A clinical study of combination therapies in people with kidney cancer (MK-3475-03C)

Prior treatment

• Has malabsorption due to prior GI surgery or GI disease.
• Has received colony-stimulating factors within 28 days prior to intervention allocation/randomization.
• Has received prior treatment with Hypoxia-Inducible Factor-2α (HIF-2α) and/or Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitor (VEGF/TKI) inhibitors.
• Is currently receiving strong inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study.
• Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention.
• Have been previously allocated/randomized to study intervention in any substudy of protocol MK-3475-U03.
• Has deep vein thrombosis within 3 months before allocation/randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before allocation/randomization.
• Has deep vein thrombosis within 3 months before allocation/randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before allocation/randomization.
• Has serious wound, ulcer or bone fracture or has had major surgery within 8 weeks before first dose of study intervention.
• Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain), ascites, or pericardial fluid requiring drainage in the last 4 weeks before allocation/randomization.

Other illness

• Has clinically significant hematuria, hematemesis, or hemoptysis of (>2.5 mL) of red blood, or other history of significant bleeding.
• Has moderate to severe hepatic impairment (Child-Pugh B or C).
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Has clinically significant cardiovascular disease within 12 months from first dose of study intervention,
• Has active autoimmune disease that has required systemic treatment in the past 2 years.
• Has an active infection requiring systemic therapy.
• Has history of human immunodeficiency virus (HIV) infection.
• Has hepatitis B or hepatitis C virus infection.
• Has history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis.
• Has gastrointestinal (GI) disorders, including those associated with a high risk of perforation or fistula formation.

Lab values

• Is currently receiving anticoagulants or platelet inhibitors that cannot be discontinued for the duration of the study,
• Has a left ventricular ejection fraction (LVEF) ≤50% or below the institutional (or local laboratory) normal range.

Other

• Ha recibido radioterapia previa dentro de las 2 semanas del comienzo de la intervención del estudio o tiene toxicidades relacionadas con la radiación que requieren corticoesteroides.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation.

• Has a histologically confirmed diagnosis of unresectable locally advanced/metastatic renal cell carcinoma (RCC) with clear cell component (with or without sarcomatoid features),
• Is an individual of any sex/gender, from 18 years to 120 years of age inclusive,
• A participant assigned male sex at birth, capable of producing sperm, continues contraception at least 7 days after the last dose of Belzutifan, and at least 96 days after the last dose of Zanzalintinib. Refrains from donating sperm and abstains from penile-vaginal intercourse and remains abstinent, or uses external condom or contraceptives consistent with local regulations.
• A participant assigned female sex at birth is not breast feeding at least 96 days after the last dose of study intervention. A participant of childbearing potential (POCBP) is not pregnant and has a negative highly sensitive pregnancy test before the first dose of study intervention. A POCBP uses a highly effective contraceptive method, and continues using contraception at least 30 days after the last dose of Belzutifan, and at least 186 days after the last dose of Zanzalintinib.
• Has received no other prior systemic therapy for treatment of advanced/metastatic clear cell RCC (ccRCC) except for adjuvant anti- programmed cell death 1/programmed cell death ligand 1 (PD-(L)1) therapy.
• Has disease recurrence during adjuvant anti- PD-(L)1 therapy or ≤24 months following the last dose of adjuvant anti-PD-(L)1 therapy.
• Has measurable disease per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) as assessed by investigator and verified by blinded independent central review (BICR).
• Is able to swallow oral medication.
• Submits an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated.
• Participants receiving bone resorptive therapy(must have therapy initiated at least 2 weeks before allocation/randomization.
• Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤140/90 mm Hg with no change in antihypertensive medications within 1 week before allocation/randomization.
• Has adequate organ function