Carcinoma, Renal CellPhase 1/2NCT04626479
Substudy 03A: A Study of Immune and Targeted Combination Therapies in Participants With First Line (1L) Renal Cell Carcinoma (MK-3475-03A)
A Phase 1/2 study testing Pembrolizumab, Favezelimab/Pembrolizumab and Belzutifan in people with Carcinoma, Renal Cell, run by Merck Sharp & Dohme LLC at 55 sites in 14 countries.
Trial summary
Substudy 03A 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 03A is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced… Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Carcinoma, Renal Cell
- What is being tested?
- Pembrolizumab, Favezelimab/Pembrolizumab and Belzutifan
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 393 participants
- Where
- 55 sitesin 14 countries
- Study dates
- 16 Dec 2020to 10 Aug 2026
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
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
Who may be able to join
- Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC
- Has received no prior systemic therapy for advanced RCC; prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed ≥12 months before randomization/allocation.
- Is able to swallow oral medication
- Has adequate organ function
- Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks before randomization/allocation
- Has resolution of toxic effects of the most recent prior therapy to ≤Grade 1
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- Has adequately controlled blood pressure (BP ≤150/90 mm Hg) with no change in hypertensive medications within 1 week before randomization/allocation
- Male participants are abstinent from heterosexual intercourse or agree to use contraception during treatment with and for at least 7 days after the last dose of lenvatinib and /or belzutifan; 7 days after lenvatinib and/or belzutifan is stopped, if the participant is only receiving pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab or a combination of the aforementioned drugs, no contraception is needed
- Female participants must not be pregnant and not be a woman of childbearing potential (WOCBP) or is a WOCBP abstinent from heterosexual intercourse or using contraception during the intervention period and for at least 120 days after the last dose of pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab for 30 days after the last dose of lenvatinib or belzutifan, whichever occurs last and must abstain from breastfeeding during the study intervention period and for at least 120 days after study intervention
Who cannot join
- Has urine protein ≥1 g/24 hours and has any of the following: (a) a pulse oximeter reading <92% at rest, or (b) requires intermittent supplemental oxygen, or (c) requires chronic supplemental oxygen (d) active hemoptysis within 3 weeks prior to the first dose of study intervention
- Has clinically significant cardiovascular disease within 12 months from the first dose of study intervention administration
- Has had major surgery within 3 weeks before first dose of study interventions
- Has a history of lung disease
- Has a history of inflammatory bowel disease
- Has preexisting gastrointestinal (GI) or non-GI fistula
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- Has malabsorption due to prior GI surgery or disease
- Has received prior radiotherapy within 2 weeks of start of study intervention
- Has received a live or live attenuated vaccine within 30 days before the first dose of study drug; killed vaccines are allowed
- Has received more than 4 previous systemic anticancer treatment regimens
- Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
- Has known additional malignancy that is progressing or has required active treatment within the past 3 years
- Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
- Has an active autoimmune disease that has required systemic treatment in the past 2 years; replacement therapy is not considered a form of systemic treatment and is allowed
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV) infection
- Has a known history of Hepatitis B
- Has had an allogenic tissue/solid organ transplant
Trial locations and contacts
55 sites in 14 countries.
55 sites in 14 countries
United States10 sites
University of Chicago ( Site 1013)
Chicago, Illinois, 60637
UTSW Medical Center ( Site 1003)
Dallas, Texas, 75390
Henry Ford Health System ( Site 1014)
Detroit, Michigan, 48202
Duke Cancer Institute ( Site 1015)
Durham, North Carolina, 27710
University of Iowa ( Site 1012)
Iowa City, Iowa, 52242
Yale-New Haven Hospital-Yale Cancer Center ( Site 1011)
New Haven, Connecticut, 06510
Laura and Isaac Perlmutter Cancer Center ( Site 1016)
New York, New York, 10016
Memorial Sloan Kettering Cancer Center ( Site 1002)
New York, New York, 10065
UPMC Cancer Center/Hillman Cancer Center ( Site 1017)
Pittsburgh, Pennsylvania, 15232
University of California at San Francisco ( Site 1008)
San Francisco, California, 94158
United Kingdom8 sites
Velindre Cancer Centre Hospital ( Site 1407)
Cardiff, Wales, CF14 2TL
Western General Hospital ( Site 1402)
Edinburgh, Midlothian, EH4 2XU
The Beatson West of Scotland Cancer Centre ( Site 1405)
Glasgow, Glasgow City, G12 0YN
Leicester Royal Infirmary ( Site 1408)
Leicester, Leicestershire, LE1 5WW
Barts Health NHS Trust ( Site 1401)
London, London, City of, EC1A 7BE
The Christie NHS Foundation Trust ( Site 1400)
Manchester, M20 4BX
Royal Preston Hospital ( Site 1406)
Preston, Lancashire, PR2 9HT
Southampton General Hospital ( Site 1403)
Southampton, England, SO16 6YD
Chile6 sites
FALP-UIDO ( Site 2100)
Santiago, Region M. de Santiago, 7500921
Oncovida ( Site 2107)
Santiago, Region M. de Santiago, 7500994
Bradfordhill-Clinical Area ( Site 2101)
Santiago, Region M. de Santiago, 8420383
James Lind Centro de Investigacion del Cancer ( Site 2108)
Temuco, Araucania, 4800827
CIDO SpA-Oncology ( Site 2106)
Temuco, Araucania, 4810148
ONCOCENTRO APYS-ACEREY ( Site 2103)
Viña del Mar, Valparaiso, 2520598
Israel5 sites
Rambam MC ( Site 1500)
Haifa, 3525408
Hadassah Medical Center-Oncology ( Site 1504)
Jerusalem, 9112001
Rabin Medical Center ( Site 1502)
Petah Tikva, 4941492
Sheba Medical Center - Oncology Division ( Site 1501)
Ramat Gan, 52621
Sourasky Medical Center ( Site 1503)
Tel Aviv, 6423906
Australia4 sites
Blacktown Hospital ( Site 1601)
Blacktown, New South Wales, 2148
Austin Health ( Site 1600)
Heidelberg, Victoria, 3084
Royal Brisbane and Women's Hospital ( Site 1603)
Herston, Queensland, 4029
St George Hospital ( Site 1602)
Kogarah, New South Wales, 2217
Colombia4 sites
Clinica Colsanitas S.A, Sede Clínica Universitaria Colombia-Center Investigator ( Site 1900)
Bogotá, Bogota D.C., 111321
Fundación Valle del Lili ( Site 1901)
Cali, Valle del Cauca Department, 760032
Instituto Médico de Alta Tecnologia S.A.S ( Site 1904)
Montería, Departamento de Córdoba, 230002
Sociedad De Oncologia Y Hematologia Del Cesar-Oncology ( Site 1905)
Valledupar, Cesar Department, 200001
France4 sites
C.H.U. de Strasbourg Hopital de Hautepierre ( Site 1203)
Strasbourg, Bas-Rhin, 67098
Institut Claudius Regaud ( Site 1200)
Toulouse, Haute-Garonne, 31059
Institut De Cancerologie De Lorraine ( Site 1204)
Vandœuvre-lès-Nancy, Ain, 54519
Gustave Roussy ( Site 1202)
Villejuif, Île-de-France Region, 94800
Poland3 sites
Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 2201)
Bydgoszcz, Kuyavian-Pomeranian Voivodeship, 85-796
Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 2202)
Gdansk, Pomeranian Voivodeship, 80-952
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 2200)
Warsaw, Masovian Voivodeship, 02-781
South Korea3 sites
Severance Hospital ( Site 1802)
Seoul, 03722
Samsung Medical Center ( Site 1801)
Seoul, 06351
Asan Medical Center ( Site 1800)
Songpagu, Seoul, 05505
Canada2 sites
Jewish General Hospital ( Site 1100)
Montreal, Quebec, H3T 1E2
Princess Margaret Cancer Centre ( Site 1101)
Toronto, Ontario, M5G 1Z5
Netherlands2 sites
Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 2402)
Amsterdam, North Holland, 1066 CX
Erasmus Medisch Centrum ( Site 2401)
Rotterdam, South Holland, 3015 GD
Spain2 sites
Hospital Universitari Vall d Hebron ( Site 1300)
Barcelona, Catalonia, 08035
Hospital Universitario Ramon y Cajal ( Site 1301)
Madrid, 28034
Hungary1 site
Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 2301)
Budapest, Pest County, 1122
About this study
Official title: A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (U03): Substudy 03A in First Line Metastatic Participants
Substudy 03A 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 03A is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced first line (1L) clear cell renal cell carcinoma (ccRCC).
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
- Carcinoma, Renal Cell
- Being tested
- Pembrolizumab, Favezelimab/Pembrolizumab, Belzutifan, Lenvatinib, Pembrolizumab/Quavonlimab
- Keywords
- receptor tyrosine kinase inhibitor, programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1)
- Medical subject headings
- Carcinoma, Renal Cell, Parkinson Disease 4, Autosomal Dominant Lewy Body
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PembrolizumabBiological
Also called MK-3475, KEYTRUDA®
Administered via IV infusion at a dose of 400 mg Q6W
Favezelimab/PembrolizumabBiological
Also called MK-4280A
Administered via IV infusion at a dose of 800 mg/200 mg Q3W
BelzutifanDrug
Also called MK-6482, WELIREG™
Administered via oral tablet at a dose of 120 mg QD
LenvatinibDrug
Also called MK-7902, E7080, LENVIMA®
Administered via oral capsule at a dose of 20 mg QD
Pembrolizumab/QuavonlimabBiological
Also called MK-1308A
Administered via IV infusion at a dose of 400 mg/25 mg Q6W
Vibostolimab/PembrolizumabDrug
Also called MK-7684A
Administered via IV infusion at a dose of 200 mg/200 mg Q6W
| Study group | Role | What they receive |
|---|---|---|
| Coformulation Pembrolizumab/Quavonlimab + Lenvatinib | Experimental | Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 17 administrations (up to ~2 years). Lenvatinib will be administered orally once-daily (QD) until progressive disease or discontinuation. Receives: Drug: Lenvatinib; Biological: Pembrolizumab/Quavonlimab |
| Coformulation Favezelimab/Pembrolizumab+ Lenvatinib | Experimental | Participants will receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg) PLUS lenvatinib 20 mg. Favezelimab/Pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation. Receives: Biological: Favezelimab/Pembrolizumab; Drug: Lenvatinib |
| Pembrolizumab + Belzutifan + Lenvatinib | Experimental | Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~2 years). Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation. Receives: Biological: Pembrolizumab; Drug: Belzutifan; Drug: Lenvatinib |
| Pembrolizumab + Lenvatinib | Experimental | Participants will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~ 2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation. Receives: Biological: Pembrolizumab; Drug: Lenvatinib |
| Coformulation Vibostolimab/Pembrolizumab+Belzutifan | Experimental | Participants will receive vibostolimab/pembrolizumab (coformulation of 200 mg vibostolimab and pembrolizumab 200 mg). Vibostolimab/pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Belzutifan will be administered orally QD until progressive disease or discontinuation. Receives: Drug: Belzutifan; Drug: Vibostolimab/Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety Lead-in Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs)
DLTs are defined as one or more of the following toxicities: (1) grade (gr) 4 nonhematologic toxicity (2) gr 4 hematologic toxicity lasting >7 days OR gr 4 platelet count decreased of any duration OR gr 3 platelet count decreased if associated with bleeding (3) gr 3 nonhematologic toxicity except gr 3 fatigue (lasting ≤3 days), diarrhea, nausea, vomiting or rash without standard of care (4) gr 3 or 4 nonhematologic abnormality if medical intervention is required or if it leads to hospitalization or persists for >1 week (5) gr 3 or 4 febrile neutropenia (6) gr 3 or 4 alanine aminotransferase, aspartate aminotransferase and/or bilirubin laboratory value (7) treatment related adverse event (AE) causing study intervention discontinuation during the first 21 days (8) treatment related AE causing intervention administration delay for >14 days during the first 21 days (9) gr 5 toxicity. The number of participants who experience one or more DLTs in the safety lead-in phase will be presented.
Measured: Up to ~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. The number of participants who experience one or more AEs in the safety lead-in phase will be presented.
Measured: Up to ~21 days
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. The number of participants who discontinue study treatment due to an AE in the safety lead-in phase will be presented.
Measured: Up to ~21 days
Efficacy Phase: Number of participants who experience one or more DLTs
DLTs are defined as one or more of the following toxicities: (1) grade (gr) 4 nonhematologic toxicity (2) gr 4 hematologic toxicity lasting >7 days OR gr 4 platelet count decreased of any duration OR gr 3 platelet count decreased if associated with bleeding (3) gr 3 nonhematologic toxicity except gr 3 fatigue (lasting ≤3 days), diarrhea, nausea, vomiting or rash without standard of care (4) gr 3 or 4 nonhematologic abnormality if medical intervention is required or if it leads to hospitalization or persists for >1 week (5) gr 3 or 4 febrile neutropenia (6) gr 3 or 4 alanine aminotransferase, aspartate aminotransferase and/or bilirubin laboratory value (7) treatment related adverse event (AE) causing study intervention discontinuation during the first 21 days (8) treatment related AE causing intervention administration delay for >14 days during the first 21 days (9) gr 5 toxicity. The number of participants who experience one or more DLTs in the efficacy phase will be presented.
Measured: Up to ~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. The number of participants who experience one or more AEs in the efficacy phase will be presented.
Measured: Up to ~43 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. The number of participants who discontinue study treatment due to an AE in the efficacy phase will be presented.
Measured: Up to ~43 months
Efficacy Phase: Objective response rate (ORR)
ORR is defined as the percentage of participants in the analysis population who have a 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, taking as reference the baseline sum of diameters). Responses are according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR).
Measured: Up to ~43 months
Secondary outcomes (4)
Efficacy Phase: Duration of response (DOR)
For participants in the analysis population who demonstrate a confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters), DOR is defined as the time from first documented evidence of CR or PR until progressive disease or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 by BICR.
Measured: Up to ~43 months
Efficacy Phase: Progression-free survival (PFS)
PFS is defined as the time from randomization to the first documented progressive disease or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 by BICR.
Measured: Up to ~43 months
Efficacy Phase: Overall survival (OS)
OS is defined as the time from randomization to death due to any cause.
Measured: Up to ~43 months
Efficacy Phase: Clinical benefit rate (CBR)
CBR is defined as the percentage of participants who have achieved CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) of ≥6 months. Responses are according to RECIST 1.1 by BICR.
Measured: Up to ~43 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Nov 2020
- Study start16 Dec 2020
- Primary completion10 Aug 2026
- Study completion10 Aug 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Carcinoma, Renal CellStudies of the same condition, open and under way.
- More trials run by Merck Sharp & Dohme LLCThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 393 participants (actual)
Sponsor and investigators
- Lead sponsor
- Merck Sharp & Dohme LLC
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director, Study director, Merck Sharp & Dohme LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04626479
- Sponsor's protocol ID
- 3475-03A
- Other IDs
- MK-3475-03A, 2023-506838-68-00, U1111-1294-4527, 2019-003609-84, 2019, 2023
- Status last verified
- Aug 2026
- First submitted
- 10 Nov 2020
- Last updated
- 25 Sep 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
Publications
Suarez C, Rojas C, Shin SJ, Yanez Weber P, Albiges L, Motzer R, Hammers H, Peer A, Lee JL, Miller WH, Waddell T, Neiman V, Keizman D, Zwenger Kloster A, Weickhardt A, Dziadziuszko R, Suttner L, Sharma M, Burgents JE, Powles T. Novel pembrolizumab-based treatments as first-line therapy in advanced clear-cell renal cell carcinoma: substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial. Ann Oncol. 2026 Feb;37(2):229-240. doi: 10.1016/j.annonc.2025.10.010. Epub 2025 Oct 18.
PubMed 41115468
Study at a glance
From the registry record, last updated by the sponsor on 25 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (U03): Substudy 03A in First Line Metastatic Participants
- ClinicalTrials.gov ID
- NCT04626479
- Acronym / sponsor ID
- 3475-03A
- Conditions
- Carcinoma, Renal Cell
- Keywords
- receptor tyrosine kinase inhibitor, programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 393 participants (actual)
- Lead sponsor
- Merck Sharp & Dohme LLCIndustry (pharma, biotech, devices)
- Study start
- 16 Dec 2020 (actual)
- Primary completion
- 10 Aug 2026 (actual)
- Study completion
- 10 Aug 2026 (actual)
- First posted
- 12 Nov 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Substudy 03A 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 03A is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced first line (1L) clear cell renal cell carcinoma (ccRCC).
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Coformulation Pembrolizumab/Quavonlimab + Lenvatinib | Experimental | Drug: Lenvatinib, Biological: Pembrolizumab/QuavonlimabParticipants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg) PLUS lenvatinib 20 mg. Pembrolizumab/quavonlimab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 17 administrations (up to ~2 years). Lenvatinib will be administered orally once-daily (QD) until progressive disease or discontinuation. |
| Coformulation Favezelimab/Pembrolizumab+ Lenvatinib | Experimental | Biological: Favezelimab/Pembrolizumab, Drug: LenvatinibParticipants will receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg) PLUS lenvatinib 20 mg. Favezelimab/Pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation. |
| Pembrolizumab + Belzutifan + Lenvatinib | Experimental | Biological: Pembrolizumab, Drug: Belzutifan, Drug: LenvatinibParticipants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~2 years). Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation. |
| Pembrolizumab + Lenvatinib | Experimental | Biological: Pembrolizumab, Drug: LenvatinibParticipants will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to ~ 2 years). Lenvatinib will be administered orally QD until progressive disease or discontinuation. |
| Coformulation Vibostolimab/Pembrolizumab+Belzutifan | Experimental | Drug: Belzutifan, Drug: Vibostolimab/PembrolizumabParticipants will receive vibostolimab/pembrolizumab (coformulation of 200 mg vibostolimab and pembrolizumab 200 mg). Vibostolimab/pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to ~2 years). Belzutifan will be administered orally QD until progressive disease or discontinuation. |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC
- Has received no prior systemic therapy for advanced RCC; prior neoadjuvant/adjuvant therapy for RCC is acceptable if completed ≥12 months before randomization/allocation.
- Is able to swallow oral medication
- Has adequate organ function
- Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks before randomization/allocation
Key exclusion criteria (18 listed)
- Has urine protein ≥1 g/24 hours and has any of the following: (a) a pulse oximeter reading <92% at rest, or (b) requires intermittent supplemental oxygen, or (c) requires chronic supplemental oxygen (d) active hemoptysis within 3 weeks prior to the first dose of study intervention
- Has clinically significant cardiovascular disease within 12 months from the first dose of study intervention administration
- Has had major surgery within 3 weeks before first dose of study interventions
- Has a history of lung disease
- Has a history of inflammatory bowel disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PembrolizumabAlso: MK-3475, KEYTRUDA®Administered via IV infusion at a dose of 400 mg Q6W | Biological | Pembrolizumab + Belzutifan + Lenvatinib, Pembrolizumab + Lenvatinib |
| Favezelimab/PembrolizumabAlso: MK-4280AAdministered via IV infusion at a dose of 800 mg/200 mg Q3W | Biological | Coformulation Favezelimab/Pembrolizumab+ Lenvatinib |
| BelzutifanAlso: MK-6482, WELIREG™Administered via oral tablet at a dose of 120 mg QD | Drug | Coformulation Vibostolimab/Pembrolizumab+Belzutifan, Pembrolizumab + Belzutifan + Lenvatinib |
| LenvatinibAlso: MK-7902, E7080, LENVIMA®Administered via oral capsule at a dose of 20 mg QD | Drug | Coformulation Favezelimab/Pembrolizumab+ Lenvatinib, Coformulation Pembrolizumab/Quavonlimab + Lenvatinib, Pembrolizumab + Belzutifan + Lenvatinib, Pembrolizumab + Lenvatinib |
| Pembrolizumab/QuavonlimabAlso: MK-1308AAdministered via IV infusion at a dose of 400 mg/25 mg Q6W | Biological | Coformulation Pembrolizumab/Quavonlimab + Lenvatinib |
| Vibostolimab/PembrolizumabAlso: MK-7684AAdministered via IV infusion at a dose of 200 mg/200 mg Q6W | Drug | Coformulation Vibostolimab/Pembrolizumab+Belzutifan |
Primary outcome
Safety Lead-in Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs)
Time frame: Up to ~21 days
DLTs are defined as one or more of the following toxicities: (1) grade (gr) 4 nonhematologic toxicity (2) gr 4 hematologic toxicity lasting >7 days OR gr 4 platelet count decreased of any duration OR gr 3 platelet count decreased if associated with bleeding (3) gr 3 nonhematologic toxicity except gr 3 fatigue (lasting ≤3 days), diarrhea, nausea, vomiting or rash without standard of care (4) gr 3 or 4 nonhematologic abnormality if medical intervention is required or if it leads to hospitalization or persists for >1 week (5) gr 3 or 4 febrile neutropenia (6) gr 3 or 4 alanine aminotransferase, aspartate aminotransferase and/or bilirubin laboratory value (7) treatment related adverse event (AE) causing study intervention discontinuation during the first 21 days (8) treatment related AE causing intervention administration delay for >14 days during the first 21 days (9) gr 5 toxicity. The number of participants who experience one or more DLTs in the safety lead-in phase will be presented.
Safety Lead-in Phase: Number of participants who experience one or more adverse events (AEs)
Time frame: Up to ~21 days
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. The number of participants who experience one or more AEs in the safety lead-in phase will be presented.
Safety Lead-in Phase: Number of participants who discontinue study treatment due to an AE
Time frame: Up to ~21 days
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. The number of participants who discontinue study treatment due to an AE in the safety lead-in phase will be presented.
Efficacy Phase: Number of participants who experience one or more DLTs
Time frame: Up to ~21 days
DLTs are defined as one or more of the following toxicities: (1) grade (gr) 4 nonhematologic toxicity (2) gr 4 hematologic toxicity lasting >7 days OR gr 4 platelet count decreased of any duration OR gr 3 platelet count decreased if associated with bleeding (3) gr 3 nonhematologic toxicity except gr 3 fatigue (lasting ≤3 days), diarrhea, nausea, vomiting or rash without standard of care (4) gr 3 or 4 nonhematologic abnormality if medical intervention is required or if it leads to hospitalization or persists for >1 week (5) gr 3 or 4 febrile neutropenia (6) gr 3 or 4 alanine aminotransferase, aspartate aminotransferase and/or bilirubin laboratory value (7) treatment related adverse event (AE) causing study intervention discontinuation during the first 21 days (8) treatment related AE causing intervention administration delay for >14 days during the first 21 days (9) gr 5 toxicity. The number of participants who experience one or more DLTs in the efficacy phase will be presented.
Efficacy Phase: Number of participants who experience one or more AEs
Time frame: Up to ~43 months
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. The number of participants who experience one or more AEs in the efficacy phase will be presented.
Efficacy Phase: Number of participants who discontinue study treatment due to an AE
Time frame: Up to ~43 months
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. The number of participants who discontinue study treatment due to an AE in the efficacy phase will be presented.
Efficacy Phase: Objective response rate (ORR)
Time frame: Up to ~43 months
ORR is defined as the percentage of participants in the analysis population who have a 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, taking as reference the baseline sum of diameters). Responses are according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR).
4 secondary outcomes
Efficacy Phase: Duration of response (DOR)
Time frame: Up to ~43 months
Efficacy Phase: Progression-free survival (PFS)
Time frame: Up to ~43 months
Efficacy Phase: Overall survival (OS)
Time frame: Up to ~43 months
Efficacy Phase: Clinical benefit rate (CBR)
Time frame: Up to ~43 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Sep 2026.
- Results publication: PubMed 41115468Suarez C, Rojas C, Shin SJ, Yanez Weber P, Albiges L, Motzer R, Hammers H, Peer A, Lee JL, Miller WH, Waddell T, Neiman V, Keizman D, Zwenger Kloster A, Weickhardt A, Dziadziuszko R, Suttner L, Sharma M, Burgents JE, Powles T. Novel pembrolizumab-based treatments as first-line therapy in advanced clear-cell renal cell carcinoma: substudy 03A of the open-label, umbrella platform, phase I/II KEYMAKER-U03 trial. Ann Oncol. 2026 Feb;37(2):229-240. doi: 10.1016/j.annonc.2025.10.010. Epub 2025 Oct 18.
- Merck Oncology Clinical Trials InformationLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director study director
Merck Sharp & Dohme LLC
55 sites in 14 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Pembrolizumab, Favezelimab/Pembrolizumab and Belzutifan in people with Carcinoma, Renal Cell, run by Merck Sharp & Dohme LLC at 55 sites in 14 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 18 exclusion criteria. 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: finished, as of the sponsor's last update on 25 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 55 sites in United States, United Kingdom, Chile, Israel, Australia and 9 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. 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 ~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 NCT04626479, which also lists 1 linked publication.
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 25 Sep 2026.