Genmab has decided to discontinue further clinical development of acasunlimab following strategic portfolio prioritization. The decision was not related to safety concerns.
Participants must meet all of the following criteria to be eligible for enrollment into the trial:
1. Adults ≥18 years of age on the day of signing the ICF.
2. Participants must have at least 1 lesion, not previously irradiated, amenable to biopsy, and must consent to provide a pre-treatment biopsy from a primary and/or metastatic lesion.
3. Has at least 1 measurable lesion according to RECIST version 1.1 per investigator assessment.
4. Participants must have progressed radiologically on or after their most recent line of systemic therapy.
5. Eastern Cooperative Oncology Group performance status of 0 or 1.
6. Additional inclusion criteria for endometrial cancer cohort
1. Pathologically or cytologically documented endometrial cancer (carcinoma of any histological subtype or carcinosarcoma), irrespective of MSI or mismatch repair status.
2. Documented disease progression after having received ≥1 line of therapy (no more than 3), including PBC-containing systemic treatment and an anti-PD-1 therapy containing regimen (combined or sequential) in the advanced/metastatic setting.
7. Additional inclusion criteria for cervical cancer cohort
1. Pathologically or cytologically documented recurrent or persistent squamous, adenosquamous, or adenocarcinoma of the uterine cervix.
2. Disease progression after having received ≥1 prior line of therapy that includes systemic therapy in the advanced or metastatic setting.
8. Additional inclusion criterion for non-HGSOC cohort
a. Pathologically or cytologically documented unresectable or metastatic CCOC, low grade endometrioid, low-grade serous, or mucinous OVC that was previously treated with at least 1 prior line of therapy.
9. Additional inclusion criteria for urothelial cancer cohort
1. Pathologically or cytologically documented unresectable or metastatic urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra. Histological variants are allowed if urothelial histology is predominant.
2. Relapsed or progressed after treatment with ≥1 prior line of therapy (maximum of 3) that contains anti-PD-(L)1 therapy in the perioperative or metastatic setting.
10. Additional inclusion criterion for the ccRCC cohort a. Pathologically or cytologically documented unresectable or metastatic ccRCC that was previously treated with no more than 3 prior systemic regimens for locally advanced or metastatic RCC, including both a PD-(L)1 checkpoint inhibitor and a VEGF-TKI in sequence or in combination.
Participants who meet any of the following criteria will be disqualified from entering the trial:
1. Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis
2. Any of the following within the past 6 months prior to enrollment: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event.
3. Uncontrolled or significant cardiovascular disease as specified in the protocol.
4. Has a history of (noninfectious) ILD/pneumonitis that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5. Clinically severe pulmonary compromise
6. Chronic steroid treatment (\>10 mg/day) with exceptions as noted in the protocol.
7. History of other active malignancy within 3 years prior to enrollment, with the exception of those with a negligible risk of metastasis or death (eg, 5-year OS rate \>90%) and treated with expected curative outcome.
8. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE Version 5.0, Grade ≤1 or baseline.
9. Prior exposure to other CDH6-targeted agents or an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, trastuzumab deruxtecan, datopotamab deruxtecan).
10. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.
11. Has active or uncontrolled HIV, HBV, or HCV infection.
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Participants must meet all of the following criteria to be eligible for enrollment into the trial:
1. Adults greater than or equal to ( ≥) 18 years of age on the day of signing the informed consent form (ICF).
2. Participants must have at least 1 lesion, amenable to biopsy, and must consent to provide a pre-treatment biopsy from a primary and/or metastatic lesion.
3. Has at least 1 measurable lesion according to RECIST version 1.1 per investigator assessment.
4. Participants must have progressed radiologically on or after their most recent line of systemic therapy.
5. Eastern Cooperative Oncology Group performance status of 0 or 1.
6. Adequate organ/bone marrow function.
7. Additional inclusion criteria for endometrial cancer cohort:
1. Pathologically or cytologically documented endometrial cancer (carcinoma of any histological subtype or carcinosarcoma), irrespective of microsatellite instability (MSI) or mismatch repair status: small cell/neuroendocrine tumors are not allowed even if mixed histology.
2. Documented disease progression after having received ≥1 line of therapy (no more than 3), including platinum-based chemotherapy (PBC)-containing systemic treatment and an anti-PD-(L)1 therapy containing regimen (combined or sequential) in the advanced/metastatic setting.
* Neo-adjuvant/adjuvant systemic therapies are counted as 1 line of therapy if there was progression or recurrence within 1 year from the final dose.
* Prior hormonal therapy is not counted as a line of therapy in regard to the maximum allowed lines of treatment.
8. Additional inclusion criterion for non-HGSOC cohort:
1. Pathologically or cytologically documented unresectable or metastatic CCOC, low-grade endometrioid (Grade2 or lower), low-grade serous (Grade2 or lower), or mucinous OVC, from ovary, fallopian tube or peritoneum origin that was previously treated with at least 1 prior line of therapy.
• Neo-adjuvant/adjuvant systemic therapies are counted as 1 line of therapy if there was progression or recurrence within 1 year from the final dose.
2. In Stage 3 only, participants with pathologically or cytologically documented unresectable or metastatic CCOC can be enrolled. Prior line of therapy requirements remains unchanged.
Participants who meet any of the following criteria will be disqualified from entering the trial:
1. Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis.
2. Any of the following within the past 6 months prior to enrollment: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event (e.g., intestinal ischemia).
3. Uncontrolled or significant cardiovascular disease as specified in the protocol.
4. Has any history of (noninfectious) interstitial lung disease (ILD)/pneumonitis irrespective of steroid use, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5. Clinically severe pulmonary compromise.
6. Chronic steroid treatment (greater than \[\>\]10 mg/day prednisone \[or equivalent\]) with exceptions as noted in the protocol.
7. History of other active malignancy within 3 years prior to enrollment, with the exception of those with a negligible risk of metastasis or death (eg, 5-year OS rate \>90%) and treated with expected curative outcome.
8. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 5.0, Grade less than or equal to (≤)1 or baseline.
9. Prior exposure to other CDH6-targeted agents or an antibody drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (e.g., trastuzumab deruxtecan, datopotamab deruxtecan).
10. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.
11. Has active or uncontrolled human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection
Key Inclusion Criteria:
* Have a Histologically or cytologically confirmed non-CNS solid tumor that is metastatic or unresectable and for whom there is no available standard therapy.
* PD-L1 positive expression (Tumor Proportion Score ≥1% or Combined Positive Score ≥1).
* Have at least one lesion, not previously irradiated that can be accurately measured per RECIST version 1.1.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Age of 18 years or older (or country's legal age of majority if the legal age was \>18 years)
* Adequate Hematologic and liver function.
Key Exclusion Criteria:
* Has received prior therapy with an anti-4-1BB(CD137) agent.
* Known active CNS metastases and/or carcinomatous meningitis.
* Known additional malignancy that is progressing or has required active treatment.
* History of chronic liver disease or evidence of hepatic cirrhosis.
* History of severe toxicities associated with a prior immunotherapy.
* Has ongoing or suspected autoimmune disease.
* Known active and clinically significant bacterial, fungal or viral infection including known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, immunocompromised patients.
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Key Inclusion Criteria:
* Have a Histologically or cytologically confirmed non-CNS solid tumor that is metastatic or unresectable and for whom there is no available standard therapy.
* PD-L1 positive expression (Tumor Proportion Score ≥1% or Combined Positive Score ≥1).
* Have at least one lesion, not previously irradiated that can be accurately measured per RECIST version 1.1.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Age of 18 years or older (or country's legal age of majority if the legal age was \>18 years)
* Adequate Hematologic and liver function.
Key Exclusion Criteria:
* Has received prior therapy with an anti-4-1BB(CD137) agent.
* Known active CNS metastases and/or carcinomatous meningitis.
* Known additional malignancy that is progressing or has required active treatment.
* History of chronic liver disease or evidence of hepatic cirrhosis.
* History of severe toxicities associated with prior immunotherapy, except for adequately controlled endocrine-related adverse events managed with hormone replacement therapy.
* Has ongoing or suspected autoimmune disease.
* Known active and clinically significant bacterial, fungal or viral infection including known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, immunocompromised patients.
Inclusion Criteria:
1. Have a histologically or cytologically confirmed diagnosis nonsquamous NSCLC.
2. Have stage IV nonsquamous NSCLC.
3. Have confirmation that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or Proto-oncogene tyrosine-protein kinase (ROS1)-directed therapy is not indicated.
4. Have measurable disease based on RECIST 1.1.
5. Have provided archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated.
Note: Adequacy of biopsy specimen for the above analyses must be confirmed by the central laboratory before the participant can start the induction phase. Submission of another tumor specimen may be required prior to enrolling the participant, if adequate tumor tissue was not provided the first time.
6. Have a life expectancy of at least 3 months.
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status assessed within 7 days prior to the administration of study intervention.
8. Have not received prior systemic treatment for their advanced/metastatic NSCLC.
9. Have adequate organ function.
10. Male and female participants who are not pregnant and of childbearing potential must follow contraceptive guidance during the treatment period and for 180 days afterwards.
11. Male participants must refrain from donating sperm, and female participants must refrain from donating eggs to others or freeze/store for her own use during the treatment period and for 180 days afterwards.
Exclusion Criteria:
1. Has predominantly squamous cell histology NSCLC.
2. Has a known additional malignancy that is progressing or has progressed within the past 3 years requiring active treatment.
3. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
4. Has a severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
5. Has a known hypersensitivity to any components or excipients of cisplatin, carboplatin, pemetrexed, or olaparib.
6. Has an active autoimmune disease that has required systemic treatment in past 2 years.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.
8. Has a known history of human immunodeficiency virus (HIV) infection, a known history of hepatitis B infection, or known active hepatitis C virus infection.
9. Has interstitial lung disease, or history of pneumonitis requiring systemic steroids for treatment.
10. Has received prior therapy with olaparib or with any other polyadenosine 5' diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor.
11. Has received prior therapy with an agent directed to programmed cell death ligand 1 (PD-L1), anti PD-L2, or directed to a stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137).
12. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
13. Has history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
14. Has completed palliative radiotherapy within 7 days of the first dose. Participants must have recovered from all radiation-related toxicities and not require corticosteroids.
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Inclusion Criteria:
1. Have a histologically or cytologically confirmed diagnosis nonsquamous NSCLC.
2. Have stage IV nonsquamous NSCLC.
3. Have confirmation that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or Proto-oncogene tyrosine-protein kinase (ROS1)-directed therapy is not indicated.
4. Have measurable disease based on RECIST 1.1.
5. Have provided archival tumor tissue sample or newly obtained core or incisional biopsy of a tumor lesion not previously irradiated.
Note: Adequacy of biopsy specimen for the above analyses must be confirmed by the central laboratory before the participant can start the induction phase. Submission of another tumor specimen may be required prior to enrolling the participant, if adequate tumor tissue was not provided the first time.
6. Have a life expectancy of at least 3 months.
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status assessed within 7 days prior to the administration of study intervention.
8. Have not received prior systemic treatment for their advanced/metastatic NSCLC.
9. Have adequate organ function.
10. Male and female participants who are not pregnant and of childbearing potential must follow contraceptive guidance during the treatment period and for 180 days afterwards.
11. Male participants must refrain from donating sperm, and female participants must refrain from donating eggs to others or freeze/store for her own use during the treatment period and for 180 days afterwards.
Exclusion Criteria:
1. Has predominantly squamous cell histology NSCLC.
2. Has a known additional malignancy that is progressing or has progressed within the past 3 years requiring active treatment.
3. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
4. Has a severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
5. Has a known hypersensitivity to any components or excipients of cisplatin, carboplatin, pemetrexed, or olaparib.
6. Has an active autoimmune disease that has required systemic treatment in past 2 years.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy.
8. Has a known history of human immunodeficiency virus (HIV) infection, a known history of hepatitis B infection, or known active hepatitis C virus infection.
9. Has interstitial lung disease, or history of pneumonitis requiring systemic steroids for treatment.
10. Has received prior therapy with olaparib or with any other polyadenosine 5' diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor.
11. Has received prior therapy with an agent directed to programmed cell death ligand 1 (PD-L1), anti PD-L2, or directed to a stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), OX-40, CD137).
12. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
13. Has completed palliative radiotherapy within 7 days of the first dose. Participants must have recovered from all radiation-related toxicities and not require corticosteroids.
Inclusion Criteria:
The main inclusion criteria include but are not limited to the following:
* Has a diagnosis of hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2)- invasive breast carcinoma that is either locally advanced disease not amenable to resection with curative intent (herein called unresectable) or metastatic disease not treatable with curative intent
* Has centrally-confirmed HR+ and HER2- results and human epidermal growth factor receptor 3 (HER3) evaluable results from a biopsy obtained from a distant metastatic site or a locally advanced lesion on or after the most recent line of therapy (with certain exceptions)
* Must have had progression or recurrence on prior cyclin-dependent kinase (CDK)4/6 inhibitor + endocrine therapy (ET) with one of the following:
* Radiographic disease progression, as assessed by the investigator, on CDK4/6 inhibitor + ET as 1L for treatment of unresectable locally advanced or metastatic HR+/HER2- breast cancer. CDK4/6 inhibitor + ET must be the only line of therapy received in the advanced setting, or
* Disease recurrence, either radiographic and/or confirmed histologically via biopsy as assessed by the investigator, while on adjuvant ET in combination with a CDK4/6 inhibitor OR within 24 months from the date of last dose of adjuvant CDK4/6 inhibitor
* Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology
* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy
* Has an Eastern Cooperative Oncology Group performance status of 0 or 1 assessed within 7 days before randomization
Exclusion Criteria:
The main exclusion criteria include but are not limited to the following:
* Has breast cancer amenable to treatment with curative intent
* Is eligible to receive additional endocrine-based treatment in the advanced setting as determined by the investigator
* Has a known germline breast cancer gene (BRCA) mutation (deleterious or suspected deleterious) where poly (ADP-ribose) polymerase (PARP) inhibitor(s) is a potential treatment option
* Has current visceral crisis or is at risk for impending visceral crisis that has or may cause imminent organ compromise and/or other life-threatening complications
* Has any of the following: a pulse oximeter reading \<92% at rest, or requires intermittent supplemental oxygen, or requires chronic supplemental oxygen
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
* Has ≥Grade 2 peripheral neuropathy.
* Has clinically significant corneal disease
* Has received prior chemotherapy for unresectable locally advanced or metastatic breast cancer
* Has received prior treatment with an anti-HER3 antibody and/or antibody-drug conjugate that consists of a topoisomerase I inhibitor (eg, T-DXd) or any other topoisomerase I inhibitor therapy
* Has received prior systemic anticancer therapy within 4 weeks (or 5 half-lives, whichever is shorter) before randomization; participants previously treated with ET plus a CDK4/6 inhibitor may participate as long as at least 2 weeks have elapsed since the last dose of therapy was administered
* Has received prior radiotherapy for non-central nervous system disease, or required corticosteroids for radiation-related toxicities, within 14 days of the first dose of study intervention
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
* Has known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has history of (noninfectious) pneumonitis/interstitial lung disease (ILD) that required steroids, has current pneumonitis/interstitial lung disease, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at Screening
* Has severe hypersensitivity (≥Grade 3) to HER3-DXd and/or any of its excipients
* Has severe hypersensitivity (≥Grade 3) to all the available TPC and/or any of their excipients
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Inclusion Criteria:
The main inclusion criteria include but are not limited to the following:
* Has a diagnosis of hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2)- invasive breast carcinoma that is either locally advanced disease not amenable to resection with curative intent (herein called unresectable) or metastatic disease not treatable with curative intent
* Has centrally-confirmed HR+ and HER2- results and human epidermal growth factor receptor 3 (HER3) evaluable results from a biopsy obtained from a distant metastatic site or a locally advanced lesion on or after the time of diagnosis of locally advanced unresectable or metastatic breast cancer. A new biopsy obtained after progression of the most recent line of therapy is preferred
* Must have had progression or recurrence on prior cyclin-dependent kinase (CDK)4/6 inhibitor + endocrine therapy (ET) with one of the following:
* Radiographic disease progression, as assessed by the investigator, on CDK4/6 inhibitor + ET as 1L for treatment of unresectable locally advanced or metastatic HR+/HER2- breast cancer. CDK4/6 inhibitor + ET must be the only line of therapy received in the advanced setting, or
* Disease recurrence, either radiographic and/or confirmed histologically via biopsy as assessed by the investigator, while on adjuvant ET in combination with a CDK4/6 inhibitor OR within 24 months from the date of last dose of adjuvant CDK4/6 inhibitor
* Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology
* Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy
* Has an Eastern Cooperative Oncology Group performance status of 0 or 1 assessed within 7 days before randomization
Exclusion Criteria:
The main exclusion criteria include but are not limited to the following:
* Has breast cancer amenable to treatment with curative intent
* Is eligible to receive additional endocrine-based treatment in the advanced setting as determined by the investigator
* Has a known germline breast cancer gene (BRCA) mutation (deleterious or suspected deleterious) where poly (ADP-ribose) polymerase (PARP) inhibitor(s) is a potential treatment option
* Has current visceral crisis or is at risk for impending visceral crisis that has or may cause imminent organ compromise and/or other life-threatening complications
* Has any of the following: a pulse oximeter reading \<92% at rest, or requires intermittent supplemental oxygen, or requires chronic supplemental oxygen
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
* Has ≥Grade 2 peripheral neuropathy.
* Has clinically significant corneal disease
* Has received prior chemotherapy for unresectable locally advanced or metastatic breast cancer
* Has received prior treatment with an anti-HER3 antibody and/or antibody-drug conjugate that consists of a topoisomerase I inhibitor (eg, T-DXd) or any other topoisomerase I inhibitor therapy
* Has received prior systemic anticancer therapy within 4 weeks (or 5 half-lives, whichever is shorter) before randomization; participants previously treated with ET plus a CDK4/6 inhibitor may participate as long as at least 2 weeks have elapsed since the last dose of therapy was administered
* Has received prior radiotherapy for non-central nervous system disease, or required corticosteroids for radiation-related toxicities, within 14 days of the first dose of study intervention
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
* Has known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has history of (noninfectious) interstitial lung disease (ILD) or pneumonitis irrespective of steroid use, or has current ILD or suspected ILD, or ILD that cannot be ruled out by imaging at Screening
* Has severe hypersensitivity (≥Grade 3) to HER3-DXd and/or any of its excipients
* Has severe hypersensitivity (≥Grade 3) to all the available TPC and/or any of their excipients
Key Inclusion Criteria
1. 18 years or older and able to sign informed consent and comply with the protocol.
2. Measurable disease as defined by RECIST V1.1 criteria for solid tumors.
3. 3\. Part A and Part B: Histologically or cytologically confirmed unresectable advanced or metastatic solid gastric, gastroesophageal junction (GEJ), biliary tract or pancreatic carcinomas previously treated for advanced (metastatic or unresectable) disease or for which treatment is not available or not tolerated.
Part C, substudy C1: 2L m/a GC/GEJ-C patients will receive Spevatamig (PT886) in combination with Paclitaxel. Patients who are HER2 positive are eligible.
Part C, substudy C2: 1L m/a PDAC patients will receive Spevatamig (PT886) in combination with Gemcitabine plus nab-Paclitaxel (Abraxane).
Part C, substudy C3: 1L m/a PDAC patients will receive Spevatamig (PT886) in combination with Gemcitabine plus FOLFIRINOX/mFFX.
Part C, substudy C4: Patients with m/a BTC who have progressed on 1L SOC chemotherapy (GemCis) ± ICI and are eligible for 2L SOC FOLFOX treatment.
Part D, substudy D3: 2L or 3L m/a GC/GEJ-C patients will receive Spevatamig (PT886) in combination with KEYTRUDA® (pembrolizumab).
Part D, substudy D4: 1L HER2 negative m/a GC/GEJ-C patients will receive Spevatamig (PT886) in combination with SOC chemotherapy and KEYTRUDA® (pembrolizumab).
4. Able to provide a formalin fixed, paraffin embedded (FFPE) tumor tissue sample (preferably fresh biopsy or if not possible, archival tissue) to be assessed for CLDN18.2 expression and other biomarkers.
5. ECOG performance status of 0 or 1.
6. Adequate organ function confirmed at screening and within 72 hours of initiating treatment.
Key Exclusion Criteria
Patients are excluded from the study if any of the following criteria apply:
1. Women who are pregnant or lactating.
2. Women of child-bearing potential (WOCBP) who do not use adequate birth control.
3. Has an active autoimmune disease that has required systemic treatment in the past 2 years.
4. Prior CLDN18.2 or CD47 targeting therapies, or SIRPα (signal regulatory protein alpha) targeting agents.
Additional inclusion and exclusion criteria will apply.
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Key Inclusion Criteria
1. 18 years or older and able to sign informed consent and comply with the protocol.
2. Measurable disease as defined by RECIST V1.1 criteria for solid tumors.
3. 3\. Part A: Histologically or cytologically confirmed unresectable advanced or metastatic solid gastric, gastroesophageal junction (GEJ), biliary tract or pancreatic carcinomas previously treated for advanced (metastatic or unresectable) disease or for which treatment is not available or not tolerated.
Part B: Patients with PDAC and GC/GEJC must meet the same criteria as those in Part A depending on which indication and line of treatment are chosen for expansion. Patients considered 2L with BTC, without actionable genomic mutations. Patients considered 3L with CRC.
Part C, substudy C1: patients with 2L m/a GC/GEJ-C will receive Spevatamig (PT886) in combination with Paclitaxel. Patients who are HER2 positive are eligible.
Part C, substudy C2: patients with 1L m/a PDAC will receive Spevatamig (PT886) in combination with Gemcitabine plus nab-Paclitaxel (Abraxane).
Part C, substudy C3: patients with 1L m/a PDAC will receive Spevatamig (PT886) in combination with Gemcitabine plus FOLFIRINOX/mFFX or NALIRIFOX.
Part C, substudy C4: Patients with m/a BTC without actionable genomic mutations who have progressed on 1L SOC chemotherapy (GemCis) ± ICI and are eligible for 2L SOC FOLFOX treatment.
Part C, substudy C5 and C7: Patients with CRC who are considered 3L, TAS-102 treatment naïve, eligible to receive 3L SOC TAS-102 treatment, and able to swallow oral tablets.
Part C, substudy C6 and C7: Patients with CRC who are considered 3L, and eligible to receive bevacizumab treatment, with no contraindication to bevacizumab
Part D, substudy D2: patients with m/a BTC with adenocarcinoma histology only, who are treatment naïve for their m/a disease and are eligible for treatment with SOC chemotherapy and ICI.
Part D, substudy D3: patients with 2L or 3L m/a GC/GEJ-C will receive Spevatamig (PT886) in combination with KEYTRUDA® (pembrolizumab).
Part D, substudy D4: patients with 1L HER2 negative m/a GC/GEJ-C will receive Spevatamig (PT886) in combination with SOC chemotherapy and KEYTRUDA® (pembrolizumab).
4. Able to provide a formalin fixed, paraffin embedded (FFPE) tumor tissue sample (preferably fresh biopsy or if not possible, archival tissue) to be assessed for CLDN18.2 expression and other biomarkers.
5. ECOG performance status of 0 or 1.
6. Adequate organ function confirmed at screening and within 72 hours of initiating treatment.
Key Exclusion Criteria
Patients are excluded from the study if any of the following criteria apply:
1. Women who are pregnant or lactating.
2. Women of child-bearing potential (WOCBP) who do not use adequate birth control.
3. Has an active autoimmune disease that has required systemic treatment in the past 2 years.
4. Prior CLDN18.2 or CD47 targeting therapies, or SIRPα (signal regulatory protein alpha) targeting agents.
Additional inclusion and exclusion criteria will apply.
Inclusion Criteria:
* Biopsy-confirmed muscle-invasive bladder cancer (cT2,T3,T4a). (Note: Tissue samples are required.) (Participants with cT3/T4a staged disease will be capped at 25% of patients treated at RP2D).
* Urothelial histology present. Mixed histologies other than small cell/neuroendocrine are allowed as long as some urothelial histology is present. Neuroendocrine histology of any component and pure variant (non-urothelial) histology tumors will be excluded. (Patients with \< 50% urothelial histology will be capped at 25% of patients treated at RP2D).
* Must be judged by the investigator to be ineligible for radical cystectomy or electing not to undergo radical cystectomy.
* Must be eligible for and agree to receive bladder irradiation as determined by the treating investigator.
* Must have a TURBT within 8 weeks of combination treatment start with viable tumor content. If no viable tumor content is present on TURBT, the patient will be replaced in the study.
* Patients who have autoimmune disease will be evaluated on a case-by-case basis and can only enroll so long as participants are not on active immunosuppression with a corticoid steroid allowance exceeding 10mg of prednisone or equivalent per day.
* Age \>= 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status \<= 1.
* Absolute neutrophil count ≥ 1,500/microliter (mcL).
* Platelets \>= 100,000/mcL.
* Hemoglobin \>= 9.0 g/dL or ≥ 5.6 mmol/L.
\* Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
* Total bilirubin \<= 1.5 × upper limit of normal, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) \<= 2.5 X institutional upper limit of normal.
* Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) \<= 2.5 X institutional upper limit of normal.
* Creatinine clearance glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2, calculated by Cockcroft-Gault or measured using 24-hour creatinine clearance.
* International normalized ratio (INR) OR prothrombin time (PT) \<= 1.5 × upper limit of normal (ULN).
\* If participant is receiving anticoagulant therapy, as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants, participant is eligible.
* Activated partial thromboplastin time (aPTT) \<= 1.5 × ULN.
\* If participant is receiving anticoagulant therapy, as long as PT or aPTT is within therapeutic range of intended use of anticoagulants, participant is eligible.
* Ability to understand and the willingness to sign a written informed consent document.
* Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* Participants who are hepatitis B virus surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) anti-viral therapy for at least 4-weeks, and have undetectable HBV viral load prior to randomization. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
\* Note: Hepatitis B screening tests are not required unless patients have a known history of HBV infection.
* Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.
\* Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to cycle 1 day 1.
* Women of child-bearing potential and men with sexual partners of childbearing potential must agree to use adequate contraception for the duration of study participation. Enfortumab vedotin (EV) may cause fetal harm. Women of child-bearing potential must use contraception during treatment with EV and for 120 days after the last dose. Men with female partners who are women of child-bearing potential must use contraception during treatment with EV and for 120 days after the last dose. 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. Acceptable methods include barrier method, hormonal method, as well as intrauterine devices
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 8 weeks after last administration of study treatment.
Exclusion Criteria:
* Presence of distant metastases on imaging (M1 disease).
* Presence of ≥ N2 disease on imaging (N1 disease allowed, but participants with N1 disease will be capped at 25% of patients treated at RP2D).
* Presence of small cell / neuroendocrine histology in tumor sample (any content).
* Absence of urothelial histology in TURBT tumor sample (pure variant histology).
* Presence of untreated upper tract urothelial cancer.
* Presence of severe hydronephrosis precluding therapy in the judgement of the treating physician.
* Presence of extensive carcinoma in situ (CIS) is exclusionary; moderate CIS that could still benefit from radiation treatment in the judgement of treating physician is allowed.
* Baseline neuropathy grade 2 (G2) or greater.
* Baseline uncontrolled diabetes mellitus.Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥ 8% or HbA1c 7 to \< 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
\* Note: Patients with prior diagnosis but with disease under control are eligible
* Prior treatment with systemic immunotherapy or chemotherapy for urothelial cancer. (with the exception of prior systematic therapy treatment \>12 months prior). Note: Prior bacillus calmette-guerin (BCG) and intravesical treatments are allowed
* Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to cycle 1 day 1.
* Has received prior radiotherapy within 2 weeks of cycle 1 day 1 or had radiation-related toxicities requiring corticosteroids.
* Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention.
\* Note: Administration of killed vaccines is allowed. Any licensed coronavirus 2019 (COVID-19) vaccine (including for emergency use) is allowed in the study as long as they are messenger ribonucleic acid (mRNA) vaccines, replication-incompetent adenoviral vaccines, or inactivated vaccines.
* Major surgery within 2 weeks prior to first dose of EV.
\* Note: Cataract surgery, standard tissue biopsies, and standard of care cardiac devices, such as a pacemaker or stent placed on an elective basis, are allowable procedures.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
\* Note: Inhaled or topical steroids are permitted.
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
* Has known active CNS metastases and/or carcinomatous meningitis.
* History of another significant life-limiting malignancy requiring systematic treatment within 2 years prior to the first dose of study drugs, or any evidence of residual disease from a previously diagnosed malignancy.
\* Note: Patients with nonmelanoma skin cancer, curatively treated localized prostate cancer, curatively treated upper tract urothelial cancer, or carcinoma in situ of any type (if complete resection was performed) are allowed.
* Hypersensitivity to pembrolizumab or enfortumab vedotin, or any of their excipients.
* Prior allogeneic stem cell or solid organ transplant.
* Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has an active infection requiring systemic therapy.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
* History of Hepatitis B with detectable HBV viral load (participants who are HBsAg positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks, and/or have undetectable HBV viral load prior to randomization) or known active hepatitis C virus (defined as detectable HCV RNA .\[qualitative\]) infection.
\* Note: Testing for Hepatitis B or C is not required unless clinically indicated or if there is a known history of hepatitis infection. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Pregnant and breast feeding participants are excluded from this study because targeted chemotherapy and radiation have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with EV+pembrolizumab, breastfeeding should be discontinued if the mother is treated with these investigational products.
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Inclusion Criteria:
* Biopsy-confirmed muscle-invasive bladder cancer (cT2,T3,T4a). (Note: Tissue samples are required.) (Participants with cT3/T4a staged disease will be capped at 25% of patients treated at RP2D).
* Urothelial histology present. Mixed histologies other than small cell/neuroendocrine are allowed as long as some urothelial histology is present. Neuroendocrine histology of any component and pure variant (non-urothelial) histology tumors will be excluded. (Patients with \< 50% urothelial histology will be capped at 25% of patients treated at RP2D).
* Must be judged by the investigator to be ineligible for radical cystectomy or electing not to undergo radical cystectomy.
* Must be eligible for and agree to receive bladder irradiation as determined by the treating investigator.
* Must have a TURBT within 8 weeks of combination treatment start with viable tumor content. If no viable tumor content is present on TURBT, archival TURBT sample confirming MIBC diagnosis can be used instead.
* Patients who have autoimmune disease will be evaluated on a case-by-case basis and can only enroll so long as participants are not on active immunosuppression with a corticoid steroid allowance exceeding 10mg of prednisone or equivalent per day.
* Age \>= 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status \<= 1.
Demonstrates adequate organ function as defined below:
* Absolute neutrophil count ≥ 1,500/microliter (mcL).
* Platelets \>= 100,000/mcL.
* Hemoglobin \>= 9.0 g/dL or ≥ 5.6 mmol/L. \* Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
Adequate Hepatic function:
* Total bilirubin \<= 1.5 × upper limit of normal, unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits.
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) \<= 2.5 X institutional upper limit of normal.
* Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) \<= 2.5 X institutional upper limit of normal.
Adequate renal function:
• Creatinine clearance glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2, calculated by Cockcroft-Gault or measured using 24-hour creatinine clearance.
Adequate coagulatiohhn:
* International normalized ratio (INR) OR prothrombin time (PT) \<= 1.5 × upper limit of normal (ULN).
* Activated partial thromboplastin time (aPTT) \<= 1.5 × ULN.
\* If participant is receiving anticoagulant therapy, as long as PT or aPTT is within therapeutic range of intended use of anticoagulants, participant is eligible.
* Ability to understand and the willingness to sign a written informed consent document.
* Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* 12\. Participants who are Hepatitis B surface antigen (HBsAg) positive are eligible if they have an undetectable hepatitis B Virus (HBV) viral load prior to randomization. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
\* Note: Hepatitis B screening tests are not required unless patients have a known history of HBV infection.
* Participants with a history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.
\* Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to cycle 1 day 1. Testing for Hepatitis C is not required unless clinically indicated or there is a known history of a hepatitis infection.
* Women of child-bearing potential and men with sexual partners of childbearing potential must agree to use adequate contraception for the duration of study participation. Enfortumab vedotin (EV) may cause fetal harm. Women of child-bearing potential must use contraception during treatment with EV and for 120 days after the last dose. Men with female partners who are women of child-bearing potential must use contraception during treatment with EV and for 120 days after the last dose. 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. Acceptable methods include barrier method, hormonal method, as well as intrauterine devices
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 8 weeks after last administration of study treatment.
Exclusion Criteria:
* Presence of distant metastases on imaging (M1 disease).
* Presence of ≥ N2 disease on imaging (N1 disease allowed, but participants with N1 disease will be capped at 25% of patients treated at RP2D).
* Presence of small cell / neuroendocrine histology in tumor sample (any content).
* Absence of urothelial histology in TURBT tumor sample (pure variant histology).
* Presence of untreated upper tract urothelial cancer.
* Presence of severe hydronephrosis precluding therapy in the judgement of the treating physician.
* Presence of extensive carcinoma in situ (CIS) is exclusionary; moderate CIS that could still benefit from radiation treatment in the judgement of treating physician is allowed.
* Baseline neuropathy grade 2 (G2) or greater.
* Baseline uncontrolled diabetes mellitus. Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥ 8% or HbA1c 7 to \< 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
\* Note: Patients with prior diagnosis but with disease under control are eligible
* Prior treatment with systemic immunotherapy or chemotherapy for urothelial cancer. (with the exception of prior systematic therapy treatment \>12 months prior). Note: Prior bacillus calmette-guerin (BCG) and intravesical treatments are allowed
* Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to cycle 1 day 1.
* Has received prior radiotherapy within 2 weeks of cycle 1 day 1 or had radiation-related toxicities requiring corticosteroids.
* Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention.
\* Note: Administration of killed vaccines is allowed. Any licensed coronavirus 2019 (COVID-19) vaccine (including for emergency use) is allowed in the study as long as they are messenger ribonucleic acid (mRNA) vaccines, replication-incompetent adenoviral vaccines, or inactivated vaccines.
* Major surgery within 2 weeks prior to first dose of EV.
\* Note: Cataract surgery, standard tissue biopsies, and standard of care cardiac devices, such as a pacemaker or stent placed on an elective basis, are allowable procedures.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
\* Note: Inhaled or topical steroids are permitted.
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
* Has known active CNS metastases and/or carcinomatous meningitis.
* History of another significant life-limiting malignancy requiring systematic treatment within 2 years prior to the first dose of study drugs, or any evidence of residual disease from a previously diagnosed malignancy.
\* Note: Patients with nonmelanoma skin cancer, curatively treated localized prostate cancer, curatively treated upper tract urothelial cancer, or carcinoma in situ of any type (if complete resection was performed) are allowed.
* Hypersensitivity to pembrolizumab or enfortumab vedotin, or any of their excipients.
* Prior allogeneic stem cell or solid organ transplant.
* Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease requiring active management.
* Has an active infection requiring systemic therapy that in the judgement of the treating team would preclude treatment with EV, pembrolizumab or RT.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Pregnant and breast feeding participants are excluded from this study because targeted chemotherapy and radiation have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with EV+pembrolizumab, breastfeeding should be discontinued if the mother is treated with these investigational products.
Inclusion Criteria:
* At least 18 years of age or 12 to 17 years of age after Safety Review Committee approval.
* Locally advanced or metastatic solid malignancy with a TP53 Y220C mutation
* Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
* Previously treated with one or more lines of anticancer therapy and progressive disease
* Adequate organ function
* Measurable disease per RECIST v1.1 (Phase 2)
Additional Criteria for Inclusion in Phase 1b (rezatapopt) + pembrolizumab combination)
* Anti-PD-1/PD-L1 naive or must have progressed on treatment
* Measurable disease
Exclusion Criteria:
* Anti-cancer therapy within 21 days (or 5 half-lives) of receiving the study drug
* Radiotherapy within 14 days of receiving the study drug
* Primary CNS tumor
* History of leptomeningeal disease or spinal cord compression
* Brain metastases, unless neurologically stable and do not require steroids to treat associated neurological symptoms
* Stroke or transient ischemic attack within 6 months prior to screening
* Heart conditions such as unstable angina within 6 months prior to screening, uncontrolled hypertension, a heart attack within 6 months prior to screening, congestive heart failure, prolongation of QT interval, or other rhythm abnormalities
* Strong CYP3A4 inducers and strong CYP2C9 inhibitors/inducers within 14 days of first dose of rezatapopt
* History of gastrointestinal (GI) disease that may interfere with absorption of study drug or patients unable to take oral medication
* History of prior organ transplant
* Known, active malignancy, except for treated cervical intraepithelial neoplasia, or non-melanoma skin cancer
* Known, active uncontrolled Hepatitis B, Hepatitis C, or human immunodeficiency virus infection
Additional Criteria for Exclusion from Phase 2 (rezatapopt monotherapy)
* Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2)
Additional Criteria for Exclusion from Phase 1b (rezatapopt) + pembrolizumab combination)
* Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor and discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE)
* Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention
* Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy within 7 days prior to the first dose of study drug
* Hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
* Active autoimmune disease that has required systemic treatment in past 2 years
* History of radiation pneumonitis
* History of (non-infectious) or active pneumonitis / interstitial lung disease that required steroids
* Active infection requiring systemic therapy
* Known history of HIV infection
* Has previously received rezatapopt
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Inclusion Criteria:
* At least 18 years of age or 12 to 17 years of age after Safety Review Committee approval.
* Locally advanced or metastatic solid malignancy with a TP53 Y220C mutation
* Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
* Previously treated with one or more lines of anticancer therapy and progressive disease
* Adequate organ function
* Measurable disease per RECIST v1.1 (Phase 2)
Additional Criteria for Inclusion in Phase 1b (rezatapopt) + pembrolizumab combination)
* Anti-PD-1/PD-L1 naive or must have progressed on treatment
* Measurable disease
Exclusion Criteria:
* Anti-cancer therapy within 21 days (or 5 half-lives) of receiving the study drug
* Radiotherapy within 14 days of receiving the study drug
* Primary CNS tumor
* History of leptomeningeal disease or spinal cord compression
* Brain metastases, unless neurologically stable and do not require steroids to treat associated neurological symptoms
* Stroke or transient ischemic attack within 6 months prior to screening
* Heart conditions such as unstable angina within 6 months prior to screening, uncontrolled hypertension, a heart attack within 6 months prior to screening, congestive heart failure, prolongation of QT interval, or other rhythm abnormalities
* Strong CYP3A4 inducers and strong CYP2C9 inhibitors/inducers within 14 days of first dose of rezatapopt
* History of gastrointestinal (GI) disease that may interfere with absorption of study drug or patients unable to take oral medication
* History of prior organ transplant
* Known, active malignancy, except for treated cervical intraepithelial neoplasia, or non-melanoma skin cancer
* Known, active uncontrolled Hepatitis B, Hepatitis C, or human immunodeficiency virus infection
Additional Criteria for Exclusion from Phase 2 (rezatapopt monotherapy)
* Known KRAS mutation, defined as a single nucleotide variant (SNV) (Phase 2). Exception: Ovarian cancer patients with a known KRAS SNV are permitted.
Additional Criteria for Exclusion from Phase 1b (rezatapopt) + pembrolizumab combination)
* Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor and discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE)
* Received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention
* Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy within 7 days prior to the first dose of study drug
* Hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
* Active autoimmune disease that has required systemic treatment in past 2 years
* History of radiation pneumonitis
* History of (non-infectious) or active pneumonitis / interstitial lung disease that required steroids
* Active infection requiring systemic therapy
* Known history of HIV infection
* Has previously received rezatapopt
The main inclusion and exclusion criteria include but are not limited to the following:
Inclusion Criteria:
* Has histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC)
* Has newly diagnosed Stage IIIB/IIIC NSCLC, not eligible for curative resection or curative chemotherapy/radiation as determined by a multidisciplinary tumor board and/or by radiation oncologist, surgeon, and medical oncologist or Stage IV (M1a, M1b, or M1c) by American Joint Committee on Cancer (AJCC) Staging Manual, Version 8
* Provides an archival tumor tissue sample (≤5 years) or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated to enable central laboratory testing of kirsten rat sarcoma (KRAS) G12C mutation status, PD-L1 status, and biomarker research
* If have had adverse events (AEs) due to previous anticancer therapies, must have recovered to \< Grade 1 or baseline
* If human immunodeficiency virus (HIV)-infected, must have well controlled HIV on antiretroviral therapy (ART)
* If Hepatitis B surface antigen (HBsAg) positive, have received Hepatitis B Virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load
* If a participant has a history of Hepatitis C virus (HCV) infection, HCV viral load is undetectable
Exclusion Criteria:
* Has diagnosis of small cell lung cancer. For mixed tumors, if small cell elements are present, the participant is ineligible
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease
* Has known history of, or active, neurologic paraneoplastic syndrome
* Has an active infection requiring systemic therapy, with exceptions
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
* Has one or more of the following ophthalmological findings/conditions: intraocular pressure \>21 mmHg and/or any diagnosis of glaucoma, diagnosis of central serous retinopathy, retinal vein occlusion, or retinal artery occlusion, diagnosis of retinal degenerative disease
* Has received prior systemic anticancer therapy for their locally advanced or metastatic NSCLC
* Has received radiation therapy to the lung that is \>30 Gray within 6 months of start of study intervention
* Has received radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not required corticosteroids, and not have had radiation pneumonitis
* Has known active central nervous system metastases and/or carcinomatous meningitis
* Known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has active autoimmune disease that has required systemic treatment in the past 2 years
* Has history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
* Is HIV-infected and has a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Has history of allogenic tissue/solid organ transplant
* Has not fully recovered from any effects of major surgical procedure
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The main inclusion and exclusion criteria include but are not limited to the following:
Inclusion Criteria:
* Has histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC)
* Has newly diagnosed Stage IIIB/IIIC NSCLC, not eligible for curative resection or curative chemotherapy/radiation as determined by a multidisciplinary tumor board and/or by radiation oncologist, surgeon, and medical oncologist or Stage IV (M1a, M1b, or M1c) by American Joint Committee on Cancer (AJCC) Staging Manual, Version 8
* Provides an archival tumor sample (≤5 years) or newly obtained core, incisional, or excisional biopsy or fine needle aspirate (FNA) of a tumor lesion, not previously irradiated to enable central laboratory testing of kirsten rat sarcoma (KRAS) G12C mutation status, programmed cell death ligand 1 (PD-L1) status, and biomarker research
* If have had adverse events (AEs) due to previous anticancer therapies, must have recovered to \< Grade 1 or baseline
* If human immunodeficiency virus (HIV)-infected, must have well controlled HIV on antiretroviral therapy (ART)
* If Hepatitis B surface antigen (HBsAg) positive, have received Hepatitis B Virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load
* If a participant has a history of Hepatitis C virus (HCV) infection, HCV viral load is undetectable
Exclusion Criteria:
* Has diagnosis of small cell lung cancer. For mixed tumors, if small cell elements are present, the participant is ineligible
* Has active inflammatory bowel disease requiring immunosuppressive medication or previous clear history of inflammatory bowel disease
* Has known history of, or active, neurologic paraneoplastic syndrome
* Has an active infection requiring systemic therapy, with exceptions
* Has uncontrolled, significant cardiovascular disease or cerebrovascular disease
* Has received prior systemic anticancer therapy for their locally advanced or metastatic NSCLC
* Has received radiation therapy to the lung that is \>30 Gray within 6 months of start of study intervention
* Has received radiotherapy to non-central nervous system (CNS) disease within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not required corticosteroids, and not have had radiation pneumonitis
* Has known active CNS metastases and/or carcinomatous meningitis
* Known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has active autoimmune disease that has required systemic treatment in the past 2 years
* Has history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
* Is HIV-infected and has a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Has history of allogenic tissue/solid organ transplant
* Has not fully recovered from any effects of major surgical procedure
Inclusion Criteria:
* Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of metastatic colorectal adenocarcinoma with liver-predominant disease, defined as liver metastases with
* No symptomatic lung or bony metastases
* No peritoneal carcinomatosis or clinically significant ascites as determined by the investigator Note: at least 1 measurable lesion must be present in the liver to assess response. It is preferable to have at least 1 other lesion present in the liver which can be biopsied. Measurable lesions chosen as target lesions in the liver should not be biopsied if it can be avoided
* Patient must have received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and a VEGF inhibitor (e.g., bevacizumab), unless contraindicated.
* Patients with KRAS/NRAS/BRAF wild-type cancers must also have received an EGFR inhibitor (e.g., cetuximab or panitumumab) in addition to the aforementioned therapies, unless contraindicated.
* Patients who experienced disease recurrence within 6 months of oxaliplatin-containing adjuvant therapy will qualify as having received an oxaliplatin-containing regimen in the metastatic setting.
* Tumor must have documented mismatch repair proficiency (MMR proficient) by immunohistochemistry or not microsatellite instability high(non-MSI-H) by PCR.
* Participants who have adverse events due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy or persistent alopecia are eligible.
* The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
* Have measurable disease based on RECIST 1.1 with at least one measurable lesion in the liver. It is preferable that one additional viable lesion in the liver that could be safely biopsied is also present, but not required for inclusion. Lesions chosen as target lesions in the liver should not be biopsied if possible. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
* Have a life expectancy of 3 months or greater as assessed by the investigator
* Have adequate organ function. Specimens must be collected within 14 days prior to the start of study intervention.
* Male participants: A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
* A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
* Not a woman of childbearing potential (WOCBP) OR
* A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
Exclusion Criteria:
* WOCBP who has a positive urine pregnancy test within 72 hours prior to receiving the first dose of study medication (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. If the serum pregnancy test is negative, then the participant will be deemed eligible on this criterion.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
* Has previous treatment with odetiglucan
* Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks prior to first dose of study treatment.
* Has received prior radiotherapy within 2 weeks of start of study intervention or has ongoing radiation-related toxicities requiring corticosteroids.
* Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week washout, is permitted.
* Has undergone treatment chemoembolization or radioembolization within 6 weeks prior to enrollment on the study
* Has undergone hepatic arterial infusion pump placement
* Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
* Has received an investigational agent or has used an investigational device within the shorter of 4 weeks or 5 half-lives of the first dose of study intervention administration.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
* Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
* Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
* Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
* Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid)
* Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has an active infection requiring systemic therapy.
* Has a known history of Human Immunodeficiency Virus (HIV) infection
* Note: No HIV testing is required unless mandated by local health authority.
* Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. Hepatitis B and C screening tests are not required unless the participant has a known history of HBV and HCV infection. Participants may be eligible if the following criteria are met (18a and/or 18b).
* Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, have undetectable HBV viral load prior to initiation of study therapy, and should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention
* Participants with history HCV infection are eligible if HCV viral load is undetectable at screening and have completed curative anti-viral therapy at least 4 weeks prior to randomization
* Has not adequately recovered from major surgery or has ongoing surgical complications.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
* Has a clinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome within ≤ 6 months prior to start of study treatment, symptomatic or uncontrolled arrhythmia, congestive heart failure, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
* Has had an allogenic tissue/solid organ transplant.
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Inclusion Criteria:
* Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of metastatic colorectal adenocarcinoma with liver-predominant disease, defined as liver metastases with
* No symptomatic lung or bony metastases
* No peritoneal carcinomatosis or clinically significant ascites as determined by the investigator Note: at least 1 measurable lesion must be present in the liver to assess response. It is preferable to have at least 1 other lesion present in the liver which can be biopsied. Measurable lesions chosen as target lesions in the liver should not be biopsied if it can be avoided
* Sum of diameters of RECIST measurable lesions (\>1cm in diameter for extra-nodal metastases or \>1.5cm in short axis for nodal metastases) outside of the liver is less than the sum of diameters of RECIST measurable lesions within the liver per the investigator's assessment.
* Patient must have received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and a VEGF inhibitor (e.g., bevacizumab), unless contraindicated.
* Patients with KRAS/NRAS/BRAF wild-type cancers must also have received an EGFR inhibitor (e.g., cetuximab or panitumumab) in addition to the aforementioned therapies, unless contraindicated.
* Patients who experienced disease recurrence within 6 months of oxaliplatin-containing adjuvant therapy will qualify as having received an oxaliplatin-containing regimen in the metastatic setting.
* Tumor must have documented mismatch repair proficiency (MMR proficient) by immunohistochemistry or not microsatellite instability high(non-MSI-H) by PCR.
* Participants who have adverse events due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have ≤Grade 2 neuropathy or persistent alopecia are eligible.
* The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
* Have measurable disease based on RECIST 1.1 with at least one measurable lesion in the liver. It is preferable that one additional viable lesion in the liver that could be safely biopsied is also present, but not required for inclusion. Lesions chosen as target lesions in the liver should not be biopsied if possible. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Assessment of ECOG performance status will be repeated on cycle 1 day 1 and needs to continue to meet this inclusion criterion to proceed with study participation and treatment.
* Have a life expectancy of 3 months or greater as assessed by the investigator
* Have adequate organ function. Specimens must be collected within 30 days prior to the start of study intervention.
* Male participants: A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
* A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
* Not a woman of childbearing potential (WOCBP) OR
* A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
Exclusion Criteria:
* Liver metastases occupy \> 50% of liver parenchmyma by volume per the investigator's assessment.
* WOCBP who has a positive urine pregnancy test within 72 hours prior to receiving the first dose of study medication (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. If the serum pregnancy test is negative, then the participant will be deemed eligible on this criterion.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
* Has previous treatment with odetiglucan
* Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks prior to first dose of study treatment.
* Has received prior radiotherapy within 2 weeks of start of study intervention or has ongoing radiation-related toxicities requiring corticosteroids.
* Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week washout, is permitted.
* Has undergone treatment chemoembolization or radioembolization within 6 weeks prior to enrollment on the study
* Has undergone hepatic arterial infusion pump placement
* Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of non-live vaccines is allowed.
* Has received an investigational agent or has used an investigational device within the shorter of 4 weeks or 5 half-lives of the first dose of study intervention administration.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
* Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
* Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
* Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
* Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid)
* Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has an active infection requiring systemic therapy.
* Has a known history of Human Immunodeficiency Virus (HIV) infection
* Note: No HIV testing is required unless mandated by local health authority.
* Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. Hepatitis B and C screening tests are not required unless the participant has a known history of HBV and HCV infection. Participants may be eligible if the following criteria are met (18a and/or 18b).
* Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, have undetectable HBV viral load prior to initiation of study therapy, and should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention
* Participants with history HCV infection are eligible if HCV viral load is undetectable at screening and have completed curative anti-viral therapy at least 4 weeks prior to randomization
* Has not adequately recovered from major surgery or has ongoing surgical complications.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
* Has a clinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome within ≤ 6 months prior to start of study treatment, symptomatic or uncontrolled arrhythmia, congestive heart failure, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
* Has had an allogenic tissue/solid organ transplant.
Inclusion Criteria:
The main inclusion criteria include but are not limited to the following:
* Has histologically confirmed HER2+ locally advanced unresectable breast cancer or metastatic breast cancer
* Human immunodeficiency virus (HIV)-infected participants must have well-controlled HIV on antiretroviral therapy (ART)
* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable hepatitis B virus (HBV) viral load before allocation
* Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 within 7 days before start of study intervention
Arm 1:
* Has received at least a minimum of 2 and a maximum of 5 prior lines of anti-HER2 therapy in the locally advanced or metastatic setting
* Had disease progression on or after any previous trastuzumab deruxtecan (T-DXd) treatment
Arm 2:
-Has received no more than 5 prior lines of anti-HER2 therapy in the locally advanced or metastatic setting
Arm 3:
-Has received and had disease progression from T-DXd treatment in any setting and a maximum of 3 prior lines of anti-HER2 therapy in the locally advanced or metastatic setting. T-DXd must be the most recent therapy received before enrollment.
Exclusion Criteria:
The main exclusion criteria include but are not limited to the following:
* Uncontrolled or significant cardiovascular disease
* History of (noninfectious) pneumonitis/interstitial lung disease (ILD) that required steroids or has current pneumonitis/interstitial lung disease
* Has clinically severe respiratory compromise
* Has any history of or evidence of any current leptomeningeal disease
* Has clinically significant corneal disease
* Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection
* HIV infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Known additional malignancy that is progressing or has required active treatment within the past 3 years
* Evidence of spinal cord compression or brain metastases
* Has an active infection requiring systemic therapy
* Concurrent active HBV and HCV infection
* Has had major surgical procedure (excluding placement of vascular access) less than 28 days
Arm 3 ONLY
\- Has received prior treatment with tucatinib, lapatinib, or neratinib, or any investigational HER2-targeted tyrosine kinase inhibitors in the locally advanced or metastatic setting
→
Inclusion Criteria:
The main inclusion criteria include but are not limited to the following:
* Has histologically confirmed HER2+ locally advanced unresectable breast cancer or metastatic breast cancer
* Human immunodeficiency virus (HIV)-infected participants must have well-controlled HIV on antiretroviral therapy (ART)
* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable hepatitis B virus (HBV) viral load before allocation
* Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 within 7 days before start of study intervention
Part 1 Arm 1:
* Has received at least a minimum of 2 and a maximum of 5 prior lines of anti-HER2 therapy in the locally advanced or metastatic setting
* Had disease progression on or after any previous trastuzumab deruxtecan (T-DXd) treatment
Part 1 Arm 2:
-Has received no more than 5 prior lines of anti-HER2 therapy in the locally advanced or metastatic setting
Part 1 Arm 3:
-Has received and had disease progression from T-DXd treatment in any setting and a maximum of 3 prior lines of anti-HER2 therapy in the locally advanced or metastatic setting. T-DXd must be the most recent therapy received before enrollment.
Part 2 : Has not received prior systemic therapy (including T-DXd) for recurrent locally advanced or metastatic breast cancer (mBC).
Exclusion Criteria:
The main exclusion criteria include but are not limited to the following:
* Uncontrolled or significant cardiovascular disease
* Has any history of (noninfectious) interstitial lung disease (ILD)/ pneumonitis irrespective of steroid use or has current ILD or suspected ILD
* Has clinically severe respiratory compromise
* Has any history of or evidence of any current leptomeningeal disease
* Has clinically significant corneal disease
* Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection
* HIV infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Known additional malignancy that is progressing or has required active treatment within the past 3 years
* Part 1: Evidence of spinal cord compression or brain metastases
* Part 2: Evidence of spinal cord compression or brain/CNS metastases.
* Has an active infection requiring systemic therapy
* Concurrent active HBV and HCV infection
* Has had major surgical procedure (excluding placement of vascular access) less than 28 days
Part1: Arm 3 ONLY
\- Has received prior treatment with tucatinib, lapatinib, or neratinib, or any investigational HER2-targeted tyrosine kinase inhibitors in the locally advanced or metastatic setting
The combination therapy arm of the study with pembrolizumab did not yield an efficacy signal, so enrollment into the combination therapy arm was terminated. The monotherapy arm of the study was fully enrolled and completed.
Inclusion Criteria:
* Phase 2: Is human immunodeficiency virus type 1 (HIV-1) positive with Plasma HIV-1 ribonucleic acid (RNA) ≥500 and ≤100,000 copies/mL.
* Phase 3: Is HIV-1 positive with Plasma HIV-1 RNA ≥500 copies/mL.
* Phase 2: Has cluster of differentiation 4-positive (CD4+) T-cell count ≥200 cells/mm\^3.
* Is naïve to antiretroviral therapy (ART), defined as having received no prior therapy with any antiretroviral agent following a diagnosis of HIV 1 infection.
Exclusion Criteria:
* Has human immunodeficiency virus type 2 (HIV-2) infection.
* Has a diagnosis of an active acquired immune deficiency syndrome (AIDS)-defining opportunistic infection.
* Has active hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection.
* Has a history of malignancy ≤5 years prior to providing documented informed consent except for adequately treated basal cell or squamous cell skin cancer, in situ cervical or in situ anal cancer, or cutaneous Kaposi's sarcoma.
* Has prior exposure to islatravir (ISL) or ulonivirine (ULO) for any duration any time prior to Day 1.
→
Inclusion Criteria:
* Phase 2: Is human immunodeficiency virus type 1 (HIV-1) positive with Plasma HIV-1 ribonucleic acid (RNA) ≥500 and ≤100,000 copies/mL.
* Phase 3: Is HIV-1 positive with Plasma HIV-1 RNA ≥500 and ≤1,000,000 copies/mL
* Phase 2: Has cluster of differentiation 4-positive (CD4+) T-cell count ≥200 cells/mm\^3.
* Is naïve to antiretroviral therapy (ART), defined as having received no prior therapy with any antiretroviral agent following a diagnosis of HIV 1 infection.
Exclusion Criteria:
* Has human immunodeficiency virus type 2 (HIV-2) infection.
* Has a diagnosis of an active acquired immune deficiency syndrome (AIDS)-defining opportunistic infection.
* Has active hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection.
* Has a history of malignancy ≤5 years prior to providing documented informed consent except for adequately treated basal cell or squamous cell skin cancer, in situ cervical or in situ anal cancer, or cutaneous Kaposi's sarcoma.
* Has prior exposure to islatravir (ISL) or ulonivirine (ULO) for any duration any time prior to Day 1.
Inclusion Criteria:
\- Primary care provider (physician or nurse practitioner) at Weill Cornell Internal Medicine Associates (WCIMA).
Exclusion Criteria:
\- Not a primary care provider (physician or nurse practitioner) at WCIMA.
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Inclusion Criteria:
* Primary care provider (physician or nurse practitioner) at Weill Cornell Internal Medicine Associates (WCIMA).
* Participated in clinical practice during the Our Practice Advisory (OPA) implementation period.
Exclusion Criteria:
* Not a primary care provider (physician or nurse practitioner) at WCIMA.
* Did not participate in clinical practice during the Our Practice Advisory (OPA) implementation period.
Inclusion Criteria:
* Patients must have radiographic or histologically confirmed melanoma brain metastases (MBM) and be planning to undergo or have undergone SRS for treatment
* Patients must have measurable disease
* Patients may be treatment-naïve or currently on therapy for systemic disease control at time of MBM development. If MBM diagnosis coincides with initial diagnosis, patients may be treatment-naïve with systemic disease.
In patients naïve to treatment, the choice of initial therapy will be left up to the treating physician. If in their clinical judgement, single agent aPD1 plus SRS is deemed the appropriate therapy then these patients may proceed to enrollment and inclusion of CA-4948 with their regimen. If in the treating physician's judgement, patient would benefit from use of combination immunotherapy with CTLA-4/aPD1 therapy, then patient must complete induction with CTLA-4/aPD1 therapy and proceed to maintenance aPD1 therapy prior to enrollment. The timing of SRS in these patients should coincide with the conclusion of induction dual agent therapy (either during or following last cycle of CTLA-4/aPD1 therapy) to then allow for a 3-week washout from last dose of CTLA-4 inhibitor exposure received prior to starting on study drug with CA-4948 and pembrolizumab.
* Completion of induction is defined as either completing the planned 4 doses of CTLA-4/aPD1 therapy or if the CTLA-4 inhibitor is discontinued after any of the initial 3 doses of therapy due to toxicity. In the event for stopping due to toxicity, then patients may still be eligible for study inclusion as long as this toxicity would not prevent them from continuing on aPD1 therapy as planned systemic treatment and no other rules for exclusion have been met below. In these patients, the timing of SRS should be consistent as above and the washout period from time of last CTLA-4 inhibitor must be at least 3 weeks prior to initiating on study drug. If a longer period of washout is required due to toxicity and safe resumption of immunotherapy, patients may still be enrolled as long as they meet the timing requirements from time of SRS to initiation of therapy as outlined below.
* In patient who develop MBM while previously having received treatment for metastatic melanoma at other systemic locations, previous treatment with dual checkpoint inhibitor therapy (CTLA-4/aPD1 or LAG-3/aPD-1) or single agent immunotherapy therapy will be allowed, as long as at the time of SRS to these MBM lesions the patient is planned to receive aPD1 therapy as long as the above criteria are met and the patients systemic disease is displaying at least SD on last surveillance imaging performed.
* SD is determined by clinician judgement at time of study enrollment. In patients on systemic single agent aPD1 there is no washout necessary in this case and patients can start pembrolizumab and study drug at next scheduled cycle of treatment following completion of SRS as long as all other rules have been met for enrollment.
* Previous oral BRAFi/MEKi treatment will also be allowed, as long as at the time of MBM treatment with SRS the patient is planned to initiate aPD1 therapy and not continue on BRAFi/MEKi. A washout period of 14 days from last dose of BRAFi/MEKi to initiation of study drug is required.
* Treatment of symptomatic MBM with corticosteroids is allowed while receiving CA- 4948, but in order to start aPD1 therapy, patient must be on ≤ 10mg of oral prednisone daily or equivalent.
* Patients must be tolerant of receiving MRI and cannot have intolerance to gadolinium contrast.
* Age ≥18 years at time of informed consent.
* ECOG performance status ≤1
* Patients must have adequate organ and marrow function as defined below:
* absolute neutrophil count ≥ 1,500/mcL
* platelets ≥ 100,000/mcL
* hemoglobin ≥ 9.0 g/dL or ≥5.6 mmol/L
* coagulation PT/INR and aPTT ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic ranged of intended use for anticoagulants
* total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) OR direct bilirubin no lower than the ULN if total bilirubin \> 1.5 × ULN
* AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN (with confirmed liver metastases: AST and ALT ≤ 5 x ULN)
* creatinine clearance (CrCl)≤ 1.5 × ULN measured or calculated OR glomerular filtration rate (GFR)≥ 30 mL/min based on modified Cockcroft and Gault formula for participants with creatinine levels \> 1.5 × institutional upper limit of normal (ULN)
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* Participants who are HBsAg positive are eligible if they have received hepatitis B antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Subjects of childbearing potential must have a negative serum pregnancy test at screening and agree to use of highly effective methods of contraception throughout the study and for at least four months following the last dose of study treatment.
* Subjects with partners of childbearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation and 4 months after completion of CA-4948 administration. Subjects should also not donate sperm from first dose of therapy until 4 months after the last dose of treatment.
* Patients 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.
* Participants must have recovered from all adverse events due to previous therapies to ≤Grade 1 or baseline with the exception of alopecia. Participants with ≤Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible.
* Archival tumor tissue sample or newly obtained biopsy of a tumor lesion not previously irradiated has been provided.
* Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
* Subject of child-bearing potential who has a positive urine pregnancy test within 72 hours prior to treatment
* Subject has received prior systemic anti-cancer therapy including investigational agents or devices within 4 weeks prior to screening
* If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
* Prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids over ≤ 10mg of oral prednisone daily or equivalent, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
* Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. mRNA COVID-1 vaccines are allowed.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
* Known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
* Has severe hypersensitivity (≥Grade 3) to pembrolizumab, CA-4948, or any of their excipients.
* Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
* Has a history of non-infectious pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has an active infection requiring systemic therapy, is patient is receiving oral antibiotics for localized infection with planned end date they may enroll on study as soon as duration is complete.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the trial's requirements.
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
* Has had an allogenic tissue/solid organ transplant.
* Unable to discontinue medications contraindicated to CA-4948 or pembrolizumab.
* Patients with uncontrolled intercurrent illness.
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Inclusion Criteria:
* Age ≥ 18 years
* Radiographic or histologically confirmed melanoma brain metastasis (MBM) and be planning to undergo or have undergone SRS for treatment, the decision on SRS should be based on institutional standards and location characteristics. A maximal number of lesions allowed at initial SRS should be determined by institutional standard, but the all lesions must measure =\< 3.0 cm in maximal extent, and total volume to be treated must measure \< 30 mL on the contrast-enhanced diagnostic magnetic resonance imaging (MRI) brain scan. Patients must be asymptomatic from their brain metastases at conclusion of SRS therapy prior to starting study drug
* Treatment-naive or currently on therapy for systemic disease as long as there is exhibited control of systemic disease at time of MBM development. If MBM diagnosis coincides with initial diagnosis, patients may be treatment-naive with systemic disease
* In patients naive to treatment, the choice of initial therapy will be left up to the treating physician. If in their clinical judgement, single agent anti-PD1 (aPD1) plus SRS is deemed the appropriate therapy then these patients may proceed to enrollment and inclusion of CA-4948 with their regimen. If in the treating physician's judgement, patient would benefit from use of combination immunotherapy with CTLA-4/aPD1 therapy, then patient must complete induction with CTLA-4/aPD1 therapy and proceed to maintenance aPD1 therapy prior to enrollment. The timing of SRS in these patients should coincide with the conclusion of induction dual agent therapy (either during or following last cycle of CTLA-4/aPD1 therapy) to then allow for a 3-week washout from last dose of CTLA-4 inhibitor exposure received prior to starting on study drug with CA-4948 and pembrolizumab
* Completion of induction is defined as either completing the planned 4 doses of CTLA-4/aPD1 therapy or if the CTLA-4 inhibitor is discontinued after any of the initial 3 doses of therapy due to toxicity. In the event for stopping due to toxicity, then patients may still be eligible for study inclusion as long as this toxicity would not prevent them from continuing on aPD1 therapy as planned systemic treatment and no other rules for exclusion have been met below. In these patients, the timing of SRS should be consistent as above and the washout period from time of last CTLA-4 inhibitor must be at least 3 weeks prior to initiating on study drug. If a longer period of washout is required due to toxicity and safe resumption of immunotherapy, patients may still be enrolled as long as they meet the timing requirements from time of SRS to initiation of therapy as outlined below
* In patient who develop MBM while previously having received treatment for metastatic melanoma at other systemic locations, previous treatment with dual checkpoint inhibitor therapy (CTLA-4/aPD1 or LAG-3/aPD-1) or single agent immunotherapy therapy will be allowed, as long as at the time of SRS to these MBM lesions the patient is planned to receive aPD1 therapy as long as the above criteria are met and the patients systemic disease is displaying at least stable disease (SD) on last surveillance imaging performed
* SD is determined by clinician judgement at time of study enrollment. In patients on systemic single agent aPD1 there is no washout necessary in this case and patients can start pembrolizumab and study drug at next scheduled cycle of treatment following completion of SRS as long as all other rules have been met for enrollment
* Previous oral BRAFi/MEKi treatment will also be allowed, as long as at the time of MBM treatment with SRS the patient is planned to initiate aPD1 therapy and not continue on BRAFi/MEKi. A washout period of 14 days from last dose of BRAFi/MEKi to initiation of study drug is required
* Treatment of symptomatic MBM with corticosteroids is allowed while receiving CA-4948, but in order to start aPD1 therapy, patient must be on =\< 10mg of oral prednisone daily or equivalent
* Able to tolerate an MRI
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, or 1, (Karnofsky \>= 70%), if patients performance status is borderline with =\< 1 to =\< 2, special consideration can be made and discussed with study principal investigator (PI) for possible enrollment. These patients should be deemed to have a decrease in their performance status linked with an acute process that is expected to improve with initiation of therapy. This is to allow for patients who have initial decline from event that caused their brain metastasis presentation that is expected to improve with short course of steroid treatment and stereotactic radiosurgery. For those with borderline performance status that is not related to acutely reversible intracranial changes expected to improve than these patients will not be allowed
* Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L \[Hemoglobin criterion must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks\] (obtained =\< 30 days prior to registration)
* Absolute neutrophil count (ANC) ≥ 1500/mm\^3 (obtained =\< 30 days prior to registration)
* Platelets ≥ 100,000/mm\^3 (obtained =\< 30 days prior to registration)
* Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin no lower than the ULN if total bilirubin \> 1.5 × ULN (obtained =\< 30 days prior to registration)
* Alanine aminotransferase (ALT) and aspartate transaminase (AST) =\< 2.5 x ULN (=\< 5 x ULN for patients with liver involvement) (obtained =\< 30 days prior to registration)
* Prothrombin time (PT)/international normalized ratio (INR)/activated partial prothrombin time (aPTT) =\< 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (obtained =\< 30 days prior to registration)
* Calculated creatinine clearance (CrCl) =\< 1.5 x ULN OR glomerular filtration rate (GFR) \>= 30 ml/min using the Cockcroft-Gault formula for participants with creatinine levels \> 1.5 × ULN (obtained =\< 30 days prior to registration)
* Negative pregnancy test done =\< 7 days prior to registration, for persons of childbearing potential only. A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile. Women in the following categories are not considered women of child bearing potential (WOCBP) :
* Premenarchal
* Premenopausal female with 1 of the following:
* Documented hysterectomy
* Documented bilateral salpingectomy
* Documented bilateral oophorectomy
* Postmenopausal female
* A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
* A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required
* Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment
* Male and female participants agree to use a highly effective method of contraception while on study and at least 120 days following their last dose of study treatment
* Male participants agree not to donate sperm from first dose of therapy until 120 days after the last dose of study treatment
* Provide written informed consent
* Ability to complete questionnaire(s) by themselves or with assistance
* Willingness to provide mandatory blood specimens for correlative research
* Willingness to provide mandatory tissue specimens for correlative research. Archival tumor tissue sample or newly obtained biopsy of a tumor lesion not previously irradiated has been provided. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue
* Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
* Participants living with HIV must have well-controlled HIV on antiretroviral therapy (ART), defined as:
* Participants on ART must have a CD4+ T-cell count \>= 350 cells/mm\^3 at the time of screening
* Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 or the lower limit of quantification (LLOQ) (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening
* It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months
* Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (day 1) and agree to continue ART throughout the study
* Hepatitis B screening tests are not required unless known history of hepatitis B virus (HBV) infection as mandated by local health authority
* Hepatitis B positive patients:
* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to registration
* Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention
* History of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* 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
* All adverse events (AEs) due to previous therapies have returned to ≤ grade 1 or baseline, with the exception of Alopecia.
* ≤ Grade 2 neuropathy
* ≤ Grade 2 endocrine-related AEs requiring treatment or hormone replacement
* Patients who have had a recent surgery or procedure should be healed and cleared by their clinician and/or surgeon per local standards, prior to registration
* Able to swallow oral medications
Exclusion Criteria:
* Any of the following because this study involves an investigational agent, the genotoxic, mutagenic and teratogenic effects of which on the developing fetus and newborn are unknown:
* Pregnant persons
* Nursing persons
* Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception while on study and at least 120 days following their last dose of study treatment
* Any of the following prior therapies:
* Radiation therapy =\< 2 weeks prior to registration, with the exception of the described SRS that patients are mandated to receive for inclusion \[Participants must have recovered from all radiation-related toxicities, not require corticosteroids over =\< 10 mg of oral prednisone daily or equivalent, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=\< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease\]
* Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
* Uncontrolled intercurrent illness including, but not limited to:
* Ongoing or active infection (is patient is receiving oral antibiotics for localized infection with planned end date they may enroll on study as soon as duration is complete)
* Symptomatic congestive heart failure
* Unstable angina pectoris
* Cardiac arrhythmia
* Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
* Or psychiatric illness/social situations that would limit compliance with study requirements
* Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
* Other active malignancy that is progressing or has required active treatment =\< 3 years prior to registration. NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded
* Intolerance to gadolinium contrast (for MRI)
* Has received a live vaccine or live-attenuated vaccine =\< 30 days before the first dose of study intervention. Administration of killed vaccines is allowed. Messenger (m)RNA Coronavirus Disease (COVID)-1 vaccines are allowed
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy =\< 7 days prior to the first dose of study drug
* Has severe hypersensitivity (\>= grade 3) to pembrolizumab, CA-4948, or any of their excipients
* Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
* History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
* History or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator
* Has had an allogenic tissue/solid organ transplant
* Unable to discontinue medications contraindicated to CA-4948 or pembrolizumab
During the COVID pandemic, our IRB halted enrollment into the study among other changes. Post COVID it was decided that too long an interval between patient enrollment was problematic for the study and a discussion was made to terminate.
Inclusion Criteria:
* Diagnosis of histologically or cytologically confirmed recurrent or metastatic HNSCC of the oral cavity, oropharynx, larynx, hypopharynx, or p16+ SCC of the neck (unknown primary).
* Measurable disease per RECIST. Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
* Incurable disease, or ineligible for (including patient declined) local therapy.
* At least 18 years of age.
* ECOG performance status ≤ 1
* Life expectancy ≥ 16 weeks.
* Normal bone marrow and organ function as defined below (specimens must be collected within 10 days prior to the start of study treatment):
* Hemoglobin ≥ 10.0 g/dL (criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 2 weeks)
* Absolute neutrophil count ≥ 1,500/mcL
* Platelets ≥ 100,000/mcL
* INR or PT ≤ 1.5 x institutional upper limit of normal (IULN) and aPTT ≤ 1.5 x IULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
* Total bilirubin ≤ 1.5 x IULN
* AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN unless liver metastases are present (in which case they must be ≤ 5 x IULN)
* Serum creatinine \<1.5 x ULN or creatinine clearance ≥ 51 mL/min by Cockcroft-Gault or based on a 24-hour urine test
* Known p16 expression, if oropharyngeal primary.
* Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 72 hours of Day 1 of study treatment:
\*Postmenopausal is defined as:
* Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
* Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
* radiation-induced oophorectomy with last menses \>1 year ago
* chemotherapy-induced menopause with \>1 year interval since last menses
* surgical sterilization (bilateral oophorectomy or hysterectomy)
* Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception (see Section 5.6) if they are of childbearing potential
* Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Exclusion Criteria:
* Progression within 6 months of curatively intended systemic therapy given for locoregionally advanced disease.
* Investigational therapy within 28 days of treatment start.
* Prior systemic therapy for recurrent or metastatic disease.
* Known CNS metastases/leptomeningeal metastatic disease.
* Other malignancy unless curatively treated with no evidence of disease for ≥ 2 years except: adequately treated non-melanoma skin cancer, curative treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1 grade 1 endometrial carcinoma; or low risk-disease per discretion of the PI.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib, pembrolizumab, carboplatin, or other agents used in the study.
* Has received prior therapy with an anti-PD-1, andti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
* Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
* Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
* Concomitant use of known strong CYP3A inducers (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, and St. John's wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
* Resting ECG indicating uncontrolled, potentially reversible cardiac conditions as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \> 500 ms, electrolyte disturbances, etc.) or patients with congenital long QT syndrome.
* Diagnosis of myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
* Major surgery within 2 weeks of starting study treatment; must have recovered from any effects of major surgery.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment.
* Received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of pembrolizumab. Administration of killed vaccines is allowed. Examples of live vaccines is allowed. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.
* Considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
* Unable to swallow orally administered medication or with gastrointestinal disorder likely to interfere with absorption of study medication.
* Pregnant and/or breastfeeding. A WOCBP who has a positive urine pregnancy test within 72 hours of first dose of treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Female patients who are expecting to conceive or Mmale patients who are expecting to father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
* Prior organ or allogeneic stem cell transplant or double umbilical cord blood transplantation.
* Has an active autoimmune disease (i.e. rheumatoid arthritis, lupus, Sjogren's syndrome) that has required IV or subcutaneous systemic treatment in the past 2 years (excluding Rituxan). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
* History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has a known history of active TB (Bacillus Tuberculosis).
→
Inclusion Criteria:
* Diagnosis of histologically or cytologically confirmed recurrent or metastatic HNSCC of the oral cavity, oropharynx, larynx, hypopharynx, or p16+ SCC of the neck (unknown primary).
* Measurable disease per RECIST. Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
* Incurable disease, or ineligible for (including patient declined) local therapy.
* At least 18 years of age.
* ECOG performance status ≤ 1
* Life expectancy ≥ 16 weeks.
* Normal bone marrow and organ function as defined below (specimens must be collected within 10 days prior to the start of study treatment):
* Hemoglobin ≥ 10.0 g/dL (criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 2 weeks)
* Absolute neutrophil count ≥ 1,500/mcL
* Platelets ≥ 100,000/mcL
* INR or PT ≤ 1.5 x institutional upper limit of normal (IULN) and aPTT ≤ 1.5 x IULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
* Total bilirubin ≤ 1.5 x IULN
* AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN unless liver metastases are present (in which case they must be ≤ 5 x IULN)
* Serum creatinine \<1.5 x ULN or creatinine clearance ≥ 51 mL/min by Cockcroft-Gault or based on a 24-hour urine test
* Known p16 expression, if oropharyngeal primary.
* Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 72 hours of Day 1 of study treatment:
\*Postmenopausal is defined as:
* Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
* Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post menopausal range for women under 50
* radiation-induced oophorectomy with last menses \>1 year ago
* chemotherapy-induced menopause with \>1 year interval since last menses
* surgical sterilization (bilateral oophorectomy or hysterectomy)
* Male patients must use a condom during treatment and for 3 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception (see Section 5.6) if they are of childbearing potential
* Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Exclusion Criteria:
* Progression within 6 months of curatively intended systemic therapy given for locoregionally advanced disease.
* Investigational therapy within 28 days of treatment start.
* Prior systemic therapy for recurrent or metastatic disease.
* Known CNS metastases/leptomeningeal metastatic disease.
* Other malignancy unless curatively treated with no evidence of disease for ≥ 2 years except: adequately treated non-melanoma skin cancer, curative treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1 grade 1 endometrial carcinoma; or low risk-disease per discretion of the PI.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib, pembrolizumab, carboplatin, or other agents used in the study.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
* Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
* Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
* Concomitant use of known strong CYP3A inducers (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, and St. John's wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
* Resting ECG indicating uncontrolled, potentially reversible cardiac conditions as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \> 500 ms, electrolyte disturbances, etc.) or patients with congenital long QT syndrome.
* Diagnosis of myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
* Major surgery within 2 weeks of starting study treatment; must have recovered from any effects of major surgery.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of treatment.
* Received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of pembrolizumab. Administration of killed vaccines is allowed. Examples of live vaccines is allowed. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist®) are live attenuated vaccines and are not allowed.
* Considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
* Unable to swallow orally administered medication or with gastrointestinal disorder likely to interfere with absorption of study medication.
* Pregnant and/or breastfeeding. A WOCBP who has a positive urine pregnancy test within 72 hours of first dose of treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Female patients who are expecting to conceive or male patients who are expecting to father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
* Prior organ or allogeneic stem cell transplant or double umbilical cord blood transplantation.
* Has an active autoimmune disease (i.e. rheumatoid arthritis, lupus, Sjogren's syndrome) that has required IV or subcutaneous systemic treatment in the past 2 years (excluding Rituxan). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
* History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
* Has a known history of active TB (Bacillus Tuberculosis).
Key Inclusion Criteria:
1. Patient is able and willing to provide written informed consent
2. Be \> 18 years of age on day of signing informed consent
3. Have histologically or cytologically confirmed SCLC that meets:
1. Extensive disease per criteria of the International Association for the Study of Lung Cancer (IASLC)-American Joint Committee on Cancer (AJCC) TNM staging system
2. Have not tolerated or have progressed or relapsed on or within 6 months of platinum-based chemotherapy
4. Have a performance status of ≤ 1 on the ECOG Performance Scale
5. Have measurable disease based on RECIST 1.1
6. Willing to undergo core needle or incisional biopsy to obtain fresh tumor tissue specimens
7. Demonstrate adequate organ function as evidenced by laboratory testing with specimens collected within 10 days prior to day 1 of cycle 1
8. Female child-bearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication
9. Sexually active male or female must be surgically sterile post-menopausal, or must agree to use a physician-approved method of birth control during the study through a minimum of 120 days after the last study drug administration.
Key Exclusion Criteria:
1. Has received more than 2 platinum-based regimens against SCLC
2. Has received pembrolizumab, or prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody as part of any previous therapy, including trials
3. Has participated in Merck MK-3475 (pembrolizumab) clinical trials
4. Has received pegzilarginase as part of any previous therapy
5. Is currently participating in a study of an investigational agent or received the last dose of an investigational agent within 4 weeks prior to the first dose of treatment in this study (a shorter interval for kinase inhibitors or other short half-life drugs could be considered after approval from the Sponsor). Is currently participating in a study of an investigational device within 4 weeks of the first dose of treatment
6. Has a diagnosis of an immunodeficiency, is receiving systemic steroid therapy (except for physiological dose levels), or immunosuppressive therapies
7. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer) that has undergone potentially curative therapy
8. Has known central nervous system (CNS) metastases. However, patients with previously treated brain metastases may participate provided neurologic symptoms have stabilized, there is no evidence of new brain metastases or hemorrhage and they are not using steroids for brain metastases or for complications derived from their treatment for at least 7 days prior to the first dose of trial treatment
9. Has known carcinomatous meningitis
10. Has an active autoimmune disease requiring systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy are an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections will not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment
11. Has evidence of interstitial lung disease, history of non-infectious pneumonitis that required steroids, or current pneumonitis
12. Inadequately controlled hypertension (defined as systolic blood pressure ≥ 200 mmHg and/or diastolic blood pressure ≥ 120 mmHg) on more than one occasion in the month before planned day of infusion
13. Currently taking 3 or more anti-hypertensive medications
14. Prior history of hypertensive crisis or hypertensive encephalopathy
15. History of myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac or vascular surgery within 6 months prior to day 1 of study treatment
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
17. Has a known history of Human Immunodeficiency Virus (HIV) (positive for HIV p24 antigen or HIV 1/2 antibodies)
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected)
19. Has a known history of active tuberculosis (Bacillus tuberculosis)
20. Has had an allogenic tissue/solid organ transplant.
→
Key Inclusion Criteria:
1. Patient is able and willing to provide written informed consent
2. Be \> 18 years of age on day of signing informed consent
3. Have histologically or cytologically confirmed SCLC that meets:
1. Extensive disease per criteria of the International Association for the Study of Lung Cancer (IASLC)-American Joint Committee on Cancer (AJCC) TNM staging system
2. Have not tolerated or have progressed or relapsed on or within 6 months of platinum-based chemotherapy
4. Have a performance status of ≤ 1 on the ECOG Performance Scale
5. Have measurable disease based on RECIST 1.1
6. Willing to undergo core needle or incisional biopsy to obtain fresh tumor tissue specimens
7. Demonstrate adequate organ function as evidenced by laboratory testing with specimens collected within 10 days prior to day 1 of cycle 1
8. Must have recovered from the effects of any prior systemic therapy, radiotherapy or surgery to Grade 1 or less
9. If received major surgery or radiation therapy of \> 30 Gy, recovered from the toxicity and/or complications from the intervention is required
10. Female child-bearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication
11. Sexually active male or female must be surgically sterile post-menopausal, or must agree to use a physician-approved method of birth control during the study through a minimum of 120 days after the last study drug administration.
Key Exclusion Criteria:
1. Has received more than 2 platinum-based regimens against SCLC
2. Has received pembrolizumab, or prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody as part of any previous therapy, including trials
3. Has participated in Merck MK-3475 (pembrolizumab) clinical trials
4. Has received pegzilarginase as part of any previous therapy
5. Is currently participating in a study of an investigational agent or received the last dose of an investigational agent within 4 weeks prior to the first dose of treatment in this study (a shorter interval for kinase inhibitors or other short half-life drugs could be considered after approval from the Sponsor). Is currently participating in a study of an investigational device within 4 weeks of the first dose of treatment
6. Has a diagnosis of an immunodeficiency, is receiving systemic steroid therapy (except for physiological dose levels), or immunosuppressive therapies
7. Has had a prior monoclonal antibody (mAb) within 4 weeks prior to first dose or who has not recovered (i.e., ≤ Grade 1) from adverse reactions due to agents administered more than 4 weeks earlier
8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to first dose or who has not recovered (i.e., ≤ Grade 1 or at baseline) from treatment-emergent adverse reactions due to a previously administered agent
9. If the patient has undergone major surgery, must have recovered adequately from the toxicity and/or complications prior to starting therapy
10. Has received transfusion of blood products or administration of colony stimulating factors within 14 days prior to first study dose
11. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer) that has undergone potentially curative therapy
12. Has known central nervous system (CNS) metastases. However, patients with previously treated brain metastases may participate provided neurologic symptoms have stabilized, there is no evidence of new brain metastases or hemorrhage and they are not using steroids for brain metastases or for complications derived from their treatment for at least 7 days prior to the first dose of study treatment
13. Has known carcinomatous meningitis
14. Has an active autoimmune disease requiring systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy are an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections will not be excluded from the study. Patients with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment
15. Has evidence of interstitial lung disease, history of non-infectious pneumonitis that required steroids, or current pneumonitis
16. Has an active infection requiring systemic therapy
17. Inadequately controlled hypertension (defined as systolic blood pressure ≥ 200 mmHg and/or diastolic blood pressure ≥ 120 mmHg) on more than one occasion in the month before planned day of infusion
18. Currently taking 3 or more anti-hypertensive medications
19. Prior history of hypertensive crisis or hypertensive encephalopathy
20. History of myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac or vascular surgery within 6 months prior to day 1 of study treatment
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
22. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
23. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
24. Has a known history of Human Immunodeficiency Virus (HIV) (positive for HIV p24 antigen or HIV 1/2 antibodies)
25. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected)
26. Has received a live-virus vaccination within 30 days prior to the planned first dose of study therapy
27. Has a known history of active tuberculosis (Bacillus tuberculosis)
28. Has a history of hypersensitivity to PEG or any component of the pegzilarginase formulation
29. Severe hypersensitivity (≥ Grade 3) to any excipient of pegzilarginase or pembrolizumab
30. Has had an allogenic tissue/solid organ transplant.
Inclusion:
* Has a histologically- or cytologically-confirmed diagnosis of Stage IV squamous or non-squamous NSCLC
* Has non-squamous NSCLC and is not eligible for an approved targeted therapy
* Is able to provide archival tumor tissue sample collected either within 5 years or within the interval from completion of last treatment but before entering the screening period or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated obtained within 90 days of treatment initiation
* Has not received prior systemic treatment for metastatic NSCLC
* Has programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%
* Is able to complete all screening procedures within the 35-day screening window.
* Male participants must agree to use contraception and refrain from donating sperm during the treatment period and for at least 120 days after the last dose of study treatment
* Female participants must not be pregnant or breastfeeding, and at least one of the following conditions apply:
1. Not a woman of childbearing potential (WOCBP) OR
2. A WOCBP who agrees to use contraception during the treatment period and for at least 120 days after the last dose of study treatment
* Has adequate organ function within 10 days of initiation of study treatment
Exclusion Criteria:
* Has a diagnosis of small cell lung cancer
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment
* Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has an active autoimmune disease that has required systemic treatment in the past 2 years
* Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
* Has an active infection requiring systemic therapy
* Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study treatment, or New York Heart Association Class III or IV congestive heart failure
* Has a known history of Human Immunodeficiency Virus (HIV) infection
* Has a known history of Hepatitis B or known active Hepatitis C virus infection
* Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study
* Has had major surgery \<3 weeks before the first dose of study treatment
* Has received prior radiation therapy to the lung that is \>30 Gray (Gy) within 6 months of the first dose of study treatment
* Has received any prior immunotherapy and was discontinued from that treatment due to a severe or worse immune-related adverse event (irAE)
* Has had chemotherapy or biological cancer therapy within 4 weeks before the first dose of study treatment or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the AEs due to cancer therapeutics administered more than 4 weeks before the first dose of study treatment (including participants who had previous immunomodulatory therapy with residual irAEs)
* Has received a live vaccine within 30 days before the first dose of study treatment. Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country is allowed as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not allowed
* Has received prior systemic cytotoxic chemotherapy or other targeted or biological antineoplastic therapy for metastatic disease.
* Has received prior therapy with an anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or prior therapy targeting other immuno-regulatory receptors or mechanisms
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study treatment
* Has had a severe hypersensitivity reaction to treatment with monoclonal antibodies (including pembrolizumab) and/or any of their excipients
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
* Has had an allogenic tissue/solid organ transplant
→
Inclusion:
* Has a histologically- or cytologically-confirmed diagnosis of Stage IV squamous or non-squamous non-small cell lung cancer (NSCLC)
* Has non-squamous NSCLC and is not eligible for an approved targeted therapy
* Is able to provide archival tumor tissue sample collected either within 5 years or within the interval from completion of last treatment but before entering the screening period or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated obtained within 90 days of treatment initiation
* Has not received prior systemic treatment for metastatic NSCLC
* Has programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%
* Is able to complete all screening procedures within the 35-day screening window.
* Male participants must agree to use contraception and refrain from donating sperm during the treatment period and for at least 120 days after the last dose of study treatment
* Female participants must not be pregnant or breastfeeding, and at least one of the following conditions apply:
1. Not a woman of childbearing potential (WOCBP) OR
2. A WOCBP who agrees to use contraception during the treatment period and for at least 120 days after the last dose of study treatment
* Has adequate organ function within 10 days of initiation of study treatment
Exclusion Criteria:
* Has a diagnosis of small cell lung cancer
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment
* Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
* Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has an active autoimmune disease that has required systemic treatment in the past 2 years
* Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
* Has an active infection requiring systemic therapy
* Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study treatment, or New York Heart Association Class III or IV congestive heart failure
* Has a known history of Human Immunodeficiency Virus (HIV) infection
* Has a known history of Hepatitis B or known active Hepatitis C virus infection
* Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study
* Has had major surgery \<3 weeks before the first dose of study treatment
* Has received prior radiation therapy to the lung that is \>30 Gray (Gy) within 6 months of the first dose of study treatment
* Has received any prior immunotherapy and was discontinued from that treatment due to a severe or worse immune-related adverse event (irAE)
* Has had chemotherapy or biological cancer therapy within 4 weeks before the first dose of study treatment or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the AEs due to cancer therapeutics administered more than 4 weeks before the first dose of study treatment (including participants who had previous immunomodulatory therapy with residual irAEs)
* Has received a live vaccine within 30 days before the first dose of study treatment. Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country is allowed as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not allowed
* Has received prior systemic cytotoxic chemotherapy or other targeted or biological antineoplastic therapy for metastatic disease.
* Has received prior therapy with an anti-programmed cell death receptor 1 (PD-1), anti-programmed cell death receptor ligand 1 (PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or prior therapy targeting other immuno-regulatory receptors or mechanisms
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study treatment
* Has had a severe hypersensitivity reaction to treatment with monoclonal antibodies (including pembrolizumab) and/or any of their excipients
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
* Has had an allogenic tissue/solid organ transplant