Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B/KEYMAKER-U03)
NCT ID: NCT04626518
Last Updated: 2025-07-25
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ACTIVE_NOT_RECRUITING
PHASE1/PHASE2
370 participants
INTERVENTIONAL
2020-12-17
2026-05-31
Brief Summary
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The goal of substudy 03B is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced second line plus (2L+) 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.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Coformulation Pembrolizumab/Quavonlimab
Participants will receive pembrolizumab/quavonlimab (coformulation of pembrolizumab 400 mg and quavonlimab 25 mg). Pembrolizumab/quavonlimab will be administered intravenously (IV) once every 6 weeks (Q6W) for up to 17 administrations (up to \~2 years).
Pembrolizumab/Quavonlimab
Administered via IV infusion at a dose of 400 mg/25 mg Q6W
Coformulation Favezelimab/Pembrolizumab
Participants will receive favezelimab/pembrolizumab (coformulation of favezelimab 800 mg and pembrolizumab 200 mg). Favezelimab/Pembrolizumab will be administered IV once every 3 weeks (Q3W) for up to 35 administrations (up to \~2 years).
Favezelimab/Pembrolizumab
Administered via IV infusion at a dose of 800 mg/200 mg Q3W
Pembrolizumab + MK-4830
Participants will receive pembrolizumab 200 mg PLUS MK-4830 800 mg. Both pembrolizumab and MK-4830 will be administered IV Q3W for up to 35 administrations (up to \~2 years).
Pembrolizumab
Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W
MK-4830
Administered via IV infusion at a dose of 800 mg Q3W
Pembrolizumab + Belzutifan
Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg. Pembrolizumab will be administered IV Q6W for up to 17 administrations (up to \~ 2 years). Belzutifan will be administered orally once-daily (QD) until progressive disease or discontinuation.
Pembrolizumab
Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W
Belzutifan
Administered via oral tablet at a dose of 120 mg QD
Belzutifan + Lenvatinib
Participants will receive Belzutifan 120 mg PLUS lenvatinib 20 mg. Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation.
Belzutifan
Administered via oral tablet at a dose of 120 mg QD
Lenvatinib
Administered via oral capsule at a dose of 20 mg QD
Pembrolizumab + Lenvatinib
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.
Pembrolizumab
Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W
Lenvatinib
Administered via oral capsule at a dose of 20 mg QD
Interventions
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Pembrolizumab
Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W
MK-4830
Administered via IV infusion at a dose of 800 mg Q3W
Belzutifan
Administered via oral tablet at a dose of 120 mg QD
Lenvatinib
Administered via oral capsule at a dose of 20 mg QD
Pembrolizumab/Quavonlimab
Administered via IV infusion at a dose of 400 mg/25 mg Q6W
Favezelimab/Pembrolizumab
Administered via IV infusion at a dose of 800 mg/200 mg Q3W
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Has experienced disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with a programmed cell death ligand 1 (PD-(L)1) checkpoint inhibitor (in sequence or in combination with a vascular endothelial growth factor. - tyrosine kinase inhibitor \[VEGF-TKI\]) where PD-(L)1 checkpoint inhibitor treatment progression is defined by meeting ALL of the following criteria: (a) has received ≥2 doses of an anti-PD-(L)1 monoclonal antibody (mAb) (b) has shown radiographic disease progression during or after an anti-PD-(L)1 mAb as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by investigator (c) disease progression has been documented within 12 weeks from the last dose of an anti-PD-(L)1 mAb
* Has experienced disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with a VEGF-TKI (in sequence or in combination with a PD-\[L\]1 checkpoint inhibitor) where VEGF-TKI treatment progression is defined by meeting the following criterion: has shown radiographic disease progression during or after a treatment with a VEGF-TKI as defined by RECIST 1.1 by investigator.
* 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 prior therapy to ≤Grade 1
* 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, MK-4830 or a combination of the aforementioned drugs, no contraception is needed
* Female participant is not pregnant or breastfeeding and is not 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, MK-4830 or 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
Exclusion Criteria
* 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
* Has malabsorption due to prior GI surgery or disease
* Has previously received treatment with a combination of pembrolizumab plus lenvatinib
* Has received prior treatment with belzutifan
* 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 intervention; 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
18 Years
120 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
Responsible Party
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Principal Investigators
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Medical Director
Role: STUDY_DIRECTOR
Merck Sharp & Dohme LLC
Locations
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University of California at San Francisco ( Site 3008)
San Francisco, California, United States
Yale-New Haven Hospital-Yale Cancer Center ( Site 3011)
New Haven, Connecticut, United States
University of Chicago ( Site 3013)
Chicago, Illinois, United States
University of Iowa ( Site 3012)
Iowa City, Iowa, United States
Henry Ford Health System ( Site 3014)
Detroit, Michigan, United States
Laura and Isaac Perlmutter Cancer Center ( Site 3016)
New York, New York, United States
Memorial Sloan Kettering Cancer Center ( Site 3002)
New York, New York, United States
Duke Cancer Institute ( Site 3015)
Durham, North Carolina, United States
UPMC Cancer Center/Hillman Cancer Center ( Site 3017)
Pittsburgh, Pennsylvania, United States
Vanderbilt University Medical Center ( Site 3004)
Nashville, Tennessee, United States
UTSW Medical Center ( Site 3003)
Dallas, Texas, United States
Blacktown Hospital ( Site 3601)
Blacktown, New South Wales, Australia
St George Hospital ( Site 3602)
Kogarah, New South Wales, Australia
Royal Brisbane and Women's Hospital ( Site 3603)
Herston, Queensland, Australia
Austin Health ( Site 3600)
Melbourne, Victoria, Australia
Princess Margaret Cancer Centre ( Site 3101)
Toronto, Ontario, Canada
Jewish General Hospital ( Site 3100)
Montreal, Quebec, Canada
FALP-UIDO ( Site 4100)
Santiago, Region M. de Santiago, Chile
Bradfordhill-Clinical Area ( Site 4101)
Santiago, Region M. de Santiago, Chile
James Lind Centro de Investigacion del Cancer ( Site 4108)
Temuco, Región de la Araucanía, Chile
CIDO SpA-Oncology ( Site 4106)
Temuco, Región de la Araucanía, Chile
ONCOCENTRO APYS-ACEREY ( Site 4103)
Viña del Mar, Región de Valparaíso, Chile
Institut De Cancerologie De Lorraine ( Site 3204)
Vandœuvre-lès-Nancy, Ain, France
Institut de cancérologie Strasbourg Europe (ICANS) ( Site 3203)
Strasbourg, Alsace, France
Institut Claudius Regaud ( Site 3200)
Toulouse, Haute-Garonne, France
Gustave Roussy ( Site 3202)
Villejuif, Île-de-France Region, France
Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 4301)
Budapest, Pest County, Hungary
Rambam Health Care Campus-Oncology Division ( Site 3500)
Haifa, , Israel
Hadassah Medical Center-Oncology ( Site 3504)
Jerusalem, , Israel
Rabin Medical Center ( Site 3502)
Petah Tikva, , Israel
Sheba Medical Center - Oncology Division ( Site 3501)
Ramat Gan, , Israel
Sourasky Medical Center ( Site 3503)
Tel Aviv, , Israel
Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 4402)
Amsterdam, North Holland, Netherlands
Erasmus Medisch Centrum ( Site 4401)
Rotterdam, South Holland, Netherlands
Auckland City Hospital ( Site 3700)
Auckland, , New Zealand
Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 4201)
Bydgoszcz, Kuyavian-Pomeranian Voivodeship, Poland
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 4200)
Warsaw, Masovian Voivodeship, Poland
Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 4202)
Gdansk, Pomeranian Voivodeship, Poland
Asan Medical Center ( Site 3800)
Songpagu, Seoul, South Korea
Severance Hospital ( Site 3802)
Seoul, , South Korea
Samsung Medical Center ( Site 3801)
Seoul, , South Korea
Hospital Universitari Vall d Hebron ( Site 3300)
Barcelona, Catalonia, Spain
Hospital Universitario Ramon y Cajal ( Site 3301)
Madrid, , Spain
Southampton General Hospital ( Site 3403)
Southampton, England, United Kingdom
The Beatson West of Scotland Cancer Centre ( Site 3405)
Glasgow, Glasgow City, United Kingdom
Royal Preston Hospital ( Site 3406)
Preston, Lancashire, United Kingdom
Leicester Royal Infirmary ( Site 3408)
Leicester, Leicestershire, United Kingdom
Barts Health NHS Trust ( Site 3401)
London, London, City of, United Kingdom
Western General Hospital ( Site 3402)
Edinburgh, Midlothian, United Kingdom
Velindre Cancer Centre Hospital ( Site 3407)
Cardiff, Wales, United Kingdom
The Christie NHS Foundation Trust ( Site 3400)
Manchester, , United Kingdom
Countries
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Related Links
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Merck Clinical Trials Information
Plain Language Summary
Other Identifiers
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MK-3475-03B
Identifier Type: OTHER
Identifier Source: secondary_id
KEYMAKER-U03
Identifier Type: OTHER
Identifier Source: secondary_id
2023-506839-15-00
Identifier Type: REGISTRY
Identifier Source: secondary_id
U1111-1294-4557
Identifier Type: REGISTRY
Identifier Source: secondary_id
2019-003610-13
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
3475-03B
Identifier Type: -
Identifier Source: org_study_id
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