Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365)

Exclusion Criteria

• •Has had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to first dose study therapy or who has not recovered (i.e., Grade ≤1 or at baseline) from AEs due to mAbs administered \>4 weeks earlier
• •Has had prior chemotherapy, targeted small molecule therapy abiraterone treatment, enzalutamide treatment, or radiation therapy within 2 weeks prior to first dose of study therapy or who has not recovered (ie, Grade ≤1 or at baseline) from AEs due to a previously administered agent
• •Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study drug or used an investigational device within 4 weeks of treatment allocation/randomization
• •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to treatment allocation/randomization
• •Has had prior treatment with therapeutic radiopharmaceuticals for prostate cancer, such as Radium-223 or Leutitium-177, within 4 weeks prior to the first dose of trial treatment
• •Has an active autoimmune disease that has required systemic treatment in past 2 years
• •Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
• •Has previously participated in any other pembrolizumab trial, or received prior therapy with an anti-programmed cell death 1 (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), and anti-programmed cell death ligand 1 (anti-PD-L2)
• •Has a known history of Human Immunodeficiency Virus (HIV)
• •Has known active Hepatitis B or Hepatitis C
• •Has received a live vaccine or live-attenuated vaccine within 30 days of the first dose of study therapy
• •Has known active central nervous system metastases and/or carcinomatous meningitis
• •Has a "superscan" bone scan defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan such that the presence of additional metastases in the future could not be evaluated
• •Has had prior solid, organ or bone marrow transplant
• •For Cohort A: Has experienced a seizure or seizures within 6 months of study start or is currently being treated with cytochrome P450 enzyme (CYP) inducing anti-epileptic drugs for seizures
• •For Cohort A: Is currently receiving strong or moderate inhibitors of CYP3A4 including azole antifungals; macrolide antibiotics; or protease inhibitors
• •For Cohort A: Is currently receiving strong or moderate inducers of CYP3A4
• •For Cohort A: Has myelodysplastic syndrome
• •For Cohort A: Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease), unstable angina pectoris, cardiac arrhythmia, or uncontrolled hypertension
• •For Cohort B: Has received prior treatment with docetaxel or another chemotherapy agent for metastatic prostate cancer
• •For Cohort B: Has peripheral neuropathy Common Terminology Criteria for Adverse Events ≥2 except due to trauma
• •For Cohort B: Has ascites and/or clinically significant pleural effusion
• •For Cohort B:Has symptomatic congestive heart failure (New York Heart Association Class III or IV heart disease)
• •For Cohort B: Is currently receiving any of the following classes of inhibitors of CYP3A4: azole antifungals; macrolide antibiotics; or protease inhibitors
• •For Cohort C: Has received prior chemotherapy for mCRPC. Prior docetaxel for metastatic hormone-sensitive prostate cancer is allowed if ≥4 weeks elapsed from last dose of docetaxel. Participants who received abiraterone acetate in the hormone-sensitive state will not be eligible
• •For Cohort C: Has a history of seizure or any condition that may predispose to seizure (including, but not limited to prior cerebrovascular accident, transient ischemic attack, or brain arteriovenous malformation; or intracranial masses such as a schwannoma or meningioma that is causing edema or mass effect)
• •For Cohort C:Has known or suspected brain metastasis or leptomeningeal carcinomatosis
• •For Cohort C: Has a history of loss of consciousness within 12 months of the screening visit
• •For Cohort C: Has hypotension (systolic blood pressure \<86 millimeters of mercury \[mmHg\]) or uncontrolled hypertension (systolic blood pressure \>170 mmHg or diastolic blood pressure \>105 mmHg) at the screening visit
• •For Cohort C: Has received treatment with 5-α reductase inhibitors (e.g., finasteride, dutasteride), estrogens, and/or cyproterone within 4 weeks prior to Cycle 1
• •For Cohort C: Has a history of prostate cancer progression on ketoconazole
• •For Cohort D: Has received prior treatment with docetaxel or another chemotherapy agent for metastatic prostate cancer
• •For Cohort D: Has progressed on prior abiraterone acetate for treatment of castration sensitive or resistant metastatic prostate cancer
• •For Cohort D: Has discontinued prior treatment with abiraterone acetate due to AEs
• •For Cohort D: Has previously been treated with ketoconazole for prostate cancer for \>7 days
• •For Cohort D: Has received prior systemic treatment with an azole drug (eg, fluconazole, itraconazole) within 4 weeks of Cycle 1, Day 1
• •For Cohort D: Has uncontrolled hypertension (systolic BP ≥ 160 mm Hg or diastolic BP ≥ 95 mm Hg)
• •For Cohort D: Has a history of pituitary or adrenal dysfunction
• •For Cohort D: Has clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association Class II-IV heart disease or cardiac ejection fraction measurement of \<50% at baseline
• •For Cohort D: Has atrial fibrillation, or other cardiac arrhythmia requiring therapy
• •For Cohort D: Has a history of chronic liver disease
• •For Cohort D: Is currently receiving strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during abiraterone acetate treatment, CYP2D6 substrates with a narrow therapeutic index (for example thioridazine), or CYP2C8 substrates with a narrow therapeutic index (for example pioglitazone)
• •For Cohorts E and F: Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
• •For Cohorts E and F: Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
• •For Cohorts E and F: Has prolongation of QT interval by Fredericia (QTcF) interval to \>480 milliseconds
• •For Cohorts E and F: Has had major surgery within 3 weeks prior to first dose of study interventions
• •For Cohorts E and F: Has pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula
• •For Cohorts E and F: Has had significant cardiovascular impairment within 12 months of the first dose of study intervention, such as history of New York Heart Association \>Class II congestive heart failure, unstable angina, myocardial infarction, or cerebrovascular accident (CVA)/stroke, cardiac revascularization procedure, or cardiac arrhythmia associated with hemodynamic instability
• •For Cohorts E and F: Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of lenvatinib
• •For Cohorts E and F: Has gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
• •For Cohorts G, H, and I: Has had a severe hypersensitivity reaction to treatment with another monoclonal antibody
• •For Cohorts G, H, and I: Has symptomatic ascites or pleural effusion
• •For Cohort I: Has clinically active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, and/or abdominal carcinomatosis
• •For Cohort I: Has received previous treatment for prostate cancer with platinum-containing compounds