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Updated May 2026 · ClinicalTrials.gov

RECRUITINGPhase 1 / Phase 2INTERVENTIONAL

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)

A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (KEYMAKER-U03): Substudy 03C in Participants With Recurrent Disease During or After Anti-PD-(L)1 Adjuvant Therapy

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) is a Phase 1 / Phase 2 interventional studying Renal Cell Carcinoma, sponsored by Merck Sharp & Dohme LLC. RECRUITING as of the most recent ClinicalTrials.gov update. Talk to your doctor before contacting the trial site.

Important: This information is not medical advice. Talk to your doctor about whether a clinical trial is right for you.

About This Trial

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

What Stage of Research Is This?

Phase 1 trials test a new treatment for the first time in humans, focusing on safety, dosing, and how the body processes the drug. For Renal Cell Carcinoma, a Phase 1 study typically enrolls a small number of participants — often healthy volunteers or patients who have exhausted standard treatment options. Phase 1 results determine whether a treatment moves into larger Phase 2 efficacy studies.

This trial is currently recruiting participants. The sponsor has registered the study with ClinicalTrials.gov as actively enrolling, which means new applicants who meet the eligibility criteria can be considered for screening. Trial status can change between updates — confirm current recruiting status with the study contact before traveling for a screening visit.

Target enrollment of 140 participants puts this in the typical range for a Phase 2-style efficacy study or a moderate Phase 3 trial in a focused Renal Cell Carcinoma subpopulation. At this scale, the study has enough statistical power to detect a clear treatment effect but is not the largest cohort in the field.

Who May Be Eligible (Plain English)

The main inclusion criteria include but are not limited to the following: - Has a diagnosed by tissue sample (biopsy-confirmed) diagnosis of unresectable locally advanced/metastatic renal cell carcinoma (RCC) with clear cell component - Has received no other previous cancer treatment that works throughout the body (like chemotherapy) 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 your organs (liver, kidneys, etc.) are working well enough based on blood tests 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 ...See full criteria on ClinicalTrials.gov Always talk to your doctor about whether this trial is right for you.

These are translations of the protocol\'s inclusion and exclusion criteria, simplified for patients and caregivers. The original clinical text appears below. Eligibility is ultimately confirmed by the trial site\'s screening process — this summary is a starting point for a conversation with your doctor, not a final determination.

Original Eligibility Criteria

View original clinical language
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

Treatments Being Tested

DRUG

Belzutifan

Oral Tablet

DRUG

Zanzalintinib

Oral Tablet

Locations (20)

Trial sites listed on ClinicalTrials.gov for this study. Site activation status can vary — confirm with the specific site before traveling for a screening visit.

UCSF Medical Center at Mission Bay ( Site 5008)
San Francisco, California, United States
Perlmutter Cancer Center at NYU Langone Hospital - Long Island ( Site 5026)
Mineola, New York, United States
Laura and Isaac Perlmutter Cancer Center ( Site 5016)
New York, New York, United States
Memorial Sloan Kettering Cancer Center ( Site 5002)
New York, New York, United States
Duke Cancer Institute ( Site 5015)
Durham, North Carolina, United States
UPMC Cancer Center/Hillman Cancer Center ( Site 5017)
Pittsburgh, Pennsylvania, United States
Centro de Estudios Clínicos SAGA ( Site 6110)
Santiago, Region M. de Santiago, Chile
Bradfordhill ( Site 6101)
Santiago, Region M. de Santiago, Chile
C.H.U. de Strasbourg Hopital de Hautepierre ( Site 5203)
Strasbourg, Bas-Rhin, France
Institut Claudius Regaud ( Site 5200)
Toulouse, Haute-Garonne, France
Centre Eugene Marquis ( Site 5205)
Rennes, Ille-et-Vilaine, France
Institut De Cancerologie De Lorraine ( Site 5204)
Vandœuvre-lès-Nancy, Meurthe-et-Moselle, France
Gustave Roussy ( Site 5202)
Villejuif, Île-de-France Region, France
Rambam Health Care Campus ( Site 5500)
Haifa, Israel
Rabin Medical Center ( Site 5502)
Petah Tikva, Israel
Sheba Medical Center ( Site 5501)
Ramat Gan, Israel
Sourasky Medical Center ( Site 5503)
Tel Aviv, Israel
Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 6201)
Bydgoszcz, Kuyavian-Pomeranian Voivodeship, Poland
Uniwersyteckie Centrum Kliniczne ( Site 6202)
Gdansk, Pomeranian Voivodeship, Poland
Severance Hospital ( Site 5802)
Seoul, South Korea

How to Talk to Your Doctor About This Trial

Bring the printable summary of this trial — including the NCT ID (NCT07049926), the sponsor (Merck Sharp & Dohme LLC), and the key eligibility criteria — to your next appointment. Your doctor can review the inclusion and exclusion criteria against your medical history, lab values, and current treatments to assess whether you are likely to qualify. They can also help you weigh whether trial participation makes sense alongside your existing care plan.

Useful questions to walk through together: What does the trial protocol require beyond standard care? How long is the active treatment phase, and how long is follow-up? Are there study visits at sites I can reach? Who pays for the trial-specific procedures, and who pays for standard-of-care portions? See our 25 questions to ask about clinical trials guide for a more complete checklist.

Authoritative Sources

The official record for this trial lives on ClinicalTrials.gov — the federal registry maintained by the National Library of Medicine at NIH. For background on how this trial fits into the FDA approval pathway, see the FDA drug approval process. For oncology-specific guidance for patients considering trials, the National Cancer Institute publishes patient-oriented overviews. International trial registries are aggregated by the WHO ICTRP.

Frequently Asked Questions

What is the NCT07049926 clinical trial studying?

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… The full protocol is registered on ClinicalTrials.gov and includes the primary outcome measures, eligibility criteria, and study endpoints.

Who can participate in NCT07049926?

Eligibility for this trial depends on the specific inclusion and exclusion criteria set by the sponsor. The plain-English summary above translates the most important criteria into accessible language; the official clinical text is preserved in the collapsible section underneath. Whether you fit any specific trial is a medical decision your doctor needs to confirm — bring the trial information to your treating physician for a full review against your medical history.

How do I contact the trial site for NCT07049926?

Contact information registered with ClinicalTrials.gov is shown in the sidebar of this page. Before reaching out, confirm with your treating physician that this trial is appropriate for your situation. The trial site will then walk you through the screening process to determine final eligibility.

Is participating in a clinical trial safe?

Clinical trials in the United States are regulated by the FDA and overseen by Institutional Review Boards (IRBs) that review the protocol for safety. Risk varies by trial — Phase 1 studies test new treatments in humans for the first time, while Phase 3 trials use treatments that have already passed earlier safety screening. The informed consent document for any specific trial details the known risks and what to expect. Discuss those risks with your physician before deciding whether to participate.

Where can I verify the data on this page?

Every detail on this page comes directly from the ClinicalTrials.gov API. Click "View on ClinicalTrials.gov" in the sidebar to see the official, unmodified record. The federal record is always authoritative; this page is a structured presentation with a plain-English eligibility translation. For background on how clinical trials are regulated, see the FDA drug approval process documentation.

How This Page Is Built

Every field on this page is pulled directly from the ClinicalTrials.gov API v2 — no estimates, no proxies. The plain-English eligibility translation is generated from the original protocol text and reviewed for fidelity to the underlying clinical criteria. The original clinical text remains visible in the collapsible section above so users and clinicians can verify the translation. Read the full methodology for the data pipeline and known limitations.

Source: ClinicalTrials.gov API v2 record for NCT07049926. Maintained by the National Library of Medicine at NIH. Public domain. Cite as: "TrialFinderData. NCT07049926. Data: ClinicalTrials.gov."

Medical disclaimer: This page is informational, not medical advice. Talk to your doctor about whether a clinical trial is right for you.

Last updated 2026-05-08 · Data from ClinicalTrials.gov.