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Renal Cell CarcinomaPhase 1/2NCT07049926

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 1/2 study testing Belzutifan and Zanzalintinib in people with Renal Cell Carcinoma, run by Merck Sharp & Dohme LLC at 33 sites in 8 countries.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 to 120 years
Conditions the study is for
Renal Cell Carcinoma
What is being tested?
Belzutifan and Zanzalintinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
140 participants
Where
33 sitesin 8 countries
Study dates
20 Jul 2025to 26 Oct 2031
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 120 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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

Trial locations and contacts

33 sites in 8 countries. Contact the study team or a site near you to ask about taking part.

Toll Free Number contact

1-888-577-8839

Trialsites@msd.com

33 sites in 8 countries

United States7 sites, 7 recruiting

  • Duke Cancer Institute ( Site 5015)

    Durham, North Carolina, 27710

    Study Coordinator, 919-681-1030

    Recruiting

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

    Mineola, New York, 11501

    Study Coordinator, 516-663-3696

    Recruiting

  • Vanderbilt University Medical Center ( Site 5004)

    Nashville, Tennessee, 37232

    Study Coordinator, 615-343-2882

    Recruiting

  • Laura and Isaac Perlmutter Cancer Center ( Site 5016)

    New York, New York, 10016

    Study Coordinator, 212-731-6000

    Recruiting

  • Memorial Sloan Kettering Cancer Center ( Site 5002)

    New York, New York, 10065

    Study Coordinator, 212-639-2000

    Recruiting

  • UPMC Cancer Center/Hillman Cancer Center ( Site 5017)

    Pittsburgh, Pennsylvania, 15232

    Study Coordinator, 412-864-6600

    Recruiting

  • UCSF Medical Center at Mission Bay ( Site 5008)

    San Francisco, California, 94158

    Study Coordinator, 415-694-3896

    Recruiting

Other trials in United States

France5 sites, 5 recruiting

  • Centre Eugene Marquis ( Site 5205)

    Rennes, Ille-et-Vilaine, 35042

    Study Coordinator, +33299253182

    Recruiting

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

    Strasbourg, Bas-Rhin, 67098

    Study Coordinator, +330368767150

    Recruiting

  • Institut Claudius Regaud ( Site 5200)

    Toulouse, Haute-Garonne, 31059

    Study Coordinator, +33531155050

    Recruiting

  • Institut De Cancerologie De Lorraine ( Site 5204)

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

    Study Coordinator, +33383598574

    Recruiting

  • Gustave Roussy ( Site 5202)

    Villejuif, Île-de-France Region, 94805

    Study Coordinator, 0033142116690

    Recruiting

Other trials in France

United Kingdom5 sites, 5 recruiting

  • Velindre Cancer Centre ( Site 5407)

    Cardiff, CF14 2TL

    Study Coordinator, +442920615888

    Recruiting

  • Western General Hospital ( Site 5402)

    Edinburgh, Edinburgh, City of, EH42XU

    Study Coordinator, +441315371000

    Recruiting

  • The Beatson West of Scotland Cancer Centre ( Site 5405)

    Glasgow, Glasgow City, G12 0YN

    Study Coordinator, +441413017064

    Recruiting

  • St Bartholomew's Hospital ( Site 5401)

    London, London, City of, EC1A7BE

    Study Coordinator, +442072533411

    Recruiting

  • The Christie NHS Foundation Trust ( Site 5400)

    Manchester, M20 4BX

    Study Coordinator, +441614463988

    Recruiting

Other trials in United Kingdom

Israel4 sites, 4 recruiting

  • Rambam Health Care Campus ( Site 5500)

    Haifa, 3109601

    Study Coordinator, 972-4-7776234

    Recruiting

  • Rabin Medical Center ( Site 5502)

    Petah Tikva, 4941492

    Study Coordinator, +97239378110

    Recruiting

  • Sheba Medical Center ( Site 5501)

    Ramat Gan, 5265601

    Study Coordinator, +972-35304498

    Recruiting

  • Sourasky Medical Center ( Site 5503)

    Tel Aviv, 6423906

    Study Coordinator, 97236947284

    Recruiting

Other trials in Israel

Chile3 sites, 3 recruiting

  • Centro de Estudios Clínicos SAGA ( Site 6110)

    Santiago, Region M. de Santiago, 7500653

    Study Coordinator, +56223592703

    Recruiting

  • CDIEM ( Site 6114)

    Santiago, Region M. de Santiago, 7500859

    Study Coordinator, +56227435608

    Recruiting

  • Bradfordhill ( Site 6101)

    Santiago, Region M. de Santiago, 8420383

    Study Coordinator, 56229490970

    Recruiting

Other trials in Chile

Poland3 sites, 3 recruiting

  • Centrum Onkologii im. Prof. Franciszka Lukaszczyka ( Site 6201)

    Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-796

    Study Coordinator, 52 374 38 62

    Recruiting

  • Uniwersyteckie Centrum Kliniczne ( Site 6202)

    Gdansk, Pomeranian Voivodeship, 80-214

    Study Coordinator, +48585844466

    Recruiting

  • Narodowy Instytut Onkologii im. Marii Skłodowskiej Curie ( Site 6203)

    Warsaw, Masovian Voivodeship, 02-781

    Study Coordinator, +48 22 546 23 31

    Recruiting

Other trials in Poland

South Korea3 sites, 3 recruiting

  • Severance Hospital ( Site 5802)

    Seoul, 03722

    Study Coordinator, 82-2-2228-8138

    Recruiting

  • Asan Medical Center ( Site 5800)

    Seoul, 05505

    Study Coordinator, +82230106981

    Recruiting

  • Samsung Medical Center ( Site 5801)

    Seoul, 06351

    Study Coordinator, +82-2-3410-3459

    Recruiting

Other trials in South Korea

Spain3 sites, 3 recruiting

  • Hospital Universitari Vall d'Hebron ( Site 5300)

    Barcelona, 08035

    Study Coordinator, +34934894350

    Recruiting

  • HOSPITAL GENERAL UNIVERSITARIO GREGORIO MARAÑON ( Site 5302)

    Madrid, Madrid, Comunidad de, 28007

    Study Coordinator, +34915868000

    Recruiting

  • Hospital Universitario Ramon y Cajal ( Site 5301)

    Madrid, Madrid, Comunidad de, 28034

    Study Coordinator, +34913368263

    Recruiting

Other trials in Spain

About this study

Official title: 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 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

Being tested
Belzutifan, Zanzalintinib
Keywords
Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor (VEGFR-TKI), Hypoxia-Inducible Factor-2α (HIF-2α)
Medical subject headings
Carcinoma, Renal Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BelzutifanDrug

    Also called WELIREG®, MK-6482, PT2977

    Oral Tablet

  • ZanzalintinibDrug

    Also called XL092

    Oral Tablet

Study groups in NCT07049926
Study groupRoleWhat they receive
Zanzalintinib at Dose Level 1 or 2 + BelzutifanExperimentalParticipants will be allocated to receive zanzalintinib at dose level 1 or 2 + belzutifan daily until progressive disease or discontinuation
Receives: Drug: Belzutifan; Drug: Zanzalintinib
BelzutifanExperimentalParticipants will receive belzutifan daily until progressive disease or discontinuation
Receives: Drug: Belzutifan

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to approximately 21 days

  2. 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.

    Measured: Up to approximately 74 months

  3. 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.

    Measured: Up to approximately 74 months

  4. 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.

    Measured: Up to approximately 21 days

  5. 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.

    Measured: Up to approximately 74 months

  6. 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.

    Measured: Up to approximately 74 months

  7. 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.

    Measured: Up to approximately 74 months

Secondary outcomes (4)

  1. Efficacy Phase: Duration of response (DOR)

    For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.

    Measured: Up to approximately 74 months

  2. Efficacy Phase: Progression-free survival (PFS)

    PFS is defined as the time from first dose of study treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurs first as assessed by RECIST 1.1. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.

    Measured: Up to approximately 74 months

  3. Efficacy Phase: Overall survival (OS)

    OS is defined as time from first dose of study treatment to death due to any cause.

    Measured: Up to approximately 74 months

  4. Efficacy Phase: Clinical benefit rate (CBR)

    CBR is defined as the percentage of participants who have achieved stable disease (SD: Neither sufficient shrinkage to qualify for PR [at least a 30% decrease in the sum of diameters of target lesions] nor sufficient increase to qualify for PD) of ≥6 months or confirmed CR (disappearance of all target lesions) or PR per RECIST 1.1. PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. The CBR as assessed by BICR will be presented.

    Measured: Up to approximately 74 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Jul 2025
  2. Study start20 Jul 2025
  3. Primary completion26 Oct 2031 (estimated)
  4. Study completion26 Oct 2031 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
140 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07049926
Sponsor's protocol ID
3475-03C
Other IDs
MK-3475-03C, 2024-516437-12-00, U1111-1310-6076, KEYMAKER-U03
Status last verified
Oct 2026
First submitted
25 Jun 2025
Last updated
27 Oct 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Belzutifan and Zanzalintinib in people with Renal Cell Carcinoma, run by Merck Sharp & Dohme LLC at 33 sites in 8 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 27 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 33 sites in United States, France, United Kingdom, Israel, Chile and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Toll Free Number (1-888-577-8839, Trialsites@msd.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the 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). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07049926.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2026.

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