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)

NCT07049926 | Recruiting Phase 1 FDA Drug

• 5 other identifiers: 3475-03CMK-3475-03C2024-516437-12-00U1111-1310-6076KEYMAKER-U03
• Study Type: interventional
• Target: 140
• Locations: 8 countries
• Sites: 27

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

Keywords

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

Outcome Measures

Primary Outcomes (7)

• Safety Lead In Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs)

  DLTs are defined as any of a pre-specified list of toxicities if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration, excluding toxicities clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc.

  Up to approximately 21 days

• Safety Lead In Phase: Number of participants who experience one or more adverse events (AEs)

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

  Up to approximately 74 months

• Safety Lead In Phase: Number of participants who discontinue study treatment due to an AE

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

  Up to approximately 74 months

• Efficacy Phase: Number of participants who experience one or more DLTs

  DLTs are defined as any of a pre-specified list of toxicities if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration, excluding toxicities clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc.

  Up to approximately 21 days

• Efficacy Phase: Number of participants who experience one or more AEs

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

  Up to approximately 74 months

• Efficacy Phase: Number of participants who discontinue study treatment due to an AE

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

  Up to approximately 74 months

• Efficacy Phase: Objective Response Rate (ORR)

  ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.

  Up to approximately 74 months

Secondary Outcomes (4)

• Efficacy Phase: Duration of response (DOR)

  Up to approximately 74 months

• Efficacy Phase: Progression-free survival (PFS)

  Up to approximately 74 months

• Efficacy Phase: Overall survival (OS)

  Up to approximately 74 months

• Efficacy Phase: Clinical benefit rate (CBR)

  Up to approximately 74 months

Study Arms (2)

Zanzalintinib at Dose Level 1 or 2 + Belzutifan

EXPERIMENTAL

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

Drug: Belzutifan; Drug: Zanzalintinib

Belzutifan

EXPERIMENTAL

Participants will receive belzutifan daily until progressive disease or discontinuation

Drug: Belzutifan

Interventions

Belzutifan DRUG

Oral Tablet

Also known as: WELIREG®, MK-6482, PT2977

Belzutifan; Zanzalintinib at Dose Level 1 or 2 + Belzutifan

Zanzalintinib DRUG

Oral Tablet

Also known as: XL092

Zanzalintinib at Dose Level 1 or 2 + Belzutifan

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead
• Exelixis: collaborator

Study Sites (27)

UCSF Medical Center at Mission Bay ( Site 5008)

San Francisco, California, 94158, United States

RECRUITING

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

Mineola, New York, 11501, United States

RECRUITING

Laura and Isaac Perlmutter Cancer Center ( Site 5016)

New York, New York, 10016, United States

RECRUITING

Memorial Sloan Kettering Cancer Center ( Site 5002)

New York, New York, 10065, United States

RECRUITING

Duke Cancer Institute ( Site 5015)

Durham, North Carolina, 27710, United States

RECRUITING

UPMC Cancer Center/Hillman Cancer Center ( Site 5017)

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

Centro de Estudios Clínicos SAGA ( Site 6110)

Santiago, Region M. de Santiago, 7500653, Chile

RECRUITING

Bradfordhill ( Site 6101)

Santiago, Region M. de Santiago, 8420383, Chile

RECRUITING

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

Strasbourg, Bas-Rhin, 67098, France

RECRUITING

Institut Claudius Regaud ( Site 5200)

Toulouse, Haute-Garonne, 31059, France

RECRUITING

Centre Eugene Marquis ( Site 5205)

Rennes, Ille-et-Vilaine, 35042, France

RECRUITING

Institut De Cancerologie De Lorraine ( Site 5204)

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

RECRUITING

Gustave Roussy ( Site 5202)

Villejuif, Île-de-France Region, 94805, France

RECRUITING

Rambam Health Care Campus ( Site 5500)

Haifa, 3109601, Israel

RECRUITING

Rabin Medical Center ( Site 5502)

Petah Tikva, 4941492, Israel

RECRUITING

Sheba Medical Center ( Site 5501)

Ramat Gan, 5265601, Israel

RECRUITING

Sourasky Medical Center ( Site 5503)

Tel Aviv, 6423906, Israel

RECRUITING

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

Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-796, Poland

RECRUITING

Uniwersyteckie Centrum Kliniczne ( Site 6202)

Gdansk, Pomeranian Voivodeship, 80-214, Poland

RECRUITING

Severance Hospital ( Site 5802)

Seoul, 03722, South Korea

RECRUITING

Asan Medical Center ( Site 5800)

Seoul, 05505, South Korea

RECRUITING

Samsung Medical Center ( Site 5801)

Seoul, 06351, South Korea

RECRUITING

Hospital Universitario Ramon y Cajal ( Site 5301)

Madrid, Madrid, Comunidad de, 28034, Spain

RECRUITING

Hospital Universitari Vall d'Hebron ( Site 5300)

Barcelona, 08035, Spain

RECRUITING

Western General Hospital ( Site 5402)

Edinburgh, Edinburgh, City of, EH42XU, United Kingdom

RECRUITING

St Bartholomew's Hospital ( Site 5401)

London, London, City of, EC1A7BE, United Kingdom

RECRUITING

The Christie NHS Foundation Trust ( Site 5400)

Manchester, M20 4BX, United Kingdom

RECRUITING

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

belzutifan

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Central Study Contacts

Toll Free Number

CONTACT

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2025
• First Posted: July 3, 2025
• Study Start: July 20, 2025
• Primary Completion (Estimated): October 26, 2031
• Study Completion (Estimated): October 26, 2031
• Last Updated: March 20, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

CL (2); US (6); GB (3); FR (5); PL (2); KR (3); IL (4); ES (2)