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NCT07049926PHASE1, PHASE2Recruiting

Substudy 03C: A Study of Combination Therapies in Participants With Renal Cell Carcinoma With Recurrent Disease During or After Anti-PD-(L)1 Therapy (MK-3475-03C/KEYMAKER-U03)

Merck Sharp & Dohme LLC

Start Date

7/20/2025

Completion Date

10/26/2031

Summary

Substudy 03C is part of a larger research study that is testing experimental treatments for renal cell carcinoma (RCC). The larger study is the umbrella study (U03). The goal of substudy 03C is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with clear cell renal cell carcinoma (ccRCC) who have recurrent disease during or after anti-programmed cell death 1/programmed cell death ligand 1 (PD-\[L\]1) adjuvant therapy. This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety lead-in phase will be used to demonstrate a tolerable safety profile for the combination of investigational agents. There will be no hypothesis testing in this study

Eligibility Criteria

Age Range: 18 years to 120 years

The main inclusion criteria include but are not limited to the following: * Has a histologically confirmed diagnosis of unresectable locally advanced/metastatic renal cell carcinoma (RCC) with clear cell component * Has received no other prior systemic therapy for treatment of advanced/metastatic clear cell renal cell carcinoma (ccRCC) except for adjuvant 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 * 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 The main exclusion criteria include but are not limited to the following: * Has clinically significant hematuria, hematemesis, or hemoptysis of (\>2.5 mL) of red blood, or other history of significant bleeding * Has clinically significant cardiovascular disease within 12 months from first dose of study intervention * 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 history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis * 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 * Has gastrointestinal (GI) disorders, including those associated with a high risk of perforation or fistula formation * Has malabsorption due to prior GI surgery or GI disease * Has moderate to severe hepatic impairment * Has received colony-stimulating factors within 28 days prior to intervention allocation/randomization * Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids * 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 * Is currently receiving anticoagulants or platelet inhibitors that cannot be discontinued for the duration of the study * Have been previously allocated/randomized to study intervention in any sub study of protocol MK-3475-U03 * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years * 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 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

Interventions

DRUG

Belzutifan

DRUG

Zanzalintinib

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Conditions

Renal Cell Carcinoma

Locations

UCSF Medical Center at Mission Bay ( Site 5008)

San Francisco, California 94158

United States

Perlmutter Cancer Center at NYU Langone Hospital - Long Island ( Site 5026)

Mineola, New York 11501

United States

Laura and Isaac Perlmutter Cancer Center ( Site 5016)

New York, New York 10016

United States

Memorial Sloan Kettering Cancer Center ( Site 5002)

New York, New York 10065

United States

Duke Cancer Institute ( Site 5015)

Durham, North Carolina 27710

United States

UPMC Cancer Center/Hillman Cancer Center ( Site 5017)

Pittsburgh, Pennsylvania 15232

United States

Vanderbilt University Medical Center ( Site 5004)

Nashville, Tennessee 37232

United States

Centro de Estudios Clínicos SAGA ( Site 6110)

Santiago, Region M. de Santiago 7500653

Chile

Bradfordhill ( Site 6101)

Santiago, Region M. de Santiago 8420383

Chile

C.H.U. de Strasbourg Hopital de Hautepierre ( Site 5203)

Strasbourg, Bas-Rhin 67098

France

Institut Claudius Regaud ( Site 5200)

Toulouse, Haute-Garonne 31059

France

Centre Eugene Marquis ( Site 5205)

Rennes, Ille-et-Vilaine 35042

France

Institut De Cancerologie De Lorraine ( Site 5204)

Vandœuvre-lès-Nancy, Meurthe-et-Moselle 54513

France

Gustave Roussy ( Site 5202)

Villejuif, Île-de-France Region 94805

France

Rambam Health Care Campus ( Site 5500)

Haifa, 3109601

Israel

Rabin Medical Center ( Site 5502)

Petah Tikva, 4941492

Israel

Sheba Medical Center ( Site 5501)

Ramat Gan, 5265601

Israel

Sourasky Medical Center ( Site 5503)

Tel Aviv, 6423906

Israel

Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 6201)

Bydgoszcz, Kuyavian-Pomeranian Voivodeship 85-796

Poland

Uniwersyteckie Centrum Kliniczne ( Site 6202)

Gdansk, Pomeranian Voivodeship 80-214

Poland

Severance Hospital ( Site 5802)

Seoul, 03722

South Korea

Asan Medical Center ( Site 5800)

Seoul, 05505

South Korea

Samsung Medical Center ( Site 5801)

Seoul, 06351

South Korea

Hospital Universitario Ramon y Cajal ( Site 5301)

Madrid, Madrid, Comunidad de 28034

Spain

Hospital Universitari Vall d'Hebron ( Site 5300)

Barcelona, 08035

Spain

Western General Hospital ( Site 5402)

Edinburgh, Edinburgh, City of EH42XU

United Kingdom

The Beatson West of Scotland Cancer Centre ( Site 5405)

Glasgow, Glasgow City G12 0YN

United Kingdom

St Bartholomew's Hospital ( Site 5401)

London, London, City of EC1A7BE

United Kingdom

Velindre Cancer Centre ( Site 5407)

Cardiff, CF14 2TL

United Kingdom

The Christie NHS Foundation Trust ( Site 5400)

Manchester, M20 4BX

United Kingdom