Recruiting
Phase 1
Phase 2

Investigational Agents

Sponsor:

Merck Sharp & Dohme LLC

Code:

NCT07049926

Conditions

Renal Cell Carcinoma

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

Interventions

Belzutifan

Zanzalintinib

Study Details

Brief 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

Conditions

Renal Cell Carcinoma

Study ID

NCT07049926

Start date

Jul 20, 2025

Status verified date

Sep, 2026

Completion date

Oct 26, 2031

Anticipated

Primary completion date

Oct 26, 2031

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

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

Study Design

Enrollment

140 participants

Anticipated

Allocation

Non randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Zanzalintinib at Dose Level 1 or 2 + Belzutifan

Participants will be allocated to receive zanzalintinib at dose level 1 or 2 + belzutifan daily until progressive disease or discontinuation

experimental: Belzutifan

Participants will receive belzutifan daily until progressive disease or discontinuation

Interventions

Belzutifan

Oral Tablet

Zanzalintinib

Oral Tablet

Primary outcome measure

  • Safety Lead In Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs) [ Time Frame: Up to approximately 21 days ]
  • Safety Lead In Phase: Number of participants who experience one or more adverse events (AEs) [ Time Frame: Up to approximately 74 months ]
  • Safety Lead In Phase: Number of participants who discontinue study treatment due to an AE [ Time Frame: Up to approximately 74 months ]
  • Efficacy Phase: Number of participants who experience one or more DLTs [ Time Frame: Up to approximately 21 days ]
  • Efficacy Phase: Number of participants who experience one or more AEs [ Time Frame: Up to approximately 74 months ]
  • Efficacy Phase: Number of participants who discontinue study treatment due to an AE [ Time Frame: Up to approximately 74 months ]
  • Efficacy Phase: Objective Response Rate (ORR) [ Time Frame: Up to approximately 74 months ]

Central Contacts and Locations

Central contacts

Toll Free Number

1-888-577-8839Trialsites@msd.com

Locations

UCSF Medical Center at Mission Bay ( Site 5008)

Recruiting

San Francisco, California, United States, 94158

Contacts

Study Coordinator

415-694-3896

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

Recruiting

Mineola, New York, United States, 11501

Contacts

Study Coordinator

516-663-3696

Laura and Isaac Perlmutter Cancer Center ( Site 5016)

Recruiting

New York, New York, United States, 10016

Contacts

Study Coordinator

212-731-6000

Memorial Sloan Kettering Cancer Center ( Site 5002)

Recruiting

New York, New York, United States, 10065

Contacts

Study Coordinator

212-639-2000

Duke Cancer Institute ( Site 5015)

Recruiting

Durham, North Carolina, United States, 27710

Contacts

Study Coordinator

919-681-1030

UPMC Cancer Center/Hillman Cancer Center ( Site 5017)

Recruiting

Pittsburgh, Pennsylvania, United States, 15232

Contacts

Study Coordinator

412-864-6600

Vanderbilt University Medical Center ( Site 5004)

Recruiting

Nashville, Tennessee, United States, 37232

Contacts

Study Coordinator

615-343-2882

More Information

Sponsor

Merck Sharp & Dohme LLC

Last update posted

Sep 2, 2026

Last verified

Sep, 2026

Keywords

  • Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor (VEGFR-TKI)
  • Hypoxia-Inducible Factor-2α (HIF-2α)

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by Merck Sharp & Dohme LLC on 2026-09-02.