
* Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major cardiovascular surgery, PCI, or carotid angioplasty within the 6 months prior to screening
* Hemodynamically significant mitral and/or aortic valve disease, or any prior valve replacement, except mitral regurgitation secondary to LV dilation at screening
* eGFR \<30 ml/min/1.73m2 at screening, as measured by the CKD-EPI formula
* BMI \>40 kg/m2
* Strong CYP3A4 inhibitors or inducers, sGC activators (vericiguat), PDE5 inhibitors, and nitroglycerin products
* Women of childbearing potential
Further eligibility criteria might apply in alignment with the trial protocol.
Inclusion Criteria:
1. Signed informed consent form (ICF) must be obtained prior to participation in the study.
2. Adult ≥18 years old at the time of informed consent.
3. Stage IIIB/IIIC (not amenable to surgery, radiation or multi-modality therapy) or Stage IV NSCLC (according to Version 8 of the AJCC Staging Manual) either treatment naive or progressed on 1 or more lines of therapy at the time of study entry.
4. Histologically or cytologically confirmed diagnosis of NSCLC with confirmed EGFR wild-type and ALK rearrangement negative and who have tested positive test for MET exon14 skipping mutation (Locally available MET report either by RT-PCR or Next Generation Sequencing \[NGS\] would be considered, in case not available MET testing would be done through NGS based platform during molecular pre-screening done as part of the study).
5. Patients must have recovered from all toxicities related to prior systemic therapies to grade ≤1 (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0).
6. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
7. Patients must have adequate organ function including the following laboratory values at the screening visit:
* Absolute neutrophil count ≥1.5 x 109/L without growth factor support
* Platelets ≥100 x 109/L
* Hemoglobin ≥9 g/dL
* Calculated creatinine clearance (using Cockcroft-Gault formula) ≥45 mL/min
* Total bilirubin ≤1.5 upper limit of normal (ULN) (except in patients with Gilbert's syndrome, who may be included if total bilirubin is ≤3.0 x ULN and direct bilirubin is ≤1.5 x ULN))
* Aspartate transaminase (AST) ≤3 x ULN, except for patients with liver metastasis, who may only be included if AST ≤5 x ULN
* Alanine transaminase (ALT) ≤3 x ULN, except for patients with liver metastasis, who may only be included if ALT ≤5 x ULN
* Alkaline phosphatase ≤5.0 x ULN
* Asymptomatic serum amylase ≤ grade 2. Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
* Serum lipase ≤ ULN.
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2.
9. Willing and able to comply with scheduled visits, treatment plan, and laboratory tests.
Exclusion Criteria:
1. Prior treatment with any MET inhibitor or hepatocyte growth factor -targeting therapy.
2. Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers and completely resected carcinoma in situ of any type
3. Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
4. Patients with known druggable molecular alterations (such as ROS1 translocation or BRAF mutation, etc.) which might be a candidate for alternative targeted therapies as applicable per local regulations and treatment guidelines.
5. Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
6. Patients with clinically significant heart diseases like unstable angina/acute myocardial infarction within 6 months prior to screening, NYHA class III-IV congestive cardiac failure, uncontrolled hypertension, arrhythmias or QTcF≥470 ms on the screening electrocardiogram (ECG)
7. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting capmatinib or who have not recovered from side effects of such procedure. Video-assisted thoracic surgery and mediastinoscopy will not be counted as major surgery and patients can be enrolled in the program ≥1 week after the procedure
8. Thoracic radiotherapy to lung fields ≤4 weeks prior to starting capmatinib or patients who have not recovered from radiotherapy-related toxicities.
For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤2 weeks prior to starting capmatinib or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤2 weeks prior to starting capmatinib is allowed.
9. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of capmatinib or patients who are unable to swallow oral tablets.
10. Patients receiving treatment with strong inducers of CYP3A that cannot be discontinued at least 1 week prior to the start of treatment with capmatinib and for the duration of the study
11. Unable or unwilling to swallow tablets as per dosing schedule
12. Patients with known hypersensitivity to capmatinib and any of the excipients of capmatinib.
13. Patients with any other severe, acute or chronic medical or psychotic conditions or significant abnormal physical findings that in the opinion of the investigator may increase the risk associated with study participation or that may interfere with the interpretation of study results.
14. Previous (within 28 days) or concomitant participation in another clinical study with investigational medicinal product(s).
15. Pregnant or nursing (lactating) women.
16. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 7 days after stopping study treatment. Highly effective contraception methods include:
* Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Note that periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not considered highly effective and therefore not acceptable methods of contraception.
* Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.
* Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient
* Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking treatment.
17. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 7 days after stopping study treatment. A condom is required for all sexually active male patients to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male patients must not donate sperm for the time period specified above.
18. Any other condition that would, in the Investigator's judgment, contraindicate patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., active infection (including active hepatitis B and C, SARS-CoV-2), inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc.
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Inclusion criteria
1. Signed informed consent must be obtained prior to participation in the study.
2. Adult ≥18 years old at the time of informed consent.
3. Metastatic NSCLC (Stage IV, according to Version 8 of the AJCC Staging Manual) either treatment naïve or progressed (clinically and/or radiologically) on 1 or more lines of systemic therapy.
4. Histologically or cytologically confirmed diagnosis of NSCLC with confirmed EGFR wild type (EGFR Negative) and ALK rearrangement negative and who have tested positive MET exon14 skipping mutation (Locally available MET report either by reverse transcriptase polymerase chain reaction \[RT-PCR\] or NGS would be considered, in case not available, MET testing would be done through NGS based molecular pre-screening done as part of the study).
5. Patients must have recovered from all toxicities related to prior systemic therapies to grade ≤1 (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5.0).
6. At least one measurable lesion as defined by RECIST 1.1.
7. Patients must have adequate organ function, including the following laboratory values at the screening visit:
1. Absolute neutrophil count ≥1.5 x 109/L without growth factor support
2. Platelets ≥100 x 109/L
3. Hemoglobin ≥9 g/dL
4. Calculated creatinine clearance (using Cockcroft-Gault formula) ≥45 mL/min
5. Total bilirubin ≤1.5 ULN (upper limit of normal) (except in patients with Gilbert's syndrome, who may be included if total bilirubin is ≤3.0 x ULN and direct bilirubin is ≤1.5 x ULN))
6. AST ≤3 x ULN, except for patients with liver metastasis, who may only be included if AST ≤5 x ULN
7. ALT ≤3 x ULN, except for patients with liver metastasis, who may only be included if ALT ≤5 x ULN
8. Alkaline phosphatase (ALP) ≤5.0 x ULN
9. Asymptomatic serum amylase ≤ grade 2. Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
10. Serum lipase ≤ ULN
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2.
9. Willing and able to comply with scheduled visits, treatment plan, and laboratory tests.
Exclusion criteria
1. Prior treatment with any MET inhibitor or hepatocyte growth factor targeting therapy.
2. Presence or history of a malignant disease other than NSCLC that has been diagnosed and/or required therapy within the past 3 years. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers and completely resected carcinoma in situ of any type.
3. Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms.
4. Patients with known druggable molecular alterations (such as ROS1 translocation or BRAF mutation, etc.) which might be a candidate for alternative targeted therapies as applicable per local regulations and treatment guidelines.
5. Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
6. Patient with clinically significant heart diseases like unstable angina/acute myocardial infraction within 6 months prior to screening, NYHA class III-IV congestive cardiac failure, uncontrolled hypertension, arrhythmias or QTcF ≥470 ms on the screening ECG.
7. Major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) within 4 weeks prior (2 weeks for resection of brain metastases) to starting Capmatinib or who have not recovered from side effects of such procedure. Video-assisted thoracic surgery and mediastinoscopy will not be counted as major surgery and patients can be enrolled in the program ≥1 week after the procedure.
8. Thoracic radiotherapy to lung fields ≤4 weeks prior to starting Capmatinib or patients who have not recovered from radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy ≤2 weeks prior to starting Capmatinib or patients who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤2 weeks prior to starting Capmatinib is allowed.
9. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Capmatinib or patients who are unable to swallow oral tablets.
10. Patients receiving treatment with strong inducers of CYP3A that cannot be discontinued at least 1 week prior to the start of treatment with Capmatinib and for the duration of the study.
11. Unable or unwilling to swallow tablets as per dosing schedule.
12. Patients with known hypersensitivity to Capmatinib and any of the excipients of Capmatinib.
13. Patients with any other severe, acute or chronic medical or psychotic conditions or significant abnormal physical findings that in the opinion of the investigator may increase the risk associated with study participation or that may interfere with the interpretation of study results.
14. Patients with prior systemic anti-cancer (chemotherapy, immunotherapy, biologic therapy, vaccine) and investigational agents within 4 weeks or ≤5 x half-life of the agent (whichever is shorter) before the first dose of Capmatinib. If previous treatment is a monoclonal antibody, then the treatment must be discontinued at least 4 weeks before first dose of Capmatinib. If previous treatment is an oral targeted agent, then the treatment must be discontinued at least 5 times the half-life of the agent.
15. Pregnant or nursing (lactating) women.
16. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 7 days after stopping study treatment. Highly effective contraception methods include:
1. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
2. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.
3. Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
4. Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system, or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking treatment.
17. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 7 days after stopping study treatment. A condom is required for all sexually active male patients to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male patients must not donate sperm for the time period specified above.
18. Any other condition that would, in the Investigator's judgment, contraindicate patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., active infection (including active hepatitis B and C, SARS-CoV-2), inflammation, intestinal obstruction, unable to swallow medication, social/psychological issues, etc
Key Inclusion Criteria:
1. Male or female participants aged ≥2 years at the time of informed consent/assent.
2. Participants with diagnosis of PROS (according to Clinical Diagnostic Criteria for PROS proposed by Keppler Noreuil et al 2014) with symptomatic AND progressive overgrowth, who have syndromic disease or isolated features (with the exception of isolated macrodactyly, macrocephaly or epidermal nevus) at the time of informed consent/assent.
3. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories using a DNA-based test AND available archival tissue (if archival tissue sample is not available, a fresh biopsy should be performed, if it is not clinically contraindicated) at the time of informed consent/assent.
4. Karnofsky (in participants \>16 years of age at study entry) or Lansky (≤16 years of age at study entry) performance status index ≥50.
5. PGI-S score of mild, moderate, severe, or very severe at screening.
6. Adequate bone marrow and organ function.
7. Presence of at least 1 PROS-related measurable lesion (longest diameter ≥2 cm) confirmed by BIRC assessment and associated with complaints, clinical symptoms or functional limitations affecting the participant's everyday life.
Key Exclusion Criteria:
1. Participant with only isolated macrodactyly, epidermal nevus/nevi and macroencephaly (the only clinical feature or a combination of any of three of them), in absence of other PROS-related lesions at the time of informed consent/assent.
2. Previous treatment with alpelisib and/or any other phosphatidylinositol 3-kinase (PI3K) inhibitor(s) (except treatment attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with treatment duration less than 2 weeks and stopped at least 4 weeks prior to the first dose of study medication with alpelisib).
3. Debulking or other major surgery performed within 3 months at the time of informed consent/assent.
4. Radiation exposure for PROS treatment purpose within 12 months prior to informed consent/assent.
5. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE v4.03) within 30 days before informed consent/assent, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent/assent.
6. Clinically meaningful bleeding from PROS-related lesion (Grade 2 and more as per CTCAE v4.03) within 30 days before study treatment initiation.
7. Participants with clinically significant worsening of PROS-related laboratory abnormalities, physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening of underlying pain, newly occurring swelling or redness) indicating an uncontrolled condition during the screening phase.
Other inclusion/exclusion criteria may apply
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Key Inclusion Criteria:
1. Male or female participants aged ≥2 years at the time of informed consent/assent.
2. Participants with diagnosis of PROS (according to Clinical Diagnostic Criteria for PROS proposed by Keppler Noreuil et al 2014) with symptomatic AND progressive overgrowth, who have syndromic disease or isolated features (with the exception of isolated macrodactyly, macrocephaly or epidermal nevus) at the time of informed consent/assent.
3. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories using a DNA-based test AND available archival tissue (if archival tissue sample is not available, a fresh biopsy should be performed, if it is not clinically contraindicated) at the time of informed consent/assent.
4. Karnofsky (in participants \>16 years of age at study entry) or Lansky (≤16 years of age at study entry) performance status index ≥50.
5. PGI-S score of mild, moderate, severe, or very severe at screening.
6. Adequate bone marrow and organ function.
7. Presence of at least 1 PROS-related measurable lesion (longest diameter ≥2 cm) confirmed by BIRC assessment and associated with complaints, clinical symptoms or functional limitations affecting the participant's everyday life.
Key Exclusion Criteria:
1. Participant with only isolated macrodactyly, epidermal nevus/nevi and macroencephaly (the only clinical feature or a combination of any of three of them), in absence of other PROS-related lesions at the time of informed consent/assent.
2. Previous treatment with alpelisib and/or any other phosphatidylinositol 3-kinase (PI3K) inhibitor(s) (except treatment attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with treatment duration less than 2 weeks and stopped at least 2 weeks prior to the first dose of study medication with alpelisib).
3. Debulking or other major surgery performed within 3 months at the time of informed consent/assent.
4. Radiation exposure for PROS treatment purpose within 12 months prior to informed consent/assent.
5. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE v4.03) within 15 days before study treatment initiation, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent/assent.
6. Clinically meaningful bleeding from PROS-related lesion (Grade 2 and more as per CTCAE v4.03) within 15 days before study treatment initiation.
7. Participants with clinically significant worsening of PROS-related laboratory abnormalities, physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening of underlying pain, newly occurring swelling or redness) indicating an uncontrolled condition during the screening phase.
Other inclusion/exclusion criteria may apply
Inclusion Criteria:
1. Written informed consent must be obtained before any study protocol specific assessment is performed.
1. Parental/legal guardian informed consent must be obtained and signed for pediatric subjects (formally documented and witnessed, via an independent trusted witness) prior to any study related procedure.
2. Subjects \< 18 years old, who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines.
3. If the subject is unable to read and write or otherwise incapable of signing an informed consent, then a witnessed consent according to local ethical standards is permitted.
2. Subjects (Adult and pediatric subjects ≥ 6 years of age and above 12.5 kg of weight) at time of consenting must have been diagnosed with fascioliasis based on clinical signs, symptoms and laboratory evaluations as per local clinical practice.
Exclusion Criteria:
1. Subjects diagnosed with ectopic fascioliasis, extrahepatic involvement (e.g., lungs, spleen, pancreas, subcutaneous tissue, gastrointestinal organs, etc.).
2. Subjects with known hypersensitivity to triclabendazole /other benzimidazole derivatives and/or any of the excipients in Egaten.
3. Subjects taking any anthelmintic medications within two weeks or 5 half-lives, whichever is longer prior to enrolling into study.
4. Inability or unwillingness to undergo study related procedures.
5. Subjects who in the judgment of the Clinical Investigator are unsuitable for the trial or who have to be excluded in order to be compliant with local fascioliasis management guidelines that may differ from the FDA approved label, including but not limited to :
1. Subjects who are machine operators or drivers.
2. Medical history of liver (other than fascioliasis), kidney or cardiac disease.
6. Females (including under the age of 18) known to be pregnant or testing positive for pregnancy at screening.
7. Lactating women unwilling to discontinue lactation up to 72 hours after the second dose administration or as per local guidelines.
8. Subjects requiring therapeutic drug monitoring of CYP2C19 substrate(s) (e.g. S-mephenytoin).
9. Subjects with medical history of QT prolongation or a history of symptoms compatible with a long QT interval or on medication which prolong the QT interval.
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Inclusion Criteria:
1. Written informed consent must be obtained before any study protocol specific assessment is performed.
1. Parental/legal guardian informed consent must be obtained and signed for pediatric subjects prior to any study related procedure.
2. Subjects \< 18 years old, who are capable of providing assent, must provide assent with parental/legal guardian consent or as per local ethical guidelines.
3. If the subject is unable to read and write or otherwise incapable of signing an informed consent, then a witnessed consent according to local ethical standards is permitted.
2. Subjects (Adult and pediatric subjects ≥ 6 years of age and above 12.5 kg of weight) at time of consenting must have been diagnosed with fascioliasis based on clinical signs, symptoms and laboratory evaluations as per local clinical practice.
Exclusion Criteria:
1. Subjects diagnosed with ectopic fascioliasis, extrahepatic involvement (e.g., lungs, spleen, pancreas, subcutaneous tissue, gastrointestinal organs, etc.).
2. Subjects with known hypersensitivity to triclabendazole /other benzimidazole derivatives and/or any of the excipients in Egaten.
3. Subjects taking any anthelmintic medications within two weeks or 5 half-lives, whichever is longer prior to enrolling into study.
4. Inability or unwillingness to undergo study related procedures.
5. Subjects who in the judgment of the Clinical Investigator are unsuitable for the trial or who have to be excluded in order to be compliant with local fascioliasis management guidelines that may differ from the FDA approved label, including but not limited to :
1. Subjects who are machine operators or drivers.
2. Medical history of liver (other than fascioliasis), kidney or cardiac disease.
6. Females (including under the age of 18) known to be pregnant or testing positive for pregnancy at screening.
7. Lactating women unwilling to discontinue lactation up to 72 hours after the second dose administration or as per local guidelines.
8. Subjects requiring therapeutic drug monitoring of CYP2C19 substrate(s) (e.g. S-mephenytoin).
9. Subjects with medical history of QT prolongation or a history of symptoms compatible with a long QT interval or on medication which prolong the QT interval.
Inclusion Criteria:
Patients who meet all of the following criteria are eligible for the project:
* Age ≥ 18 years
* Able to understand and willing to sign written Informed Consent and to complete patient-reported-outcome assessment instruments
Main project (Metatstatic NSCLC):
* Confirmed non-small cell lung cancer (NSCLC)
* Informed consent no later than four weeks after start of first-line systemic treatment or no later than four weeks after diagnosis for patients receiving "best supportive care only"
* Stage IV, or stage IIIB/C (UICC8) if patient is ineligible for curative surgery and/or radiochemotherapy
* Systemic therapy or best supportive care
Satellite Stage I/II/III (NSCLC):
* Confirmed non-small cell lung cancer (NSCLC)
* Informed consent no later than four weeks after start of first anti-tumor treatment (including surgery and radiotherapy) or no later than four weeks after diagnosis for patients receiving "best supportive care only" (i.e. no anti-tumor treatment = no surgery, radiotherapy or systemic therapy)
* Stage I, Stage II, stage IIIA, or stage IIIB/C (UICC8)
* Systemic (chemo)therapy and/or radiation therapy and/or surgery or best supportive care
Satellite SCLC
* Confirmed Small cell lung cancer (SCLC)
* Informed consent no later than four weeks after start of first anti-tumor treatment or no later than four weeks after diagnosis for patients receiving "best supportive care only" (i.e. no anti-tumor treatment = no surgery, radiotherapy or systemic therapy)
* Systemic (chemo)therapy and/or radiation therapy and/or surgery or best supportive care
Exclusion Criteria:
none
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Inclusion Criteria:
Patients who meet all of the following criteria are eligible for the project:
* Age ≥ 18 years
* Able to understand and willing to sign written Informed Consent and to complete patient-reported-outcome assessment instruments
Main project (NSCLC Stage IV):
* Confirmed non-small cell lung cancer (NSCLC)
* Stage IV (UICC8)
* Systemic therapy
* Informed consent no later than four weeks after start of first-line systemic treatment
Satellite NSCLC Stage I-III:
* Confirmed non-small cell lung cancer (NSCLC)
* Informed consent no later than four weeks after start of first anti-tumor treatment (including surgery and radiotherapy) or if first treatment is surgery no longer than 3 months after start of surgery.
* Stage I-III (UICC8)
* Systemic (chemo)therapy and/or radiation therapy and/or surgery
Satellite SCLC
* Confirmed Small cell lung cancer (SCLC)
* Informed consent no later than four weeks after start of first anti-tumor treatment
* Systemic (chemo)therapy and/or radiation therapy and/or surgery
Exclusion Criteria:
none
Study prematurely terminated due to recruitment challenges, low incidence of the target population, evolving treatment landscape, ethical considerations, and inability to ensure funding through study completion.
Inclusion Criteria:
\- Participant has completed treatment per protocol in a Novartis study of remibrutinib (unless otherwise specified in a parent study protocol) in a dermatological or allergology indication.
Participants, who derive benefit from the treatment with remibrutinib but have not completed the treatment in certain parent studies due to parent study termination by Novartis, may be eligible if the termination was due to reasons other than safety or lack of efficacy (e.g., technical / administrative reasons).
* Participant is deriving benefit from remibrutinib, investigator believes he/she would continue to derive benefit from remibrutinib and the benefit outweighs the risk, based on the investigator's judgement.
* Participant is unable to obtain access to the marketed remibrutinib formulation per local post study drug supply program, prescription and/or reimbursement guidelines.
Exclusion Criteria:
Participants meeting any of the following criteria are not eligible for inclusion in this study.
* Participant has prematurely discontinued study treatment in the parent study.
* Use of prohibited medications
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Inclusion Criteria:
\- Participant has completed treatment per protocol in a Novartis study of remibrutinib (unless otherwise specified in a parent study protocol) in a dermatological or allergology indication.
Participants, who derive benefit from the treatment with remibrutinib but have not completed the treatment in certain parent studies due to parent study termination by Novartis, may be eligible if the termination was due to reasons other than safety or lack of efficacy (e.g., technical / administrative reasons).
* Participant is deriving benefit from remibrutinib, investigator believes he/she would continue to derive benefit from remibrutinib and the benefit outweighs the risk, based on the investigator's judgement.
* Participant is unable to obtain access to the marketed remibrutinib formulation per local post study drug supply program, prescription and/or reimbursement guidelines.
Exclusion Criteria:
Participants meeting any of the following criteria are not eligible for inclusion in this study.
* Participant has prematurely discontinued study treatment in the parent study.
* Use of prohibited medications
Other protocol-defined inclusion/exclusion criteria may apply.
Key Inclusion Criteria:
* Participant has histologically confirmed diagnosis of high-grade serous or high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer
* Measurable disease, i.e., at least one measurable lesion per RECIST 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation)
* If no measurable disease is present, the disease should be assessable by Gynecologic Cancer Intergroup criteria (GCIC) for CA-125
* Participant has no germline BRCA1/2 mutation as determined by an FDA-approved assay
* Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Participant has platinum-resistant (progression within one to six months after completing platinum-based therapy) or platinum refractory disease (progression during treatment or within 4 weeks after the last dose), where platinum-based therapy is not an option, according to the GCIG 5th Ovarian Cancer Consensus Conference definitions (Wilson et al 2016). The platinum-based chemotherapy regimen does not necessarily need to be the last regimen the participant received prior to study entry
* Participant must have received at least one but no more than three prior systemic treatment regimens and for whom single-agent chemotherapy is appropriate as the next line of treatment
* Participant has received prior bevacizumab or is not eligible to receive bevacizumab due to medical reasons.
Key Exclusion Criteria:
* Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor
* Participant is concurrently using other anti-cancer therapy
* Participant is in a state of small or large bowel obstruction or has other impairment of gastrointestinal (GI) function or GI disease
* Participant has had surgery within 14 days prior to starting study drug or has not recovered from major adverse effects
* Participant has not recovered from all toxicities related to prior anticancer therapies to baseline or NCI CTCAE Version 4.03 Grade ≤1. Exception to this criterion: participants with any grade of alopecia are allowed to enter the study
* Participant has an established diagnosis of diabetes mellitus type I or uncontrolled type II based on fasting plasma glucose and HbA1c
* Participants with liver impairment and Child Pugh score B or C
* Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization, and who has not recovered to baseline, grade 1 or better from related adverse effects of such therapy (with the exception of alopecia)
* Participant has a known hypersensitivity to any of the study drugs or excipients
* Participant has a history of myelodysplastic syndrome or acute myeloid leukemia, or presents clinical and/ or laboratory features suggestive thereof.
Other inclusion/exclusion criteria may apply
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Key Inclusion criteria:
* Participant had histologically confirmed diagnosis of high-grade serous or high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
* Measurable disease, i.e., at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation).
* If no measurable disease was present, the disease was assessable by Gynecologic Cancer Intergroup criteria (GCIC) for CA-125.
* Participant had no germline BRCA1/2 mutation as determined by an FDA-approved assay.
* Participant had an ECOG performance status of 0 or 1.
* Participant had platinum-resistant (progression within one to six months after completing platinum-based therapy) or platinum refractory disease (progression during treatment or within 4 weeks after the last dose), where platinum-based therapy was not an option, according to the Gynecologic Cancer Intergroup criteria (GCIG) 5th Ovarian Cancer Consensus Conference definitions.
* Participant must have received at least one but no more than three prior systemic treatment regimens and for whom single-agent chemotherapy was appropriate as the next line of treatment.
* Participant had received prior bevacizumab or was not eligible to receive bevacizumab due to medical reasons.
Key Exclusion criteria:
* Participant had received prior treatment with any phosphoinositide 3-kinase, mammalian Target Of Rapamycin or Protein Kinase B inhibitor.
* Participant was concurrently using other anti-cancer therapy.
* Participant was in a state of small or large bowel obstruction or had other impairment of gastrointestinal (GI) function or GI disease.
* Participant had surgery within 14 days prior to starting study drug or had not recovered from major adverse effects.
* Participant had not recovered from all toxicities related to prior anticancer therapies to baseline or National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 Grade ≤1. Exception to this criterion: participants with any grade of alopecia were allowed to enter the study.
* Participant had an established diagnosis of diabetes mellitus type I or uncontrolled type II based on fasting plasma glucose and HbA1c.
* Participants with liver impairment and Child Pugh score B or C.
* Participant had received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization, and who had not recovered to baseline, grade 1 or better from related adverse effects of such therapy (with the exception of alopecia).
* Participant had known hypersensitivity to any of the study drugs or excipients.
* Participant had a history of myelodysplastic syndrome or acute myeloid leukemia, or presented clinical and/ or laboratory features suggestive thereof.
Other inclusion/exclusion criteria may apply
Inclusion Criteria:
1. Ability to use a mobile device or computer with broadband internet access (or data streaming available)
2. Ability to read, understand, and respond in English
3. Adult aged 18 years of age or over at the time of the survey
4. Self-confirmed diagnosis of MS
5. Prescribed either OMB or OCR SC and will receive their first injection (Day 0) followed by completing the study survey between Day 1 and Day 7
Exclusion Criteria:
1. Participated in an OMB or OCR randomized clinical trial
2. Previously treated with OMB or OCR SC
3. Cognitive impairment that impacts the patient's ability to participate in a survey study
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Inclusion Criteria:
1. Ability to use a mobile device or computer with broadband internet access (or data streaming available)
2. Ability to read, understand, and respond in English
3. Adult aged 18 years of age or over at the time of the survey
4. Self-confirmed diagnosis of MS
5. Prescribed either OMB or OCR SC and received their first injection (Day 0) and completed the study survey between Day 1 and Day 7
Exclusion Criteria:
1. Participated in an OMB or OCR randomized clinical trial
2. Previously treated with OMB or OCR SC
3. Cognitive impairment that impacts the patient's ability to participate in a survey study
Inclusion Criteria:
* Inclusions at Screening
* Signed informed consent must be obtained prior to participation in the study
* Male and female participants ≥ 18 years of age
* History of at least 2 episodes of AF (atrial fibrillation or atrial flutter), at least one episode must be atrial fibrillation
* At least 1 of the AF episodes specified in inclusion #3 must be within the last 12 months (or during screening) and documented by 12-lead ECG, Holter, or any other ECG recording method, as confirmed by the Investigator
* One or more of the following:
* AFB of 1% or higher on a local ambulatory Holter, mobile cardiac telemetry, ECG patch monitor, or other ambulatory electrocardiographic monitor within the last 12 months
* CHA2DS2-VASc score of 2 or higher in males, 3 or higher in females (1 point for congestive heart failure, hypertension, age 65-74 years, diabetes, vascular disease, female sex; 2 points for age 75 years or older, prior stroke or transient ischemic attack)
* Stable heart failure or with New York Heart Association class I or II symptoms
* NT-proBNP level of 300 pg/mL or higher on a local lab test within the last 12 months
* On guideline-directed stroke prevention treatment, as confirmed by the Investigator
* Participants must have a body mass index (BMI) ≥ 18 kg/m2. BMI is calculated as body weight (kg) divided by height (m) squared
* Inclusions at Day 1
* Sinus rhythm at Baseline documented by 12-lead ECG (participants with persistent AF should be cardioverted at least 12 hours before randomization)
Exclusion Criteria:
-Exclusions at Screening
* Permanent AF
* Ongoing reversible causes of AF (e.g., hyperthyroidism, myocarditis, acute alcohol, sepsis- or infection related AF, surgery-related AF, pulmonary embolism)
* Ongoing use of antiarrhythmic therapy (Vaughan Williams class I or III anti-arrhythmic therapy must be discontinued at least 7 days before Screening phase ECG patch monitor; amiodarone must be discontinued at least 6 weeks before Screening phase ECG patch monitor)
* History of an AF ablation procedure without a recurrence of AF at least 2 or more months after the ablation.
* Implanted pacemaker, defibrillator, or cardiac monitor
* Infiltrative (e.g., amyloidosis, sarcoidosis) or hypertrophic cardiomyopathy
* Left ventricular ejection fraction of 40% or less documented within the last 12 months, or during Screening. If multiple LVEF measurements are recorded within the last 12 months, the most recent LVEF measurement should be used
* Current decompensated heart failure or hospitalization for heart failure within 3 months prior to Screening
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Inclusion Criteria:
-Inclusions at Screening
* Signed informed consent must be obtained prior to participation in the study
* Male and female participants ≥ 18 years of age
* History of atrial fibrillation
* AF (atrial fibrillation or atrial flutter) within the last 12 months (or during screening) documented by 12-lead ECG, Holter, or any other ECG recording method, as confirmed by the Investigator
* Meets one or more of the following criteria:
A. Recurrent AF (≥ 2 episodes), and ≥ 1 of the following
* AFB of 1% or higher on a local ambulatory Holter, mobile cardiac telemetry, ECG patch monitor, or other ambulatory electrocardiographic monitor within the last 12 months
* CHA2DS2-VASc score of 2 or higher in males, 3 or higher in females (1 point for congestive heart failure, hypertension, age 65-74 years, diabetes, vascular disease, female sex; 2 points for age 75 years or older, prior stroke or transient ischemic attack)
* Stable heart failure or with New York Heart Association class I or II symptoms
* NT-proBNP level of 300 pg/mL or higher on a local lab test within the last 12 months B. AFB ≥ 1% or an AF episode lasting ≥ 2 h during Screening, including when detected using a study provided ECG patch monitor C. Persistent AF, as confirmed by the Investigator
* On guideline-directed stroke prevention treatment, as confirmed by the Investigator
* Participants must have a body mass index (BMI) ≥ 18 kg/m2. BMI is calculated as body weight (kg) divided by height (m) squared
* Inclusions at Day 1
* Sinus rhythm at Baseline documented by 12-lead ECG (participants with persistent AF should be cardioverted at least 12 hours before randomization)
Exclusion Criteria:
-Exclusions at Screening
* Permanent AF
* Ongoing reversible causes of AF (e.g., hyperthyroidism, myocarditis, acute alcohol, sepsis- or infection related AF, surgery-related AF, pulmonary embolism)
* Ongoing use of antiarrhythmic therapy (Vaughan Williams class I or III anti-arrhythmic therapy must be discontinued at least 7 days before Screening phase ECG patch monitor; amiodarone must be discontinued at least 6 weeks before Screening phase ECG patch monitor)
* History of an AF ablation procedure without a recurrence of AF at least 2 or more months after the ablation.
* Implanted pacemaker, defibrillator, or cardiac monitor
* Infiltrative (e.g., amyloidosis, sarcoidosis) or hypertrophic cardiomyopathy
* Left ventricular ejection fraction of 40% or less documented within the last 12 months, or during Screening. If multiple LVEF measurements are recorded within the last 12 months, the most recent LVEF measurement should be used
* Current decompensated heart failure or hospitalization for heart failure within 3 months prior to Screening
Inclusion Criteria:
* Age ≥ 18 years old.
* Patients with one of the following histologically or cytologically confirmed advanced cancers:
Phase I (patients with one of the following cancers, from whom no standard therapy is available or appropriate in the judgment of the investigator):
* HR+/HER2- advanced breast cancer (aBC) with disease progression on or following at least one line of hormone-based therapy in combination with a CDK4/6i and at least one additional line of systemic therapy for metastatic disease.
* Locally advanced or metastatic cancer with a CCNE1 amplification. For dose expansion only: no more than 3 prior lines of therapy for advanced or metastatic disease.
* Metastatic castration-resistant prostate adenocarcinoma, with no documented neuroendocrine component, castrate level of testosterone, and no more than 3 prior lines of systemic therapy for metastatic disease.
Phase II:
* HR+/HER2- aBC with disease progression on or after an endocrine therapy in combination, with a CDK4/6 inhibitor for advanced disease with no more than 2 lines of endocrine therapy and no prior cytotoxic chemotherapy or antibody-drug-conjugate for advanced disease.
\- Measurable disease as determined by RECIST v1.1.
* BC only: If no measurable disease is present, then at least one predominantly lytic bone lesion must be present that can be accurately assessed at baseline and is suitable for repeated assessment.
* metastatic Castration-Resistant Prostate Cancer (mCRPC) only: If no measurable disease is present per PCWG3 modified RECIST, then at least 1 metastatic lesion must be present on bone scan imaging.
Exclusion Criteria:
* Patients with inadequate bone marrow and/or organ functions with out-of-range laboratory values.
* Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including myocardial infarction (MI), coronary artery bypass graft (CABG), long QT syndrome, or risk factors for Torsades de Pointes (TdP).
* Presence of symptomatic central nervous system (CNS) metastases or CNS metastases that require local therapy or increasing doses of corticosteroids within 2 weeks prior to study entry.
* Patients with symptomatic visceral disease, including visceral crisis.
* For patients with BC: Patient is concurrently using hormone replacement therapy.
* Women of childbearing potential who are unwilling to use highly effective contraception methods, pregnant or nursing women.
Other protocol-defined inclusion/exclusion criteria may apply.
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Inclusion Criteria:
* Age ≥ 18 years old.
* Patients with one of the following histologically or cytologically confirmed advanced cancers:
* Phase I (patients with one of the following cancers, from whom no standard therapy is available or appropriate in the judgment of the investigator):
* HR+/HER2- advanced breast cancer (aBC) with disease progression on or following at least one line of hormone-based therapy in combination with a CDK4/6i and at least one additional line of systemic therapy for metastatic disease.
* Locally advanced or metastatic cancer with a CCNE1 amplification. For dose expansion only: no more than 3 prior lines of therapy for advanced or metastatic disease.
* Metastatic castration-resistant prostate adenocarcinoma (mCRPC), with no documented neuroendocrine component, castrate level of testosterone. For dose expansion only: no more than 3 prior lines of systemic therapy for metastatic disease.
* Phase II:
• HR+/HER2- aBC with disease progression on or after an endocrine therapy in combination, with a CDK4/6 inhibitor for advanced disease with no more than 2 lines of endocrine therapy and no prior cytotoxic chemotherapy or antibody-drug-conjugate for advanced disease.
* Measurable disease as determined by RECIST v1.1.
* BC only: If no measurable disease is present, then at least one predominantly lytic bone lesion must be present that can be accurately assessed at baseline and is suitable for repeated assessment.
* mCRPC only: If no measurable disease is present per PCWG3 modified RECIST, then at least 1 metastatic lesion must be present on bone scan imaging.
Exclusion Criteria:
* Patients with inadequate bone marrow and/or organ functions with out-of-range laboratory values.
* Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including myocardial infarction (MI), coronary artery bypass graft (CABG), long QT syndrome, or risk factors for Torsades de Pointes (TdP).
* Presence of symptomatic central nervous system (CNS) metastases or CNS metastases that require local therapy or increasing doses of corticosteroids within 2 weeks prior to study entry.
* Patients with visceral crisis.
* For patients with BC: Patient is concurrently using hormone replacement therapy.
* Women of childbearing potential who are unwilling to use highly effective contraception methods, pregnant or nursing women.
Other protocol-defined inclusion/exclusion criteria may apply.