Inclusion Criteria:
* 12 years of age or older (\*Restrictions apply. Not all therapies are available for patients \<18)
* Histologically-proven locally advanced or metastatic solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma who is no longer benefiting from standard anti-cancer treatment or for whom, in the opinion of the treating physician, no such treatment is available or indicated
* Performance status 0-2 (Per Eastern Cooperative Oncology Group (ECOG) criteria)
* Patients must have acceptable organ function as defined below. However, as noted above, drug-specific inclusion/exclusion criteria specified in the protocol appendix for each agent will take precedence for this and all inclusion criteria:
1. Absolute neutrophil count ≥ 1.5 x 106/µl
2. Hemoglobin \> 9.0 g/dl
3. Platelets \> 75,000/µl
4. Total bilirubin \< 2.0 mg/ dl, except in patients with Gilbert's Syndrome
5. Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) \< 2.5 x institutional upper limit of normal (ULN) (or \< 5 x ULN in patients with known hepatic metastases)
6. Serum creatinine ≤ 1.5 × ULN or calculated or measured creatinine clearance ≥ 50 mL/min/1.73 m2
* Patients must have disease that can be objectively measured by physical or radiographic exam (per RECIST v1.1 for solid tumor, Lugano criteria for non-Hodgkin lymphoma or International Myeloma Working Group criteria for multiple myeloma), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or a subcutaneous or superficial lesion that can be measured with calipers by clinical exam. For lymph nodes, the short axis must be ≥15 mm. Patient's whose disease cannot be objectively measured by physical or radiographic examination (e.g., elevated serum tumor marker only, bone-only disease without an identifiable soft tissue component, or patients with only assessable non-measurable disease) are NOT eligible.
* Results must be available from a genomic test or immunohistochemistry (IHC) test for protein expression performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited or New York State accredited (for labs offering services to residents of NY) laboratory. Labs that have registered the test with the NIH Genetic Testing Registry or that provide a report that has been designated as optimized for TAPUR participation are preferred, but not required. The genomic or IHC test used to qualify a patient for participation in TAPUR may have been performed on any specimen of the patient's tumor obtained at any point during the patient's care at the discretion of the patient's treating physician. Genomic assays performed on cell-free DNA in plasma ("liquid biopsies") will also be acceptable if the genomic analysis is performed in a laboratory that meets the criteria described above.
* Ability to understand and the willingness to sign a written informed consent/assent document.
* Have a tumor genomic profile for which single agent treatment with one of the FDA approved targeted anti-cancer drugs included in this study has potential clinical benefit based on the criteria described in protocol.
* For orally administered drugs, the patient must be able to swallow and tolerate oral medication and must have no known malabsorption syndrome.
* Because of the risks of drug treatment to the developing fetus, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation, and for four months following completion of study therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study or if she is the partner of a male participant in this study and becomes pregnant while he is participating in this study, she should inform her or her partner's treating physician immediately as well as her obstetrician. Female study patients who become pregnant must immediately discontinue treatment with any study therapy. Male patients should avoid impregnating a female partner. Male study patients, even if surgically sterilized, (i.e. post-vasectomy) must agree to one of the following: practice effective barrier contraception during the entire study treatment period and for a specified amount of time the last dose of study drug, or completely abstain from sexual intercourse.
Note: TAPUR does not explicitly exclude any type of solid tumor, but the patient must have measurable and evaluable disease per RECIST v1.1.
Exclusion Criteria:
* Patients whose disease is not measurable or cannot be assessed by radiographic imaging or physical examination (e.g., elevated serum tumor marker only) are not eligible
* Patients with primary brain tumors or new, untreated or progressive leptomeningeal metastases are excluded
* Patients with previously treated brain metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the 3 months prior to registration. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month prior to study enrollment.
* Patients with known progressive brain metastases are eligible but additional eligibility criteria apply.
Note: there are additional exclusion criteria that may apply
→
Inclusion Criteria:
* 12 years of age or older (\*Restrictions apply. Not all therapies are available for patients \<18)
* Histologically-proven locally advanced or metastatic solid tumor, multiple myeloma or B cell non-Hodgkin lymphoma who is no longer benefiting from standard anti-cancer treatment or for whom, in the opinion of the treating physician, no such treatment is available or indicated (except under the circumstance in which the TAPUR arm is designed to provide additional evidence to support an existing FDA indication).
* Performance status 0-2 (Per Eastern Cooperative Oncology Group (ECOG) criteria)
* Patients must have acceptable organ function as defined below. However, as noted above, drug-specific inclusion/exclusion criteria specified in the protocol appendix for each agent will take precedence for this and all inclusion criteria:
1. Absolute neutrophil count ≥ 1500 µl
2. Hemoglobin ≥ 9.0 g/dl
3. Platelets ≥ 75,000/µl
4. Total bilirubin \< 2.0 mg/ dl, except in patients with Gilbert's Syndrome
5. Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) \< 2.5 x institutional upper limit of normal (ULN) (or \< 5 x ULN in patients with known hepatic metastases)
6. Serum creatinine ≤ 1.5 × ULN or calculated or measured creatinine clearance ≥ 50 mL/min/1.73 m2
* Patients must have disease that can be objectively measured by physical, laboratory or radiographic exam (per RECIST v1.1 for solid tumor, Lugano criteria for non-Hodgkin lymphoma or International Myeloma Working Group criteria for multiple myeloma).
* Results must be available from a genomic test or immunohistochemistry (IHC) test for protein expression performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited or New York State accredited (for labs offering services to residents of NY) laboratory. Labs that have registered the test with the NIH Genetic Testing Registry or that provide a report that has been designated as optimized for TAPUR participation are preferred, but not required. The genomic or IHC test used to qualify a patient for participation in TAPUR may have been performed on any specimen of the patient's tumor obtained at any point during the patient's care at the discretion of the patient's treating physician. Genomic assays performed on cell-free DNA in plasma ("liquid biopsies") will also be acceptable if the genomic analysis is performed in a laboratory that meets the criteria described above.
* Ability to understand and the willingness to sign a written informed consent/assent document.
* Have a tumor genomic profile for which single agent treatment with one of the FDA approved targeted anti-cancer drugs included in this study has potential clinical benefit based on the criteria described in protocol.
* For orally administered drugs, the patient must be able to swallow and tolerate oral medication and must have no known malabsorption syndrome.
* Because of the risks of drug treatment to the developing fetus, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation, and for four months following completion of study therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study or if she is the partner of a male participant in this study and becomes pregnant while he is participating in this study, she should inform her or her partner's treating physician immediately as well as her obstetrician. Female study patients who become pregnant must immediately discontinue treatment with any study therapy. Male patients should avoid impregnating a female partner. Male study patients, even if surgically sterilized, (i.e. post-vasectomy) must agree to one of the following: practice effective barrier contraception during the entire study treatment period and for a specified amount of time the last dose of study treatment, or completely abstain from sexual intercourse.
Note: TAPUR does not explicitly exclude any type of solid tumor, but the patient must have measurable and evaluable disease per RECIST v1.1.
Exclusion Criteria:
* Patients whose disease is not measurable or cannot be assessed by radiographic imaging or physical examination (e.g., elevated serum tumor marker only) are not eligible
* Patients with primary brain tumors or new, untreated or progressive leptomeningeal metastases are excluded
* Patients with previously treated brain metastases or previously treated leptomeningeal disease are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the 1 months prior to registration. All patients with previously treated brain metastases must be clinically stable for at least 1 month after completion of treatment and off steroid treatment for one month prior to study enrollment.
* Patients with known progressive brain metastases are eligible but additional eligibility criteria apply.
Note: there are additional exclusion criteria that may apply
Key Inclusion Criteria:
* Signed Informed Consent
* Documented histological or cytologic diagnosis of NSCLC with each of the following:
1. locally advanced, unresectable, stage III disease (according to the 9th edition of the Union for International Cancer Control and American Joint Committee on Cancer lung cancer TNM staging system); and
2. measurable disease at time of screening (assessment per RECIST v1.1); and
3. must have completed platinum-based chemotherapy concurrent with radiation therapy, within 7 to 42 days prior to the randomization; and
4. no evidence of progression of disease following definitive, platinum-based, concurrent chemoradiation therapy; and
5. must be due to receive consolidation immunotherapy with durvalumab for up to 12 months, with the first dose of blinded study intervention to coincide with the first dose of durvalumab +/- 7 days; and
6. absence of actional genomic mutations (eg, EGFR, ALK).
* Cachexia defined by Fearon criteria:
1. BMI \<20 kg/m2 and involuntary weight loss of \>2% within 6 months prior to screening; or
2. Involuntary weight loss of \>5% over the past 6 months prior to screening irrespective of BMI
* Participant has been evaluated and determined that available anticachexic treatments have either been administered with no positive effect or the participant is not suitable for these treatments.
* Participants who are assessed by the investigator to have an ECOG PS ≤1.
Key Exclusion Criteria:
* Current active reversible causes of decreased food intake, as determined by the investigator. These causes may include, but are not limited to:
1. NCI CTCAE Grade 3 or 4 oral mucositis
2. Mechanical obstructions interfering with the participant's ability to eat
* Receiving tube feedings or parenteral nutrition (either total or partial) at the time of screening or randomization.
* Any prior or current clinical diagnosis of heart failure, irrespective of left ventricular ejection fraction or New York Heart Association classification.
* Cachexia caused by reasons other than NSCLC, as determined by the investigator (eg, severe COPD).
* Mixed small cell and non-small cell lung cancer histology.
* Undergoing major surgery within 4 weeks prior to randomization or planned major surgical procedures during the study.
* History of immune-related adverse event(s) in setting of immunotherapy that required treatment with systemic corticosteroids.
* Chronic use of systemic corticosteroid.
* History of any secondary malignancy in the last 2 years, except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ.
* Symptomatic brain metastasis or leptomeningeal disease.
* Any Grade ≥3 pulmonary disease unrelated to underlying malignancy including, but not limited to:
1. Severe asthma requiring systemic corticosteroids within 30 days prior to first dose of study intervention or not well controlled with low-dose inhaled corticosteroids/long-acting beta-2 agonists.
2. Severe chronic obstructive pulmonary disease requiring supplemental oxygen or systemic corticosteroids.
3. Clinically severe and/or Grade 4 pulmonary emboli within 3 months of the first dose of study intervention. Pulmonary emboli in main or lobar pulmonary arteries are also excluded.
4. Any autoimmune or inflammatory disorders with significant pulmonary parenchymal involvement at time of screening (ie, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc).
* Renal disease requiring dialysis or eGFR \<30 mL/min/1.73 m².
* History of severe liver disease or cirrhosis, unrelated to metastatic cancer. LFT abnormalities at the time of screening; confirmed by a single repeat test if deemed necessary: AST or ALT level ≥ 3 x ULN (\>5 x ULN if liver involvement by the tumor), alkaline phosphatase \> 3 x ULN (\>5 x ULN if liver involvement by the tumor and/or in case of bone metastases), or total bilirubin level ≥ 1.5 x ULN (For Gilbert's syndrome, direct bilirubin \> ULN is exclusionary).
* Left ventricular ejection fraction \<50% on screening echocardiogram (or MUGA scan).
→
Key Inclusion Criteria:
* Signed Informed Consent
* Documented histological or cytologic diagnosis of NSCLC with each of the following:
1. locally advanced, unresectable, stage III disease (according to the 9th edition of the Union for International Cancer Control and American Joint Committee on Cancer lung cancer TNM staging system); and
2. measurable disease at time of screening (assessment per RECIST v1.1); and
3. must have completed platinum-based chemotherapy concurrent with radiation therapy, within 7 to 42 days prior to the randomization; and
4. no evidence of progression of disease following definitive, platinum-based, concurrent chemoradiation therapy; and
5. must be due to receive consolidation immunotherapy with durvalumab for up to 12 months, with the first dose of blinded study intervention to coincide with the first dose of durvalumab +/- 7 days; and
6. absence of actional genomic mutations (eg, EGFR, ALK).
* Cachexia defined by Fearon criteria:
1. BMI \<20 kg/m2 and involuntary weight loss of \>2% within 6 months prior to screening; or
2. Involuntary weight loss of \>5% over the past 6 months prior to screening irrespective of BMI
* Participant has been evaluated and determined that available anticachexic treatments have either been administered with no positive effect or the participant is not suitable for these treatments.
* Participants who are assessed by the investigator to have an ECOG PS ≤1.
Key Exclusion Criteria:
* Current active reversible causes of decreased food intake, as determined by the investigator. These causes may include, but are not limited to:
1. NCI CTCAE Grade 3 or 4 oral mucositis
2. Mechanical obstructions interfering with the participant's ability to eat
* Receiving tube feedings or having an ongoing clinical indication for parenteral nutrition (either total or partial) at the time of screening or randomization. Of note: short-term parenteral nutritional support for the management of acute, transient medical indications is allowed if discontinued prior to randomization.
* Any prior or current clinical diagnosis of heart failure, irrespective of left ventricular ejection fraction or New York Heart Association classification.
* Cachexia caused by reasons other than NSCLC, as determined by the investigator (eg, severe COPD).
* Mixed small cell and non-small cell lung cancer histology.
* Clinically significant ascites that requires medical intervention or underwent a paracentesis within 4 weeks prior to randomization.
* Undergoing major surgery within 4 weeks prior to randomization or planned major surgical procedures during the study.
* History of adrenal disorders (e.g. adrenal insufficiency, Cushing syndrome), pituitary adenoma or ectopic ACTH.
* Chronic use of systemic corticosteroid.
* History of any secondary malignancy in the last 2 years, except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ.
* Symptomatic brain metastasis or leptomeningeal disease.
* Any Grade ≥3 pulmonary disease unrelated to underlying malignancy including, but not limited to:
1. Severe asthma requiring systemic corticosteroids within 30 days prior to first dose of study intervention or not well controlled with low-dose inhaled corticosteroids/long-acting beta-2 agonists.
2. Severe chronic obstructive pulmonary disease requiring supplemental oxygen or systemic corticosteroids.
3. Clinically severe and/or Grade 4 pulmonary emboli within 3 months of the first dose of study intervention. Pulmonary emboli in main or lobar pulmonary arteries are also excluded.
4. Any autoimmune or inflammatory disorders with significant pulmonary parenchymal involvement at time of screening (ie, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc).
* Renal disease requiring dialysis or eGFR \<30 mL/min/1.73 m².
* History of severe liver disease or cirrhosis, unrelated to metastatic cancer. LFT abnormalities at the time of screening; confirmed by a single repeat test if deemed necessary: AST or ALT level ≥ 3 x ULN (\>5 x ULN if liver involvement by the tumor), or total bilirubin level ≥ 1.5 x ULN (For Gilbert's syndrome, direct bilirubin \> ULN is exclusionary).
* Left ventricular ejection fraction \<50% on screening echocardiogram (or MUGA scan).
Inclusion Criteria: -Participants must have histologically confirmed hormone receptor positive (HR+) HER2 negative metastatic or locally recurrent unresectable invasive breast cancer. ER, PR and HER2 measurements should be performed according to institutional guidelines, in a CLIA-approved setting. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines. -Men and pre- and postmenopausal women are eligible. Ongoing monthly GNRH agonist is required in pre-menopausal women or male participants for at least 4 weeks prior to study entry. -Participants must have radiological or objective evidence of progression on an endocrine and CDK 4/6 inhibitor regimen in the metastatic setting, and/or relapse/progression during or within 12 months of completion of an endocrine and CDK4/6 inhibitor regimen in the adjuvant setting. --Participants must have previously been exposed to CDK4/6 inhibitor therapy in combination with endocrine therapy. Exposure to any prior CDK4/6 inhibitor, (including palbociclib, abemaciclib, and ribociclib) is allowed. Patients may have a line of endocrine therapy after combination endocrine and CDK4/6 inhibitor exposure. --Participants must have remained on prior endocrine and CDK4/6 therapy in the metastatic setting without progression for at least 6 months prior to study entry. --It is not mandatory to have a CDK 4/6 inhibitor containing regimen as the most recent treatment. -Participants may have 0-1 prior lines of cytotoxic chemotherapy in the metastatic setting. -Prior endocrine therapy in the metastatic setting may include any aromatase inhibitor (AI) or tamoxifen, but may not include prior fulvestrant. In the metastatic setting, 1-2 prior lines of endocrine therapy are allowed. -Participants may have received radiotherapy for palliative purpose, but must not be experiencing \> grade 1 treatment related toxicities, and must have completed treatment \> 14 days prior to registration. -Age ≥18 years. Because no dosing or adverse event data are currently available on the use of study agents in participants \<18 years of age, children are excluded from this study. -ECOG performance status 0-1 (see Appendix A). -Participants must have normal organ and marrow function as defined below: -Absolute neutrophil count \> 1,500/µL --Platelets \> 100,000/µL --Hemoglobin \> 9g/dL --Total bilirubin \< 1.5 x institutional upper limit of normal (ULN) (participants with documented Gilbert's disease are allowed total bilirubin up to 1.5X ULN) --AST (SGOT)/ALT (SGPT) \< 2.5 x institutional ULN, or ≤ 5 x ULN for subjects with documented metastatic disease to the liver. --Creatinine \< institutional ULN or creatinine clearance \> 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN. --Baseline QTc \< 480 ms -The effects of palbociclib and avelumab on the developing human fetus are unknown. If, for any reason, a woman should become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately. Women of childbearing age, women who are made postmenopausal through use of GNRH agonists, and men must agree to use adequate contraception for the duration of protocol treatment and for at least 60 days after the last dose of study medication if the risk of contraception exists. -Adequate contraception is defined as one highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the participant and/or partner. -Highly Effective Non-Hormonal Contraception -Methods of birth control which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly are considered highly-effective forms of contraception. -The following non-hormonal methods of contraception are acceptable: --True abstinence when this is in line with the preferred and usual lifestyle of the participant. \[Periodic abstinence (e.g., calendar, ovulation, symptothermal post-ovulation methods) and withdrawal are not acceptable methods of contraception\]. --Male sterilization (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female participants, the vasectomized male partner should be the sole partner. OR -Effective Non-Hormonal Contraception Alternatively two of the following effective forms of contraception may be used instead: --Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS). Consideration should be given to the type of device being used, as there is higher failure rates quoted for certain types, e.g., steel or copper wire. --Condom with spermicidal foam/gel/film/cream/suppository. --Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. --The use of barrier contraceptives should always be supplemented with the use of spermicide. The following should be noted: --Failure rates indicate that, when used alone, the diaphragm and condom are not highly effective forms of contraception. Therefore, the use of additional spermicides does confer additional theoretical contraceptive protection. --However, spermicides alone are ineffective at preventing pregnancy when the whole ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception and should not be used alone. It should be noted that two forms of effective contraception are required. A double barrier method is acceptable, which is defined as condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream /suppository. -Premenopausal women must have a negative serum or urine pregnancy test. Pregnancy testing does not need to be pursued in female participants who are: --Age \> 60 years; or --Age \< 60 with intact uterus and amenorrhea for 12 consecutive months or more AND estrogen (estradiol) levels within postmenopausal range; or --Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. -Participant must be able to swallow and retain oral medication. -Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: -Participants who have had endocrine, chemotherapy, and/or biologic therapy within 14 days prior to entering the study or those who have not recovered from any prior treatment-related toxicities (must recover to no more than grade 1. Alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 toxicity not constituting a safety risk based on investigator's judgment are acceptable). -Participants who are receiving concurrent therapy with other investigational agents. -Rapidly progressive, symptomatic, visceral spread of disease placing participant at risk of life-threatening complications in the short term. -Participants with active brain metastases. Stable treated brain metastases are allowed (this includes participants who have documented radiologic stability at least 4 weeks after radiotherapy, and do not require systemic steroids for management of symptoms from CNS metastatic lesions). -Participants who have discontinued prior palbociclib for toxicity, or have needed more than one dose or schedule reduction for toxicity from prior palbociclib therapy. If a participant required a single dose reduction during prior palbociclib therapy and tolerated it well, for example prior dosing at 100 mg qd 3 weeks on 1 week off schedule, than that dose may be selected for this trial. -History of allergic reactions to palbociclib or attributed to compounds of similar chemical or biologic composition to palbociclib. -Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3) -Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes are ineligible. Lists including medications and substances known or with the potential to interact with the CYP3A isoenzymes are provided in Appendix B, and can also be found within Section 5.4. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product. -Current use of drugs listed in Appendix C that are known to prolong the QT interval (See Appendix C) -Prior organ transplantation including allogenic stem-cell transplantation -Current use of immunosuppressive medication, except for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). -Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring systemic therapy, clinically significant cardiovascular disease including: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication, uncontrolled diabetes mellitus, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation. -Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. -Known history of testing positive for HIV or known acquired immunodeficiency syndrome, or need to receive combination antiretroviral therapy for HIV -Known history of immune-mediated conditions including colitis, inflammatory bowel disease requiring steroid or immunosuppressive therapy, pneumonitis, or pulmonary fibrosis. -Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive) -Live vaccination within 4 weeks of the first dose of avelumab -Pregnant women are excluded from this study because effect of palbociclib and avelumab on a developing fetus is unknown. Breastfeeding should be discontinued prior to entry onto the study. -Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
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Inclusion Criteria:
* Participants must have histologically confirmed hormone receptor positive (HR+) HER2 negative metastatic or locally recurrent unresectable invasive breast cancer. ER, PR and HER2 measurements should be performed according to institutional guidelines, in a CLIA-approved setting. Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines.
* Men and pre- and postmenopausal women are eligible. Ongoing monthly GNRH agonist is required in pre-menopausal women or male participants for at least 4 weeks prior to study entry.
* Participants must have radiological or objective evidence of progression on an endocrine and CDK 4/6 inhibitor regimen in the metastatic setting, and/or relapse/progression during or within 12 months of completion of an endocrine and CDK4/6 inhibitor regimen in the adjuvant setting.
* Participants must have previously been exposed to CDK4/6 inhibitor therapy in combination with endocrine therapy. Exposure to any prior CDK4/6 inhibitor, (including palbociclib, abemaciclib, and ribociclib) is allowed. Patients may have a line of endocrine therapy after combination endocrine and CDK4/6 inhibitor exposure.
* Participants must have remained on prior endocrine and CDK4/6 therapy in the metastatic setting without progression for at least 6 months prior to study entry.
* It is not mandatory to have a CDK 4/6 inhibitor containing regimen as the most recent treatment.
* Participants may have 0-1 prior lines of cytotoxic chemotherapy in the metastatic setting.
* Prior endocrine therapy in the metastatic setting may include any aromatase inhibitor (AI) or tamoxifen, but may not include prior fulvestrant. In the metastatic setting, 1-2 prior lines of endocrine therapy are allowed.
* Participants may have received radiotherapy for palliative purpose, but must not be experiencing \> grade 1 treatment related toxicities, and must have completed treatment \> 14 days prior to registration.
* Age ≥18 years. Because no dosing or adverse event data are currently available on the use of study agents in participants \<18 years of age, children are excluded from this study.
* ECOG performance status 0-1 (see Appendix A).
* Participants must have normal organ and marrow function as defined below:
* Absolute neutrophil count \> 1,500/µL
* Platelets \> 100,000/µL
* Hemoglobin \> 9g/dL
* Total bilirubin \< 1.5 x institutional upper limit of normal (ULN) (participants with documented Gilbert's disease are allowed total bilirubin up to 1.5X ULN)
* AST (SGOT)/ALT (SGPT) \< 2.5 x institutional ULN, or ≤ 5 x ULN for subjects with documented metastatic disease to the liver.
* Creatinine \< institutional ULN or creatinine clearance \> 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional ULN.
* Baseline QTc \< 480 ms
* The effects of palbociclib and avelumab on the developing human fetus are unknown. If, for any reason, a woman should become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately. Women of childbearing age, women who are made postmenopausal through use of GNRH agonists, and men must agree to use adequate contraception for the duration of protocol treatment and for at least 60 days after the last dose of study medication if the risk of contraception exists.
* Adequate contraception is defined as one highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the participant and/or partner.
* Highly Effective Non-Hormonal Contraception
* Methods of birth control which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly are considered highly-effective forms of contraception.
* The following non-hormonal methods of contraception are acceptable:
* True abstinence when this is in line with the preferred and usual lifestyle of the participant. \[Periodic abstinence (e.g., calendar, ovulation, symptothermal post-ovulation methods) and withdrawal are not acceptable methods of contraception\].
* Male sterilization (with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female participants, the vasectomized male partner should be the sole partner.
OR
-Effective Non-Hormonal Contraception
Alternatively two of the following effective forms of contraception may be used instead:
* Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS). Consideration should be given to the type of device being used, as there is higher failure rates quoted for certain types, e.g., steel or copper wire.
* Condom with spermicidal foam/gel/film/cream/suppository.
* Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
* The use of barrier contraceptives should always be supplemented with the use of spermicide. The following should be noted:
* Failure rates indicate that, when used alone, the diaphragm and condom are not highly effective forms of contraception. Therefore, the use of additional spermicides does confer additional theoretical contraceptive protection.
* However, spermicides alone are ineffective at preventing pregnancy when the whole ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception and should not be used alone.
It should be noted that two forms of effective contraception are required. A double barrier method is acceptable, which is defined as condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream /suppository.
* Premenopausal women must have a negative serum or urine pregnancy test. Pregnancy testing does not need to be pursued in female participants who are:
* Age \> 60 years; or
* Age \< 60 with intact uterus and amenorrhea for 12 consecutive months or more AND estrogen (estradiol) levels within postmenopausal range; or
* Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation.
* Participant must be able to swallow and retain oral medication.
* Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
* Participants who have had endocrine, chemotherapy, and/or biologic therapy within 14 days prior to entering the study or those who have not recovered from any prior treatment-related toxicities (must recover to no more than grade 1. Alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 toxicity not constituting a safety risk based on investigator's judgment are acceptable).
* Participants who are receiving concurrent therapy with other investigational agents.
* Rapidly progressive, symptomatic, visceral spread of disease placing participant at risk of life-threatening complications in the short term.
* Participants with active brain metastases. Stable treated brain metastases are allowed (this includes participants who have documented radiologic stability at least 4 weeks after radiotherapy, and do not require systemic steroids for management of symptoms from CNS metastatic lesions).
* Participants who have discontinued prior palbociclib for toxicity, or have needed more than one dose or schedule reduction for toxicity from prior palbociclib therapy. If a participant required a single dose reduction during prior palbociclib therapy and tolerated it well, for example prior dosing at 100 mg qd 3 weeks on 1 week off schedule, than that dose may be selected for this trial.
* History of allergic reactions to palbociclib or attributed to compounds of similar chemical or biologic composition to palbociclib.
* Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)
* Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes are ineligible. Lists including medications and substances known or with the potential to interact with the CYP3A isoenzymes are provided in Appendix B, and can also be found within Section 5.4. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
* Current use of drugs listed in Appendix C that are known to prolong the QT interval (See Appendix C)
* Prior organ transplantation including allogenic stem-cell transplantation
* Current use of immunosuppressive medication, except for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
* Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection requiring systemic therapy, clinically significant cardiovascular disease including: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication, uncontrolled diabetes mellitus, or psychiatric illness/social situations that would limit compliance with study requirements. Ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation.
* Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
* Known history of testing positive for HIV or known acquired immunodeficiency syndrome, or need to receive combination antiretroviral therapy for HIV
* Known history of immune-mediated conditions including colitis, inflammatory bowel disease requiring steroid or immunosuppressive therapy, pneumonitis, or pulmonary fibrosis.
* Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
* Live vaccination within 4 weeks of the first dose of avelumab
* Pregnant women are excluded from this study because effect of palbociclib and avelumab on a developing fetus is unknown. Breastfeeding should be discontinued prior to entry onto the study.
* Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
Inclusion Criteria:
* Pathologically confirmed locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV) squamous or non-squamous NSCLC and are not a candidate for complete surgical resection and curative concurrent/sequential chemoradiotherapy
* PD-L1 status available
* Part B only: PD-L1 ≥ TPS 1%
* Measurable disease based on RECIST v1.1 per investigator.
* Eastern Cooperative Oncology Group performance status of 0 or 1.
* Adequate organ function
Exclusion Criteria:
* Participants with known AGAs including EGFR, ALK and ROS1, NTRK, BRAF, and MET
* History of another malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy
* Known active CNS lesions, including brainstem, meningeal, or spinal cord metastases or compression
* Leptomeningeal disease
* Active autoimmune diseases requiring systemic treatment within the past 2 years
* Previous systemic anti-tumor therapy for locally advanced, unresectable, or metastatic NSCLC
* Previous treatment with immunotherapy (exception is (neo)adjuvant anti-PD-(L)1), ADCs containing MMAE payload, systemic anti-angiogenic therapy, or prior radiotherapy to the lung within 6 months of first dose of study intervention
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Inclusion Criteria:
* Pathologically confirmed locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV) squamous or non-squamous NSCLC and are not a candidate for complete surgical resection and curative concurrent/sequential chemoradiotherapy
* PD-L1 status available
* Part B only: PD-L1 ≥ TPS 1%
* Measurable disease based on RECIST v1.1 per investigator.
* Eastern Cooperative Oncology Group performance status of 0 or 1.
* Adequate organ function
Exclusion Criteria:
* Participants with known AGAs including EGFR, ALK and ROS1, NTRK, BRAF, and MET for which there are available first-line therapies per local standard-of-care (SOC)
* History of another malignancy within 2 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy
* Known active CNS lesions, including brainstem, meningeal, or spinal cord metastases or compression
* Leptomeningeal disease
* Active autoimmune diseases requiring systemic treatment within the past 2 years
* Previous systemic anti-tumor therapy for locally advanced or metastatic NSCLC
* Previous treatment with immunotherapy (exception is (neo)adjuvant or consolidation anti-PD-(L)1), ADCs containing MMAE payload, systemic anti-angiogenic therapy, or prior radiotherapy \>30 Gy to the lung within 6 months of first dose of study intervention
Inclusion Criteria:
* Male and female participants aged 18 years (or the minimum age of consent in accordance with local regulations if \>18 years) to 65 years (inclusive) at screening who are overtly healthy as determined by medical evaluation including a detailed medical history, complete physical examination (PE), including blood pressure (BP) and pulse rate (PR) measurement, 12-lead ECG (electrocardiogram) and clinical laboratory tests.
* Body mass index (BMI) of ≥16 to ≤32 kg/m2; Body weight ≥50 kg (110 lb).
Exclusion Criteria:
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
* Use of prescription or nonprescription drug, dietary and herbal supplements within 7 days or 5 half-lives (whichever is longer), with the exception of moderate or strong cytochrome P450 (CYP)3A inducers or inhibitors which are prohibited within 14 days plus 5 half-lives, prior to the first dose of study intervention.
* Current use of any prohibited concomitant medication(s) or participant unwilling/able to use a permitted concomitant medication(s).
* Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Participation in studies of other investigational products (drug or vaccine) at any time during their participation in this study.
* For females, pregnancy, as indicated by a positive serum pregnancy test (serum) at screening and/or a positive pregnancy test (serum and/or urine) on Day -1 in women of childbearing potential.
* Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic) for participants \<60 years; and ≥150/90 mm/Hg for participants ≥60 years old, following at least 5 minutes of supine rest.
* Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF \[QTc corrected using Fridericia's formula\] \>450 ms, complete left bundle branch block (LBBB), signs of an acute or indeterminate-age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second- or third- degree AV (atrioventricular) block, or serious bradyarrhythmias or tachyarrhythmias).
* Participants with defined abnormalities in kidney and liver laboratory tests at screening.
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Inclusion Criteria:
* Male and female participants aged 18 years (or the minimum age of consent in accordance with local regulations if \>18 years) to 65 years (inclusive) at screening who are overtly healthy as determined by medical evaluation including a detailed medical history, complete physical examination (PE), including blood pressure (BP) and pulse rate (PR) measurement, 12-lead ECG (electrocardiogram) and clinical laboratory tests.
* Body mass index (BMI) of ≥16 to ≤32 kg/m2; Body weight ≥50 kg (110 lb).
Exclusion Criteria:
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
* Use of prescription or nonprescription drug, dietary and herbal supplements within 7 days or 5 half-lives (whichever is longer), with the exception of moderate or strong cytochrome P450 (CYP)3A inducers or inhibitors which are prohibited within 14 days plus 5 half-lives, prior to the first dose of study intervention.
* Current use of any prohibited concomitant medication(s) or participant unwilling/able to use a permitted concomitant medication(s).
* Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Participation in studies of other investigational products (drug or vaccine) at any time during their participation in this study.
* For females, pregnancy, as indicated by a positive serum pregnancy test (serum) at screening and/or a positive pregnancy test (serum and/or urine) on Day -1 in women of childbearing potential.
* Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic) for participants \<60 years; and ≥150/90 mm/Hg for participants ≥60 years old, following at least 5 minutes of supine rest.
* Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF \[QTc corrected using Fridericia's formula\] \>450 ms, complete left bundle branch block (LBBB), signs of an acute or indeterminate-age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second- or third- degree AV (atrioventricular) block, or serious bradyarrhythmias or tachyarrhythmias).
* Participants with defined abnormalities in kidney and liver laboratory tests at screening.
* Participants in Sub-Saharan Africa or who have relocated from Sub-Saharan Africa within 6 months of screening.
Inclusion Criteria:
* 1\. This study will enroll patients with relapsed and refractory multiple myeloma who have had at least 2 prior lines of therapy including patients who have had previous treatment with both immunomodulatory drugs (IMiDs) and a proteasome inhibitor (PI). Prior therapy with anti-CD38 and anti-B cell maturation antigen (BCMA) target will be permitted except an anti-BCMA T cell engager. Patients cannot be refractory to an anti-CD38 antibody.
* 2\. Measurable disease of multiple myeloma as defined by at least one of the following:
* a. Serum monoclonal protein ≥ 0.5 g/dL. Patients with IgD disease and lower amounts of monoclonal protein may be permitted to enroll with PI approval
* b. ≥ 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
* c. Serum free light chain ≥ 100 mg/L (10 mg/dL) and abnormal serum free kappa to serum free lambda light chain (FLC) ratio (\<0.26 or \>1.65)
* 3\. Age ≥18 years.
--a. The effects of elranatamab and isatuximab on the developing human fetus are unknown. For this reason and because anti-BCMA bispecific antibodies are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 4 months after the last dose of elranatamab and 5 months after the last dose of isatuximab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* 4\. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
* 5\. Participants must have adequate organ and marrow function as defined below:
* a. ANC ≥ 1000/μL. G-CSF is not permitted within 7 days of screening.
* b. Platelet count ≥ 50,000/µL. Platelet transfusion is not permitted within 7 days of screening.
* c. Hemoglobin ≥ 8 g/dL. Red blood cell transfusions are permitted to meet eligibility criteria.
* d. Calculated creatinine clearance of ≥ 30 mL/min by Cockcroft-Gault equation.
* e. Patient has adequate hepatic function, as evidenced by each of the following:
* Serum bilirubin values \< 2 mg/dL; and
* Serum aspartate transaminase (ALT) and/or aspartate transaminase (AST) values\< 2.5 × the upper limit of normal (ULN) of the institutional laboratory reference range. Patients with elevated bilirubin due to Gilbert's syndrome may be permitted with PI approval (i.e., total bilirubin \<3 mg/dL and normal direct bilirubin).
* 6\. Participants with a prior or concurrent 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.
* 7\. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
* 8\. Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* 1\. Patients with active plasma cell leukemia, POEMS syndrome, or amyloidosis are excluded from this trial.
* 2\. Stem cell transplant within 12 weeks prior to enrollment, or active GVHD.
* 3\. Ongoing Grade ≥2 peripheral sensory or motor neuropathy.
* 4\. History of any grade peripheral sensory or motor neuropathy with prior BCMA directed therapy. History of GBS or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.
* 5\. Previous treatment with an anti-BCMA bispecific T cell engager.
--a. Prior treatment with anti-BCMA CAR-T and/or ADC therapy is permitted; however, the participant cannot be refractory to this therapy if it was administered as the last line prior to study enrollment.
* 6\. Participants who are receiving any investigational agents currently.
* 7\. Participants who have had myeloma therapy or investigational drug within 2 weeks prior to start of treatment or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
* 8\. Known or suspected hypersensitivity to the study drug or any components of the device (e.g. adhesive which contains acrylic).
* 9\. Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as any of the following within 6 months prior to enrollment:
* a. Acute myocardial infarction, acute coronary syndromes (e.g., unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, pericardial effusion);
* b. Clinically significant cardiac arrhythmias (e.g., uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
* c. Thromboembolic or cerebrovascular events (e.g., transient ischemic attack, cerebrovascular accident, deep vein thrombosis \[unless associated with a central venous access complication\] or pulmonary embolism);
* 10\. Participants with known active HBV, HCV, HIV, or any active, uncontrolled bacterial, fungal, or viral infection. Active infections must be resolved at least 14 days prior to enrollment. Per institutional protocol, HBV DNA testing by PCR is mandatory for subjects at risk for HBV reactivation.
* 11\. Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ and or other cancers treated with curative intent.
* 12\. Other surgical (including major surgery within past 14 days prior to enrollment) medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
* 13\. Live attenuated vaccine within 30 days of the first dose of study intervention.
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Inclusion Criteria:
* 1\. This study will enroll patients with relapsed and refractory multiple myeloma who have had at least 1 prior line of therapy including patients who have had previous treatment with both immunomodulatory drugs (IMiDs) and a proteasome inhibitor (PI). Prior therapy with anti-CD38 and anti-B cell maturation antigen (BCMA) target will be permitted except an anti-BCMA T cell engager.
* 2\. Measurable disease of multiple myeloma as defined by at least one of the following:
* a. Serum monoclonal protein ≥ 0.5 g/dL. Patients with IgD disease and lower amounts of monoclonal protein may be permitted to enroll with PI approval
* b. ≥ 200 mg of monoclonal protein in the urine on 24-hour electrophoresis
* c. Serum free light chain ≥ 100 mg/L (10 mg/dL) and abnormal serum free kappa to serum free lambda light chain (FLC) ratio (\<0.26 or \>1.65)
* d. Evidence of EMD as observed through clinical examination, MRI, computed tomography scans (if there is no contraindication to the use of IV contrast), or PET/CT fusion studies
* 3\. Age ≥18 years.
--a. The effects of elranatamab and isatuximab on the developing human fetus are unknown. For this reason and because anti-BCMA bispecific antibodies are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 4 months after the last dose of elranatamab and 5 months after the last dose of isatuximab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* 4\. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
* 5\. Participants must have adequate organ and marrow function as defined below:
* a. ANC ≥ 1000/μL. G-CSF is not permitted within 7 days of screening.
* b. Platelet count ≥ 50,000/µL. Platelet transfusion is not permitted within 7 days of screening.
* c. Hemoglobin ≥ 8 g/dL. Red blood cell transfusions are permitted to meet eligibility criteria.
* d. Calculated creatinine clearance of ≥ 30 mL/min by Cockcroft-Gault equation.
* e. Patient has adequate hepatic function, as evidenced by each of the following:
* Serum bilirubin values \< 2 mg/dL; and
* Serum aspartate transaminase (ALT) and/or aspartate transaminase (AST) values\< 2.5 × the upper limit of normal (ULN) of the institutional laboratory reference range. Patients with elevated bilirubin due to Gilbert's syndrome may be permitted with PI approval (i.e., total bilirubin \<3 mg/dL and normal direct bilirubin).
* 6\. Participants with a prior or concurrent 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.
* 7\. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
* 8\. Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* 1\. Patients with active plasma cell leukemia, POEMS syndrome, or amyloidosis are excluded from this trial.
* 2\. Stem cell transplant within 12 weeks prior to enrollment, or active GVHD.
* 3\. Ongoing Grade ≥2 peripheral sensory or motor neuropathy.
* 4\. History of any grade peripheral sensory or motor neuropathy with prior BCMA directed therapy. History of GBS or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.
* 5\. Previous treatment with an anti-BCMA bispecific T cell engager.
--a. Prior treatment with anti-BCMA CAR-T and/or ADC therapy is permitted; however, the participant cannot be refractory to this therapy if it was administered as the last line prior to study enrollment.
* 6\. Participants who are receiving any investigational agents currently.
* 7\. Participants who have had myeloma therapy or investigational drug within 2 weeks prior to start of treatment or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
* 8\. Known or suspected hypersensitivity to the study drug or any components of the device (e.g. adhesive which contains acrylic).
* 9\. Impaired cardiovascular function or clinically significant cardiovascular diseases, defined as any of the following within 6 months prior to enrollment:
* a. Acute myocardial infarction, acute coronary syndromes (e.g., unstable angina, coronary artery bypass graft, coronary angioplasty or stenting, pericardial effusion);
* b. Clinically significant cardiac arrhythmias (e.g., uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
* c. Thromboembolic or cerebrovascular events (e.g., transient ischemic attack, cerebrovascular accident, deep vein thrombosis \[unless associated with a central venous access complication\] or pulmonary embolism);
* 10\. Participants with known active HBV, HCV, HIV, or any active, uncontrolled bacterial, fungal, or viral infection. Active infections must be resolved at least 14 days prior to enrollment. Per institutional protocol, HBV DNA testing by PCR is mandatory for subjects at risk for HBV reactivation.
* 11\. Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ and or other cancers treated with curative intent.
* 12\. Other surgical (including major surgery within past 14 days prior to enrollment) medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
* 13\. Live attenuated vaccine within 30 days of the first dose of study intervention.
Inclusion Criteria:
1. Participants must meet the following criteria:
1. Have pathologically confirmed Stage IIIB or IIIC NSCLC and not be a candidate for surgical resection or definitive chemoradiation, or Stage IV NSCLC per the AJCC Staging Manual (Version 8.0) and the UICC Staging System (Eighth edition).
2. Participants with non-squamous histology must have documented negative test results for EGFR, ALK, and ROS1 AGAs and no known AGAs in NTRK, BRAF, RET, MET, or other AGAs with approved front-line therapies per local standard of care.
3. Large cell neuroendocrine carcinoma is excluded.
4. Candidate for treatment with pembrolizumab monotherapy per local guidelines.
2. Tumor has PD-L1 expression in ≥50% of tumor cells (TPS ≥50%) as determined by local testing
3. Measurable disease based on RECIST v1.1 per investigator.
4. Resolution of acute effects of any prior therapy to either baseline severity or NCI CTCAE Grade 1 or less (except for AEs not constituting a safety risk in the investigator's judgment), unless otherwise excluded.
Exclusion Criteria:
1. Life expectancy of \<3 months in the opinion of the investigator.
2. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or make the participant inappropriate for the study.
3. Participants with any history of another malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy.
4. Known or suspected hypersensitivity, intolerance, or contraindication to any excipient contained in the drug formulation of sigvotatug vedotin or pembrolizumab.
5. Participants with any of the following respiratory conditions:
1. Evidence of noninfectious or drug-induced ILD or pneumonitis
2. Known DLCO (adjusted for hemoglobin) \<50% predicted.
3. Grade ≥3 pulmonary disease unrelated to underlying malignancy
6. Known active CNS lesions are excluded. Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be eligible. Clinically inactive brain metastases of longest diameter \<0.5 cm are permitted.
7. Major surgery (defined as a surgery requiring inpatient hospitalization of at least 48 hours) within 21 days or minor surgery within 7 days prior to first dose of study intervention.
8. Receipt of a live vaccine within 30 days prior to first dose of study intervention.
9. Pre-existing peripheral neuropathy Grade ≥2 per NCI CTCAE v5.0.
10. Uncontrolled diabetes mellitus, defined as HbA1c ≥8.0% or HbA1c between 7.0% and 8.0% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
11. Prior immune-related AE that led to anti-PD-(L)1 treatment discontinuation, required a high-dose steroid taper (≥0.5 mg/kg prednisone or equivalent per day) for \>2 weeks, or required treatment with systemic immunosuppressive therapy.
12. History of autoimmune disease that has required systemic treatment in the past 2 years
13. Participants with prior solid organ or bone marrow transplantation.
14. Currently receiving a high-dose steroid (\>10 mg prednisone or equivalent per day) or other immune suppressant or has a condition requiring a chronic high-dose steroid or immune suppressant.
15. Prior and concomitant therapy:
1. Any prior treatment with MMAE-derived drugs or IB6 targeting agents.
2. Prior systemic therapy, including anti-PD-(L)1 therapy, for locally advanced, unresectable, or metastatic NSCLC.
* (Neo)adjuvant anti-PD-(L)1 is allowed if recurrence or progression occurred ≥9 months after the last dose.
* Other (neo)adjuvant or definitive therapy is allowed if recurrence or progression occurred ≥6 months after the last dose.
3. Prior radiotherapy to the lung within 6 months of first dose of study intervention, referencing the last date radiotherapy was received.
4. Chemotherapy, biologics, and/or other antitumor treatment with immunotherapy not specifically prohibited that is completed less than 4 weeks prior to first dose of study intervention, or 2 weeks for palliative radiotherapy.
5. Any prior therapy with an immune-oncology agent directed to a stimulatory or co-inhibitory T-cell receptor
16. History of or current ongoing infection, including participants positive for active HIV, HBV, or HCV.
17. Severe uncontrolled cardiac or cerebrovascular condition within the previous 6 months
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Inclusion Criteria:
1. Participants must meet the following criteria:
1. Have pathologically confirmed Stage IIIB or IIIC NSCLC and not be a candidate for surgical resection or definitive chemoradiation, or Stage IV NSCLC per the AJCC Staging Manual (Version 8.0) and the UICC Staging System (Eighth edition).
2. Participants with known AGAs including EGFR, ALK, ROS1, NTRK, BRAF, RET, and MET, for which there are approved and available first-line therapies per local SOC are ineligible. Documented negative results for EGFR, ALK, and ROS1 AGAs are required for participants with non-squamous histology.
3. Participants with large cell neuroendocrine carcinoma are excluded.
4. Must be an appropriate candidate for treatment with pembrolizumab monotherapy per local guidelines.
2. Tumor has PD-L1 expression in ≥50% of tumor cells (TPS ≥50%) as determined by local testing.
3. Measurable disease based on RECIST v1.1 per investigator.
4. Resolution of acute effects of any prior therapy to either baseline severity or NCI CTCAE Grade 1 or less (except for AEs not constituting a safety risk in the investigator's judgment), unless otherwise excluded.
Exclusion Criteria:
1. Life expectancy of \<3 months in the opinion of the investigator.
2. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or make the participant inappropriate for the study.
3. Participants with any history of another malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy.
4. Known or suspected hypersensitivity, intolerance, or contraindication to any excipient contained in the drug formulation of sigvotatug vedotin or pembrolizumab.
5. Participants with any of the following respiratory conditions:
1. Evidence of noninfectious or drug-induced ILD or pneumonitis
2. Known DLCO (adjusted for hemoglobin) \<50% predicted.
3. Grade ≥3 pulmonary disease unrelated to underlying malignancy
6. Known active CNS lesions are excluded. Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be eligible. Up to 5 clinically asymptomatic brain metastases of longest diameter \<1.0 cm are permitted without definitive surgery and/or radiotherapy.
7. Major surgery (defined as a surgery requiring inpatient hospitalization of at least 48 hours) within 21 days or minor surgery (excluding peripherally inserted central catheter placement and implantable central venous port placement) within 3 days prior to first dose of study intervention.
8. Receipt of a live vaccine within 30 days prior to first dose of study intervention.
9. Pre-existing peripheral neuropathy Grade ≥2 per NCI CTCAE v5.0.
10. Uncontrolled diabetes mellitus, defined as HbA1c ≥8.0% or HbA1c between 7.0% and 8.0% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
11. Prior immune-related AE that led to anti-PD-(L)1 treatment discontinuation, required a high-dose steroid taper (≥0.5 mg/kg prednisone or equivalent per day) for \>2 weeks, or required treatment with systemic immunosuppressive therapy.
12. History of autoimmune disease that has required systemic treatment in the past 2 years
13. Participants with prior solid organ or bone marrow transplantation.
14. Currently receiving a high-dose steroid (\>10 mg prednisone or equivalent per day) or other immune suppressant or has a condition requiring a chronic high-dose steroid or immune suppressant.
15. Prior and concomitant therapy:
1. Any prior treatment with MMAE-derived drugs or IB6 targeting agents.
2. Prior systemic therapy, including anti-PD-(L)1 therapy, for locally advanced, unresectable, or metastatic NSCLC.
* (Neo)adjuvant anti-PD-(L)1 is allowed if recurrence or progression occurred ≥9 months after the last dose.
* Other (neo)adjuvant or definitive therapy is allowed if recurrence or progression occurred ≥6 months after the last dose.
3. Prior radiotherapy to the lung within 6 months of first dose of study intervention, referencing the last date radiotherapy was received. This includes both curative and palliative radiotherapy.
4. Chemotherapy, biologics, and/or other antitumor treatment with immunotherapy not specifically prohibited that is completed less than 4 weeks prior to first dose of study intervention, or 2 weeks for palliative radiotherapy.
5. Any prior therapy with an immune-oncology agent directed to a stimulatory or co-inhibitory T-cell receptor
16. History of or current ongoing infection, including participants positive for active HIV, HBV, or HCV.
17. Severe uncontrolled cardiac or cerebrovascular condition within the previous 6 months
Inclusion Criteria:
Part A, Part B, and Part C:
* Patients at least 18 years of age at the time of signing the informed consent.
* Patients must have histologically or cytologically confirmed ER+ and HER2- advanced breast cancer for which standard curative therapy is no longer effective or does not exist.
* Patients must have measurable or non-measurable disease by RECIST criteria (version1.1), with radiologic tumor assessments performed within 28 days of the first dose of therapy.
* Patients must be willing to undergo a core biopsy of accessible tumor within 4 weeks prior to the initiation of study treatment and a follow-up biopsy on treatment for ER immunohistochemistry (IHC) testing and pharmacodynamics (PD) studies. (Patients without accessible tumor tissue may be eligible after discussion with the Medical Monitor.)
* Women must be postmenopausal due to surgical or natural menopause.
Part A:
\- Patients must have received at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or advanced/metastatic) a CDK4/6 inhibitor and up to 3 prior regimens of cytotoxic chemotherapy in the locally advanced or metastatic setting.
Part B:
* Patients must have received at least 1 prior endocrine regimen for a minimum of 6 months in the locally advanced or metastatic setting; if more than 1 prior endocrine regimen has been administered, only one of the regimens must have been administered for a minimum of 6 months in the locally advanced or metastatic setting
* Patients must have received a CDK4/6 inhibitor
* Patients must have received up to 1 prior regimen of cytotoxic chemotherapy in the locally advanced or metastatic setting
* Women must be postmenopausal due to surgical or natural menopause.
Part C:
* Patients must have received at least one prior endocrine regimen.
* Patients must have received no more than two prior chemotherapy regimens for advanced disease.
* Women must be postmenopausal due to surgical or natural menopause.
Exclusion Criteria:
Part A, Part B, and Part C:
* Patients with known symptomatic brain metastases requiring steroids (above physiologic replacement doses). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to first dose of study drug, have discontinued high-dose corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable as judged by the Investigator.
* Receipt of prior anti-cancer or other investigational therapy within 14 days prior to the first administration of study drug.
* Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to \>25% of the bone marrow. Palliative radiation for the alleviation of pain due to bone metastasis will be allowed during the study.
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Inclusion Criteria:
Part A, Part B, and Part C:
* Participants at least 18 years of age at the time of signing the informed consent.
* Participants must have histologically or cytologically confirmed ER+ and HER2- advanced breast cancer for which standard curative therapy is no longer effective or does not exist.
* Participants must have measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) (version1.1), with radiologic tumor assessments performed within 28 days of the first dose of therapy.
* Participants must be willing to undergo a core biopsy of accessible tumor within 4 weeks prior to the initiation of study treatment and a follow-up biopsy on treatment for ER immunohistochemistry (IHC) testing and pharmacodynamics studies. (Patients without accessible tumor tissue may be eligible after discussion with the Medical Monitor.)
* Women must be postmenopausal due to surgical or natural menopause.
Part A:
\- Participants must have received at least 2 prior endocrine regimens in any setting (neoadjuvant, adjuvant or advanced/metastatic) a CDK4/6 inhibitor and up to 3 prior regimens of cytotoxic chemotherapy in the locally advanced or metastatic setting.
Part B:
* Participants must have received at least 1 prior endocrine regimen for a minimum of 6 months in the locally advanced or metastatic setting; if more than 1 prior endocrine regimen has been administered, only one of the regimens must have been administered for a minimum of 6 months in the locally advanced or metastatic setting
* Participants must have received a CDK4/6 inhibitor
* Participants must have received up to 1 prior regimen of cytotoxic chemotherapy in the locally advanced or metastatic setting
Part C:
* Participants must have received at least one prior endocrine regimen.
* Participants must have received no more than two prior chemotherapy regimens for advanced disease.
Exclusion Criteria:
Part A, Part B, and Part C:
* Participants with known symptomatic brain metastases requiring steroids (above physiologic replacement doses). Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to first dose of study drug, have discontinued high-dose corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable as judged by the Investigator.
* Receipt of prior anti-cancer or other investigational therapy within 14 days prior to the first administration of study drug.
* Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to \>25% of the bone marrow. Palliative radiation for the alleviation of pain due to bone metastasis will be allowed during the study.
Inclusion Criteria:
* 18 years of age or older
* Advanced cancer of the bladder, lung, head and neck, esophagus, or pancreas
* Measurable disease
* ECOG Performance status 0-1
* Part 1: progression or relapse following standard treatments
* Part 2: maximum of 2 prior lines of systemic therapy in the advanced setting
* Resolution of acute effects of prior anticancer therapy to baseline or Grade 1
* Consent to submit required pre-treatment tumor tissue as medically feasible
Exclusion criteria:
* Received prior treatment with an antibody drug conjugate with a camptothecin-class payload (e.g. sacituzumab govitecan, trastuzumab deruxtecan )
* Active anorexia, nausea or vomiting, and/or signs of intestinal obstruction meeting protocol exclusion
* Pulmonary disease meeting protocol exclusion
* Other unacceptable abnormalities as defined by protocol
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Inclusion Criteria:
* 18 years of age or older
* Advanced cancer of the bladder, lung, head and neck, esophagus, or pancreas
* Measurable disease
* ECOG Performance status 0-1
* Part 1: progression or relapse following standard treatments
* Part 2: maximum of 2 prior lines of systemic therapy in the advanced setting
* Part 3: advanced cancer of the lung or bladder, prior treatment requirements vary by combination therapy group
* Resolution of acute effects of prior anticancer therapy to baseline or Grade 1
* Consent to submit required pre-treatment tumor tissue as medically feasible
Exclusion criteria:
* Received prior treatment with an antibody drug conjugate with a camptothecin-class payload (e.g. sacituzumab govitecan, trastuzumab deruxtecan )
* Active anorexia, nausea or vomiting, and/or signs of intestinal obstruction meeting protocol exclusion
* Pulmonary disease meeting protocol exclusion
* Other unacceptable abnormalities as defined by protocol
* Part 3: Meet contraindications of combination products per protocol and/or local labels
Inclusion Criteria:
* Out-of-hospital cardiac arrest treated by paramedics
* Initial recorded cardiac rhythm of VF or pulseless VT, or, AED shock on first analysis administered or witnessed by EMS (paramedic or fire)
* Established intravenous vascular access
Exclusion Criteria:
* Known or apparent age \<18 years
* Initial recorded cardiac rhythm of VF or pulseless VT, or, AED shock on first analysis administered or confirmed by paramedics
* Cardiac arrest due to an obvious non-cardiac primary cause (e.g. blunt or penetrating trauma, exsanguination, burns, drug overdose, drowning, anaphylaxis, sudden asphyxiation, etc.)
* Administration of intramuscular, endotracheal tube, or intraosseous epinephrine
* Prisoners or persons in police custody
* Known allergy or sensitivity to epinephrine
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Inclusion Criteria:
* Out-of-hospital cardiac arrest treated by paramedics AND
* Initial recorded cardiac rhythm of VF or pulseless VT, or, AED shock on first analysis administered or confirmed by paramedics or fire services, AND
* Established intravenous vascular access
Exclusion Criteria:
* Known or apparent age \<18 years
* Initial recorded cardiac rhythm of VF or pulseless VT, or, AED shock on first analysis administered or confirmed by paramedics
* Cardiac arrest due to an obvious non-cardiac primary cause (e.g. blunt or penetrating trauma, exsanguination, burns, drug overdose, drowning, anaphylaxis, sudden asphyxiation, etc.)
* Administration of intramuscular, endotracheal tube, or intraosseous epinephrine
* Prisoners or persons in police custody
* Known allergy or sensitivity to epinephrine
Inclusion Criteria:
* Any participant who is receiving study intervention and deriving clinical benefit (as determined by the principal investigator) in an encorafenib/binimetinib Parent Study, with no ongoing NCI CTCAE version 4.03 Grade ≥3 or intolerable Grade 2 AEs considered to be related to study treatment.
* Participants must agree to follow the reproductive criteria as outlined in the applicable Encorafenib/Binimetinib Continuation Sub-Study Protocol.
Exclusion Criteria:
* Any medical reason that, in the opinion of the investigator or sponsor, precludes the participant from inclusion in the study.
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Inclusion Criteria:
* Any participant who is receiving study intervention and deriving clinical benefit (as determined by the principal investigator) in an encorafenib/binimetinib Parent Study, with no ongoing NCI CTCAE version 4.03 Grade ≥3 or intolerable Grade 2 AEs considered to be related to study treatment.
* Participants must agree to follow the reproductive criteria as outlined in the applicable Encorafenib/Binimetinib Continuation Sub-Study Protocol.
Exclusion Criteria:
\- Any medical reason that, in the opinion of the investigator or sponsor, precludes the participant from inclusion in the study.
The study was terminated early due to Sponsor and participants may transition into a long-term follow-up study. The decision to terminate the trial was not based on any safety and/or efficacy concerns.
Inclusion Criteria:
Must meet the following asthma criteria:
1. History of persistent, moderate-to-severe asthma for at least 12 months prior to screening.
2. Must have experienced at least 1 asthma exacerbation requiring treatment with systemic steroids (oral or parenteral) for 3 days or more within 12 months of the screening visit.
3. At least 2 of the 3 pre-bronchodilator FEV1 values collected in the run-in period and the mean of the of pre-bronchodilator FEV1 values collected in the run-in period are ≥30% to \<80% of predicted normal values.
4. Positive bronchodilator responsiveness as evidenced by increase in FEV1 of at least 12% and 200 mL for spirometry conducted during screening period.
5. Maintenance (controller) treatment that minimally includes a medium to high dose ICS - LABA combination consistent with GINA Step 4/5 (either Track 1 or Track 2) for 12 months prior to the screening visit and at a stable dose for at least 3 months prior to the screening visit.
6. ACQ-5 score of ≥1.5 at screening visit and prior to randomization.
Other Inclusion Criteria:
7. Body mass index between 18 40 kg/m2 at screening.
Exclusion Criteria:
Medical Conditions:
1. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
2. Evidence of lung disease(s) other than asthma, either clinical evidence, spirometry, or imaging (Chest X-ray, CT, MRI) within 12 months of the screening visit, as per local standard of care, including but not limited to: Chronic obstructive pulmonary disease, Other emphysematous lung disease such as alpha-1 antitrypsin disease, Cystic fibrosis, Emphysema, Idiopathic pulmonary fibrosis, Churg-Strauss syndrome, Allergic bronchopulmonary aspergillosis, Sarcoidosis
3. Diagnosed with any of the following acute or chronic infections or infection history:
* Active helminth or parasitic infection requiring treatment within 2 weeks prior to screening;
* Infection requiring hospitalization or systemic (parenteral) antimicrobial therapy within 60 days prior to Day 1;
* Any infection judged to be an opportunistic infection or clinically significant by the investigator, within 6 months prior to Day 1.
Prior/Concomitant Therapy:
4. Prior or current use of any prohibited concomitant medication(s) or unwillingness or inability to use a required concomitant medication(s).
5. Prior or concurrent treatment with either approved or experimental biologic treatment (such as inhibitors of IL-4, IL-13, IL-33/ST2, IL-4Rα, TSLP, IL-5, OX40/OX40L or IgE) or targeted synthetic drugs (such as JAK inhibitors) for the treatment of asthma or other type 2 inflammatory diseases, including but not limited to: AD, EoE, CRS.
6. Treatment with any dose level of systemic (oral, injectable, or intraarticular) corticosteroids within 28 days of the screening visit.
7. Prior (within 12 weeks prior to screening) or planned concomitant treatment with immunoglobulin supplementation (eg, IV Ig or SC Ig).
8. History of anaphylaxis to antibody therapeutic or to PF-07275315 or to the excipients of the formulated drug products.
9. Bronchial thermoplasty within the previous 24 months.
Prior/Concurrent Clinical Study Experience:
10. Administration of an investigational drug product within 30 days or 5 half lives preceding the screening visit (whichever is longer). Participation in studies of other investigational products (drug or vaccine) at any time during participation in this study.
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Inclusion Criteria:
Must meet the following asthma criteria:
1. History of persistent, moderate-to-severe asthma for at least 12 months prior to screening.
2. Must have experienced at least 1 asthma exacerbation requiring treatment with systemic steroids (oral or parenteral) for 3 days or more within 24 months of the screening visit.
3. At least 2 of the 3 pre-bronchodilator FEV1 values collected in the run-in period and the mean of the of pre-bronchodilator FEV1 values collected in the run-in period are ≥30% to \<80% of predicted normal values.
4. Positive bronchodilator responsiveness as evidenced by increase in FEV1 of at least 12% and 200 mL for spirometry conducted during screening period.
5. Maintenance (controller) treatment that minimally includes a medium to high dose ICS - LABA combination consistent with GINA Step 4/5 (either Track 1 or Track 2) for 6 months prior to the screening visit and at a stable dose for at least 3 months prior to the screening visit.
6. ACQ-5 score of ≥1.5 at screening visit and prior to randomization.
Other Inclusion Criteria:
7. Body mass index between 18 -40 kg/m2 at screening.
Exclusion Criteria:
Medical Conditions:
1. Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
2. Evidence of lung disease(s) other than asthma, either clinical evidence, spirometry, or imaging (Chest X-ray, CT, MRI) within 12 months of the screening visit, as per local standard of care, including but not limited to: Chronic obstructive pulmonary disease, Other emphysematous lung disease such as alpha-1 antitrypsin disease, Cystic fibrosis, Emphysema, Idiopathic pulmonary fibrosis, Churg-Strauss syndrome, Allergic bronchopulmonary aspergillosis, Sarcoidosis
3. Diagnosed with any of the following acute or chronic infections or infection history:
* Active helminth or parasitic infection requiring treatment within 2 weeks prior to screening;
* Infection requiring hospitalization or systemic (parenteral) antimicrobial therapy within 60 days prior to Day 1;
* Any infection judged to be an opportunistic infection or clinically significant by the investigator, within 6 months prior to Day 1.
Prior/Concomitant Therapy:
4. Prior or current use of any prohibited concomitant medication(s) or unwillingness or inability to use a required concomitant medication(s).
5. Prior or concurrent treatment with either approved or experimental biologic treatment (such as inhibitors of IL-4, IL-13, IL-33/ST2, IL-4Rα, TSLP, IL-5, OX40/OX40L or IgE) or targeted synthetic drugs (such as JAK inhibitors) for the treatment of asthma or other type 2 inflammatory diseases, including but not limited to: AD, EoE, CRS.
6. Treatment with any dose level of systemic (oral, injectable, or intraarticular) corticosteroids within 28 days of the screening visit.
7. Prior (within 12 weeks prior to screening) or planned concomitant treatment with immunoglobulin supplementation (eg, IV Ig or SC Ig).
8. History of anaphylaxis to antibody therapeutic or to PF-07275315 or to the excipients of the formulated drug products.
9. Bronchial thermoplasty within the previous 24 months.
Prior/Concurrent Clinical Study Experience:
10. Administration of an investigational drug product within 30 days or 5 half lives preceding the screening visit (whichever is longer). Participation in studies of other investigational products (drug or vaccine) at any time during participation in this study.
Inclusion Criteria:
* Age ≥ 18 years at time of consent
* ECOG performance status (PS) 0 or 1
* Histologically and immunophenotypically confirmed PBL
* Ann Arbor stage at initial diagnosis: stage I with lactate dehydrogenase (LDH) \> upper limit of normal (ULN) and/or bulky disease \>7.5 cm or stage II-IV
* Received definitive front-line therapy for PBL with end-of-treatment PR or CR
* Adequate bone marrow function with recovery from prior therapy, defined as:
* ANC ≥ 500 cells/mcL
* Platelet count ≥ 50,000 cells/mcL
* Availability of archival tumor tissue (block or unstained slides) for mandatory central pathology review and correlative BCMA testing. Central pathology review and BCMA testing may be completed after enrollment.
* Able to provide written informed consent and HIPAA authorization for release of personal health information, via an approved UIC Institutional Review Board (IRB) informed consent form and HIPAA authorization. If a subject is unable to consent, a LAR may provide consent on their behalf.
* As determined at the discretion of the enrolling physician or protocol designee, the ability of the subject to understand and comply with study procedures for the entire length of the study
* If capable of becoming pregnant: Negative serum or urine pregnancy test
* If HIV-positive:
* Receiving effective combined antiretroviral therapy
* CD4+ T-cell count ≥ 50 cells/mcL within 4 weeks before enrollment
Exclusion Criteria:
Key inclusion criteria:
* Age ≥ 18 years at time of consent
* ECOG performance status (PS) 0 or 1
* Histologically and immunophenotypically confirmed PBL
* Ann Arbor stage at initial diagnosis: stage I with lactate dehydrogenase (LDH) \> upper limit of normal (ULN) and/or bulky disease \>7.5 cm or stage II-IV
* Received definitive front-line therapy for PBL with end-of-treatment PR or CR
* Adequate bone marrow function with recovery from prior therapy, defined as:
* ANC ≥ 500 cells/mcL
* Platelet count ≥ 50,000 cells/mcL
* Availability of archival tumor tissue (block or unstained slides) for mandatory central pathology review and correlative BCMA testing. Central pathology review and BCMA testing may be completed after enrollment.
* Able to provide written informed consent and HIPAA authorization for release of personal health information, via an approved UIC Institutional Review Board (IRB) informed consent form and HIPAA authorization. If a subject is unable to consent, a LAR may provide consent on their behalf.
* As determined at the discretion of the enrolling physician or protocol designee, the ability of the subject to understand and comply with study procedures for the entire length of the study
* If capable of becoming pregnant: Negative serum or urine pregnancy test
* If HIV-positive:
* Receiving effective combined antiretroviral therapy
* CD4+ T-cell count ≥ 50 cells/mcL within 4 weeks before enrollment
Key exclusion criteria:
* Prior BCMA bispecific therapy
* Stable or progressive disease following front-line therapy as determined by the investigator
* Receiving any other investigational agents
* Expected survival \< 2 months
* Known or suspected PBL involvement of the parenchymal brain or spinal cord at diagnosis. Asymptomatic leptomeningeal disease only will be allowed.
* Uncontrolled intercurrent illness, including but not limited to uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Concurrent malignancy requiring active therapy within the last 3 years, except for the following:
* Basal cell carcinoma limited to the skin
* Squamous cell carcinoma limited to the skin
* Carcinoma in situ of the cervix or breast
* Adequately treated lentigo malignant melanoma
* Localized prostate cancer
* Active therapy consists of adjuvant or maintenance therapy to reduce the risk of recurrence of a malignancy that was previously treated with curative intent and with no evidence of active disease within 2 years prior to screening
* Pregnant or nursing
* PWH with a history of AIDS-defining opportunistic infection within the past year
* Receipt of a live vaccine within 28 days prior to the first dose of study treatment
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Inclusion Criteria:
* Age ≥ 18 years at time of consent
* ECOG PS 0 or 1
* Histologically and immunophenotypically confirmed PBL
* Ann Arbor stage at initial diagnosis: stage I with LDH \> ULN and/or bulky disease \>7.5 cm or stage II-IV
* Received definitive front-line therapy for PBL with end-of-treatment PR or CR. Date of end-of-treatment response evaluation must be within 8 weeks prior to enrollment.
* Adequate bone marrow function with recovery from prior therapy (without growth factor or transfusion support), defined as:
* ANC ≥ 500 cells/mcL
* Platelet count ≥ 50,000 cells/mcL
* Hemoglobin ≥8 g/dL
* Adequate renal function defined by an estimated creatinine clearance ≥30 mL/min (according to the Cockcroft Gault formula, by 24-hour urine collection for creatinine clearance, or according to local institutional standard method).
* Adequate hepatic function characterized by the following:
* Total bilirubin ≤2 x ULN (≤3 x ULN if documented Gilbert's syndrome)
* AST ≤2.5 x ULN
* ALT ≤2.5 x ULN
* Availability of archival tumor tissue (block or unstained slides) for mandatory central pathology review and correlative BCMA testing. Central pathology review and BCMA testing may be completed after enrollment.
* Able to provide written informed consent and HIPAA authorization for release of personal health information via an approved UIC IRB ICF and HIPAA authorization. If a subject is unable to consent, an LAR may provide consent on their behalf.
* As determined at the discretion of the enrolling physician or protocol designee, the ability of the subject to understand and comply with study procedures for the entire length of the study
* If capable of becoming pregnant: Negative serum or urine pregnancy test
* If HIV-positive:
* Receiving effective combined antiretroviral therapy
* CD4+ T-cell count ≥ 50 cells/mcL within 4 weeks before enrollment
Exclusion criteria:
* Prior BCMA bispecific therapy
* Stable or progressive disease following front-line therapy as determined by the investigator
* Receiving any other investigational agents
* Expected survival \< 2 months
* Known or suspected PBL involvement of the parenchymal brain or spinal cord at diagnosis. Asymptomatic leptomeningeal disease only will be allowed.
* Uncontrolled intercurrent illness, including but not limited to uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Concurrent malignancy requiring active therapy within the last 3 years, except for the following:
* Basal cell carcinoma limited to the skin
* Squamous cell carcinoma limited to the skin
* Carcinoma in situ of the cervix or breast
* Adequately treated lentigo malignant melanoma
* Localized prostate cancer
* Active therapy consists of adjuvant or maintenance therapy to reduce the risk of recurrence of a malignancy that was previously treated with curative intent and with no evidence of active disease within 2 years prior to screening
* Pregnant or nursing
* PWH with a history of AIDS-defining opportunistic infection within the past year
* Receipt of a live vaccine within 28 days prior to the first dose of study treatment
Inclusion Criteria:
* Male participants of appropriate age and required minimum weight
* Participants aged 12 to 17 years must be at least 25 kgs at time of consent.
* Participants aged 6 to 11 years must be at least 19 kgs at time of consent.
* Minimum weight requirement for participants aged 1 to 5 years is to be determined.
* Participants with a diagnosis of severe hemophilia A or moderately severe to severe hemophilia B
* Participants must have at least 1 year of diary and/or medical records available in which exogenous FVIII or FIX replacement or bypass agent infusions and hemophilic bleeding episodes were consistently documented over the 12 months prior to the time of consent.
Participants who are enrolled into the Non-Inhibitor Cohort must also meet the following criteria:
* No current detectable inhibitor and no documented history of inhibitors in the 5 years prior to consent
* Must have at least 50 exposure days to FVIII/FIX replacement products
* Must be at least 80% compliant with a stable and effective routine prophylaxis regimen with FVIII/FIX replacement products, for at least 12 months prior to consent
Participants who are enrolled into the Inhibitor Cohort must also meet the following criteria:
* Documentation of current high titer inhibitor (≥5 BU/mL); or current low titer inhibitor (\<5 BU/mL) refractory to FVIII or FIX replacement and with FVIII or FIX recovery \<60% of expected within previous 12 months prior to the time of consent
* Participants who have documented inhibitors while on factor-replacement therapy but who do not meet the high quantitative inhibitor criteria described in the prior bullet at the time of screening (eg, participant with a previously documented high-titer inhibitor ≥5 BU/mL) and whose condition precludes re-challenge with FVIII or FIX replacement may be considered for eligibility on a case-by-case basis with discussion and agreement from the Pfizer medical monitor.
* Hemophilia A participants with on-demand treatment regimen with ≥12 bleeding episodes or hemophilia B participants with on-demand treatment regimen with ≥8 bleeding episodes (spontaneous or traumatic) necessitating treatment with bypass factor in the 12 months prior to informed consent
* Participants must be on an on-demand bypass treatment regimen during the 12 months prior to informed consent
Exclusion Criteria:
* Known coronary artery, thrombotic, or ischemic disease, or current evidence of congenital or acquired thrombophilic disease such as Anti-thrombin III deficiency, Factor V Leiden mutation, prothrombin 20210 mutation, protein C deficiency, protein S deficiency and antiphospholipid syndrome.
* Known planned surgical procedure during the planned study period
* Known hemostatic defect other than hemophilia A or B
* Abnormal hematology, renal or hepatic function laboratory results at screening
* Other acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator
* Individuals with known allergic reaction or hypersensitivity to hamster protein or other components of the study intervention
* Current routine prophylaxis with bypassing agent, non-coagulation non-factor replacement therapy (eg, emicizumab), or any previous treatment with a gene therapy product for treatment of hemophilia
* Participants with inhibitors who are being treated using a prophylaxis treatment regimen with a bypass agent, and, participants who have previously received non-factor-based hemophilia therapy (eg, fitusiran, concizumab, emicizumab) will be considered on a case-by-case basis, only after discussion and agreement between the investigator and the Pfizer medical monitor
* Regular use of immunomodulatory medications (eg, IVIG, routine systemic corticosteroids, rituximab)
* Use of systemic antifibrinolytics, medications that may increase the risk of bleeding, and certain non-steroidal anti-inflammatory drugs within 120 hours of first dose of study intervention and while on study
* Ongoing or planned use of ITI, or prophylaxis with FVIII or FIX replacement at any time after initiation of treatment with study intervention
* Participation in other studies involving investigational drug(s) or investigational vaccine(s) within 30 days (or as determined by local requirements) or 5 half-lives prior to study entry or during study participation
* Previous exposure to marstacimab during participation in other marstacimab clinical studies
* CD4 cell count ≤200/uL if HIV-positive
* Abnormal ECG of clinical relevance that may affect participant safety or interpretation of study results
* Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members
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Inclusion Criteria:
* Male participants of appropriate age and required minimum weight
* Participants aged 12 to 17 years must be at least 25 kgs at time of consent.
* Participants aged 6 to 11 years must be at least 19 kgs at time of consent.
* Participants aged 1 to 5 years must be at least 5 kgs at time of consent.
* Participants with a diagnosis of severe hemophilia A or moderately severe to severe hemophilia B
* Participants must have at least 1 year (if aged 6 to 17 years), or at least 3 months (if aged 1 to 5 years) of diary and/or medical records available in which exogenous FVIII or FIX replacement or bypass agent infusions and hemophilic bleeding episodes were consistently documented over over the above specified timeframe to the time of consent.
Participants who are enrolled into the Non-Inhibitor Cohort must also meet the following criteria:
* No current detectable inhibitor and no documented history of inhibitors in the 5 years prior to consent
* Must have at least 50 exposure days to FVIII/FIX replacement products for participants aged 6 to 17 years. Participants from 1 to 5 years do not require a minimum documented number of exposure days
* Must be at least 80% compliant with a stable and effective routine prophylaxis regimen with FVIII/FIX replacement products, for at least 12 months prior to consent for participants aged 6 to 17 years, for at least 3 months prior to consent for participants from 1 to 5 years
Participants who are enrolled into the Inhibitor Cohort must also meet the following criteria:
* Documentation of current high titer inhibitor (≥5 BU/mL); or current low titer inhibitor (\<5 BU/mL) refractory to FVIII or FIX replacement and with FVIII or FIX recovery \<60% of expected within previous 12 months prior to the time of consent
* Participants who have documented inhibitors while on factor-replacement therapy but who do not meet the high quantitative inhibitor criteria described in the prior bullet at the time of screening (eg, participant with a previously documented high-titer inhibitor ≥5 BU/mL) and whose condition precludes re-challenge with FVIII or FIX replacement may be considered for eligibility on a case-by-case basis with discussion and agreement from the Pfizer medical monitor.
* Participants aged 6 to 17 years: Hemophilia A participants with on-demand treatment regimen with ≥12 bleeding episodes or hemophilia B participants with on-demand treatment regimen with ≥8 bleeding episodes (spontaneous or traumatic) necessitating treatment with bypass factor in the 12 months prior to informed consent
* Participants aged 1 to 5 years of age with at least 3 months' on-demand bypass treatment regimen and at least 1 treated hemophilic bleeding in the last 3 months or at least 2 treated hemophilic bleedings in the last 6 months documented prior to the time of informed consent
* Participants aged 6 to 17 years must be on an on-demand bypass treatment regimen during the 12 months prior to informed consent
* Participants aged 1 to 5 years of age must be on an on-demand bypass treatment regimen during the 3 months prior to informed consent
Exclusion Criteria:
* Known coronary artery, thrombotic, or ischemic disease, or current evidence of congenital or acquired thrombophilic disease such as Anti-thrombin III deficiency, Factor V Leiden mutation, prothrombin 20210 mutation, protein C deficiency, protein S deficiency and antiphospholipid syndrome.
* Known planned surgical procedure during the planned study period
* Known hemostatic defect other than hemophilia A or B
* Abnormal hematology, renal or hepatic function laboratory results at screening
* Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis. Participants aged 1 to 5 years with known hepatitis B or C will also be excluded
* Known HIV-positive for participants aged 1 to 5 years of age
* Other acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator
* Individuals with known allergic reaction or hypersensitivity to hamster protein or other components of the study intervention
* Current routine prophylaxis with bypassing agent, non-coagulation non-factor replacement therapy (eg, emicizumab), or any previous treatment with a gene therapy product for treatment of hemophilia
* Participants with inhibitors who are being treated using a prophylaxis treatment regimen with a bypass agent, and, participants who have previously received non-factor-based hemophilia therapy (eg, fitusiran, concizumab, emicizumab) will be considered on a case-by-case basis, only after discussion and agreement between the investigator and the Pfizer medical monitor
* Regular use of immunomodulatory medications (eg, IVIG, routine systemic corticosteroids, rituximab)
* Use of systemic antifibrinolytics, medications that may increase the risk of bleeding, and certain non-steroidal anti-inflammatory drugs within 120 hours of first dose of study intervention and while on study. Some of these agents may be permitted if it is authorized for use in the respective country, is part of the standard of care in the study population, its use is short term and on a PRN basis and following discussion with the Pfizer medical monitor.
* Ongoing or planned use of ITI, or prophylaxis with FVIII or FIX replacement at any time after initiation of treatment with study intervention
* Participation in other studies involving investigational drug(s) or investigational vaccine(s) within 30 days (or as determined by local requirements) or 5 half-lives prior to study entry or during study participation
* Previous exposure to marstacimab during participation in other marstacimab clinical studies
* CD4 cell count ≤200/uL if HIV-positive, for participants aged 6 to 17 years
* Abnormal ECG of clinical relevance that may affect participant safety or interpretation of study results
* Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members
Inclusion Criteria
* Part 1: Breast Cancer (BC)
* Refractory Hormone Receptor Positive (HR+), Human Epidermal Growth Factor Receptor 2 Negative (HER2-) BC
* Part 1A/Part 1D/Part1E also include: Refractory HR-positive/HER2-positive BC
* Part 1: Tumors other than BC (Part 1A/Part 1D/Part 1E): NSCLC, prostate, CRC, liposarcoma, or tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests
* Part 1F: prostate cancer
* Part 2A, 2B, 2C and 2E:
* HR-positive/HER2-negative BC
* Patients who are either postmenopausal women or pre/peri-menopausal (Part 2C only)
* Part 1D: metastatic castration resistant prostate cancer
* Lesion:
* Part 1: evaluable lesion (including skin or bone lesion only)
* Part 2A, 2B, 2C and 2E: measurable lesion per RECIST v1.1
* Part 2D: Participants with evaluable disease as per PCWG3; participants with bone metastases only are allowed. Participants with biochemical recurrence only are excluded.
* Prior systemic Treatment
* Part 1: HR-positive/HER2-negative BC
* At least 1 line of SOC, including CD4/6 inhibitor therapy for advanced or metastatic disease, or if CDK4/6 inhibitors are not considered appropriate in the opinion of the investigator
* At least 1 line of anti-endocrine in countries without CDK4/6 inhibitor approval or reimbursement, for advanced or metastatic disease
* HR-positive/HER2-positive BC (Parts 1A/1D/1E): at least 1 prior treatment of approved HER2 targeting therapy
* Tumors other than BC (Parts 1A/1D/1E/1F): tumor that is resistant to at least 2 lines of SOC for advanced or recurrent disease or for which no standard therapy is available
* Part 2A and 2E: participants must have received at least 1 line of standard of care (including prior CDK4/6i) for advanced/metastatic disease; Prior chemo is allowed; Prior fulvestrant, mTOR and/or PI3K inhibitors are allowed
* Part 2B: participants who have not received any prior systemic anti-cancer therapies for advanced/metastatic BC
* Part 2C:
* Progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor if postmenopausal, or tamoxifen if pre or perimenopausal, or
* Progressed while on or within 1 month after the endo the prior aromatase inhibitor therapy for advanced/metastatic BC if postmenopausal or prior endocrine treatment for advanced/metastatic BC if pre or perimenopausal
* One previous line of chemotherapy for advanced/metastatic disease is allowed in addition to endocrine therapy
* Part 2D:
* Received prior abiraterone; enzalutamide and CDK4i naive
* 0-1 line of chemotherapy is allowed General Inclusion Criteria
* All participants must be refractory to or intolerant of existing therapies known to provide clinical benefit for their condition.
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
* Adequate renal, liver, and bone marrow function
Exclusion Criteria:
* Part 1D: participants who have had a gastrectomy or have dietary or other restrictions that preclude a 10 hour overnight fast or consumption of the high fat, high calorie meal
* Part 2B: prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor with disease recurrence while on or within 12 months of completing treatment. Prior treatment with any CDK4/6 inhibitor
* Part 2C: prior treatment with any CDK inhibitor, fulvestrant, everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway
* Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases carcinomatous meningitis, or leptomeningeal disease
* Other active malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ
* Major surgery or radiation within 4 weeks prior to study intervention
* Last anti-cancer treatment within 2 weeks prior to study intervention
* Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry
* Pregnant or breastfeeding female participant
* Active inflammatory gastrointestinal (GI) disease, known diverticular disease or previous gastric resection or lap band surgery including impairment of gastrointestinal function or GI disease
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Inclusion Criteria
* Part 1: Breast Cancer (BC)
* Refractory Hormone Receptor Positive (HR+), Human Epidermal Growth Factor Receptor 2 Negative (HER2-) BC
* Part 1A/Part 1D/Part 1E also include: Refractory HR-positive/HER2-positive BC
* Part 1: Tumors other than BC (Part 1A/Part 1D/Part 1E): NSCLC, prostate, CRC, liposarcoma, or tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests
* Part 1F: prostate cancer
* Part 1G: HR-positive/HER2-negative BC
* Part 2A, 2B, 2C, 2E, and 2F: HR-positive/HER2-negative BC
* Part 1D: metastatic castration resistant prostate cancer
* Giredestrant Combination Cohort: ER-positive/HER2-negative BC
* Prior systemic Treatment
* Part 1: HR-positive/HER2-negative BC
* At least 1 line of SOC, including CD4/6 inhibitor therapy for advanced or metastatic disease, or if CDK4/6 inhibitors are not considered appropriate in the opinion of the investigator
* HR-positive/HER2-positive BC (Parts 1A/1D/1E): at least 1 prior treatment of approved HER2 targeting therapy
* Tumors other than BC (Parts 1A/1D/1E/1F): tumor that is resistant to at least 2 lines of SOC for advanced or recurrent disease or for which no standard therapy is available
* Part 2A and 2E: at least 1 line of standard of care (including prior CDK4/6i) for advanced/metastatic disease; Prior chemo is allowed; Prior fulvestrant, mTOR and/or PI3K inhibitors are allowed
* Part 2B: no prior systemic anti-cancer therapies for advanced/metastatic BC
* Part 2C:
* Progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor if postmenopausal, or tamoxifen if pre or perimenopausal, or
* Progressed while on or within 1 month after the endo the prior aromatase inhibitor therapy for advanced/metastatic BC if postmenopausal or prior endocrine treatment for advanced/metastatic BC if pre or perimenopausal
* One previous line of chemotherapy for advanced/metastatic disease is allowed in addition to endocrine therapy
* Part 1G and 2F: at least 2 lines of SOC for advanced or metastatic disease, including CDK4/6 inhibitor and endocrine therapy
* Giredestrant Combination Cohort: at least 1 (no more than 3) prior line(s) of SOC for advanced or metastatic disease, including CDK4/6 inhibitor and endocrine therapy
General Inclusion Criteria
* All participants must be refractory to or intolerant of existing therapies known to provide clinical benefit for their condition.
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
* Adequate renal, liver, and bone marrow function
Exclusion Criteria:
* Part 2B: prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor with disease recurrence while on or within 12 months of completing treatment. Prior treatment with any CDK4/6 inhibitor
* Part 2C: prior treatment with any CDK inhibitor, fulvestrant, everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway
* Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases carcinomatous meningitis, or leptomeningeal disease
* Other active malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ
* Major surgery or radiation within 4 weeks prior to study intervention
* Last anti-cancer treatment within 2 weeks prior to study intervention; Part 1G and 2F: tamoxifen treatment within 35 days of Day -4
* Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry
* Part 1G and 2F: history of or current pulmonary embolism or deep vein thrombosis
* Giredestrant Combination Cohort: history (within 6 months of screening) of or presence of idiopathic symptomatic bradycardia or resting heart rate \<50 bpm at screening
* Pregnant or breastfeeding female participant
* Active inflammatory gastrointestinal (GI) disease, known diverticular disease or previous gastric resection or lap band surgery including impairment of gastrointestinal function or GI disease
Inclusion Criteria:
1. patient developed clinical symptoms compatible with bloodstream infection, hospital-acquired or ventilator-associated pneumonia (hospital-acquired and ventilator-associated pneumonia should fulfil US CDC NHSN criteria) AND,
2. an appropriate specimen has been received by the participating laboratory - that is, a blood culture bottle showing Gram negative bacilli or a respiratory sample collected for clinical purposes showing Gram negative bacilli on Gram stain;
Exclusion Criteria:
1. Refractory shock or comorbid condition such that patient not expected to survive more than 48 hours; OR,
2. where the bloodstream infection is thought to be related to a vascular catheter and the catheter is unable to be removed; OR,
3. treatment is not with the intent to cure the infection; OR,
4. patient is incarcerated in a correctional facility; OR,
5. patients previously randomised in this trial within the last 60 days.
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Inclusion Criteria:
1. Adult patients aged 18 years or older (21 years or older in Singapore) who meet at least one of the following criteria:
* At risk of developing bloodstream infection, hospital-acquired pneumonia (HAP), or ventilator-associated pneumonia (VAP) due to Pseudomonas aeruginosa or carbapenem-resistant Enterobacterales; OR
* Blood culture bottles showing Gram-negative bacilli on Gram stain; OR
* Suspected HAP or VAP with respiratory specimens showing Gram-negative bacteria on Gram stain.
2. For randomisation, all of the following criteria must be fulfilled:
* Written informed consent obtained from the participant or their authorised representative.
* An appropriate blood or respiratory specimen received by the participating microbiology laboratory, with Gram-negative bacilli detected on Gram stain.
* Patients with HAP or VAP must fulfil the US Centers for Disease Control and Prevention National Healthcare Safety Network (CDC NHSN) criteria.
* No exclusion criteria are met.
Exclusion Criteria:
1. Refractory shock or comorbid condition such that the patient is not expected to survive more than 48 hours.
2. Suspected catheter-related bloodstream infection where the implicated vascular catheter cannot be removed.
3. Treatment is not intended to cure the infection.
4. Infection requiring prolonged antibiotic treatment (more than two weeks).
5. Incarceration in a correctional facility.
6. Previous enrolment in the RAPID trial within the preceding 60 days.
7. Patients younger than 18 years (younger than 21 years in Singapore).
Enrollment was permanently closed for strategic business reasons after 20 participants enrolled in Ph 1b. The decision was not related to safety, efficacy, benefit-risk, or participant welfare. The planned Ph 2 and DDI components were not initiated.
children seen on an outpatient
Inclusion Criteria:
* both sexes
* suffering from suppurative AOM or healthy children
* age: 6 months to 36 months for AOM
* age: 6 months to 15 years for healthy children
* informed consent from parents or guardians
* Children who haven't received antibiotic treatment within 7 days before enrollment,
Exclusion Criteria:
* severe underlying disease,
* inclusion in the study during the previous 12 months
* Children with bullous myringitis cannot be included.
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children seen on an outpatient
Inclusion Criteria:
* both sexes
* suffering from suppurative AOM or healthy children
* age: 4 months to 36 months for AOM
* age: 4 months to 15 years for healthy children
* informed consent from parents or guardians
* Children who haven't received antibiotic treatment within 7 days before enrollment,
Exclusion Criteria:
* severe underlying disease,
* inclusion in the study during the previous 12 months
* Children with bullous myringitis cannot be included.
Enrollment was permanently closed for strategic business reasons after 11 participants enrolled in Ph1b. The decision was not related to safety, efficacy, benefit-risk, or participant welfare. The planned Ph2 and DDI components were not initiated.