Substudy 03A: A Study of Immune and Targeted Combination Therapies in Participants With First Line (1L) Renal Cell Carcinoma (MK-3475-03A)

NCT04626479 | Active Not Recruiting Phase 1 FDA Drug

• 5 other identifiers: 3475-03AMK-3475-03A2023-506838-68-00U1111-1294-45272019-003609-84
• Study Type: interventional
• Target: 400
• Locations: 14 countries
• Sites: 55

Brief 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 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

Keywords

receptor tyrosine kinase inhibitor; programmed cell death 1 (PD-1, PD1); programmed cell death ligand 1 (PD-L1, PDL1)

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 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.

  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.

  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.

  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.

  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.

  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.

  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).

  Up to ~43 months

Secondary Outcomes (4)

• Efficacy Phase: Duration of response (DOR)

  Up to ~43 months

• Efficacy Phase: Progression-free survival (PFS)

  Up to ~43 months

• Efficacy Phase: Overall survival (OS)

  Up to ~43 months

• Efficacy Phase: Clinical benefit rate (CBR)

  Up to ~43 months

Study Arms (5)

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.

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.

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.

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.

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.

Drug: Belzutifan; Drug: Vibostolimab/Pembrolizumab

Interventions

Favezelimab/Pembrolizumab BIOLOGICAL

Administered via IV infusion at a dose of 800 mg/200 mg Q3W

Also known as: MK-4280A

Coformulation Favezelimab/Pembrolizumab+ Lenvatinib

Belzutifan DRUG

Administered via oral tablet at a dose of 120 mg QD

Also known as: MK-6482, WELIREG™

Coformulation Vibostolimab/Pembrolizumab+Belzutifan; Pembrolizumab + Belzutifan + Lenvatinib

Lenvatinib DRUG

Administered via oral capsule at a dose of 20 mg QD

Also known as: MK-7902, E7080, LENVIMA®

Coformulation Favezelimab/Pembrolizumab+ Lenvatinib; Coformulation Pembrolizumab/Quavonlimab + Lenvatinib; Pembrolizumab + Belzutifan + Lenvatinib; Pembrolizumab + Lenvatinib

Pembrolizumab/Quavonlimab BIOLOGICAL

Administered via IV infusion at a dose of 400 mg/25 mg Q6W

Also known as: MK-1308A

Coformulation Pembrolizumab/Quavonlimab + Lenvatinib

Vibostolimab/Pembrolizumab DRUG

Administered via IV infusion at a dose of 200 mg/200 mg Q6W

Also known as: MK-7684A

Coformulation Vibostolimab/Pembrolizumab+Belzutifan

Pembrolizumab BIOLOGICAL

Administered via IV infusion at a dose of 400 mg Q6W

Also known as: MK-3475, KEYTRUDA®

Pembrolizumab + Belzutifan + Lenvatinib; Pembrolizumab + Lenvatinib

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 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (55)

University of California at San Francisco ( Site 1008)

San Francisco, California, 94158, United States

Location

Yale-New Haven Hospital-Yale Cancer Center ( Site 1011)

New Haven, Connecticut, 06510, United States

Location

University of Chicago ( Site 1013)

Chicago, Illinois, 60637, United States

Location

University of Iowa ( Site 1012)

Iowa City, Iowa, 52242, United States

Location

Henry Ford Health System ( Site 1014)

Detroit, Michigan, 48202, United States

Location

Laura and Isaac Perlmutter Cancer Center ( Site 1016)

New York, New York, 10016, United States

Location

Memorial Sloan Kettering Cancer Center ( Site 1002)

New York, New York, 10065, United States

Location

Duke Cancer Institute ( Site 1015)

Durham, North Carolina, 27710, United States

Location

UPMC Cancer Center/Hillman Cancer Center ( Site 1017)

Pittsburgh, Pennsylvania, 15232, United States

Location

UTSW Medical Center ( Site 1003)

Dallas, Texas, 75390, United States

Location

Western Sydney Local Health District ( Site 1601)

Blacktown, New South Wales, 2148, Australia

Location

St George Hospital ( Site 1602)

Kogarah, New South Wales, 2217, Australia

Location

Royal Brisbane and Women s Hospital ( Site 1603)

Herston, Queensland, 4029, Australia

Location

Austin Health ( Site 1600)

Heidelberg, Victoria, 3084, Australia

Location

Princess Margaret Cancer Centre ( Site 1101)

Toronto, Ontario, M5G 1Z5, Canada

Location

Jewish General Hospital ( Site 1100)

Montreal, Quebec, H3T 1E2, Canada

Location

James Lind Centro de Investigación del Cáncer ( Site 2108)

Temuco, Araucania, 4800827, Chile

Location

CIDO SpA-Oncology ( Site 2106)

Temuco, Araucania, 4810148, Chile

Location

FALP-UIDO ( Site 2100)

Santiago, Region M. de Santiago, 7500921, Chile

Location

Oncovida ( Site 2107)

Santiago, Region M. de Santiago, 7510032, Chile

Location

Bradfordhill-Clinical Area ( Site 2101)

Santiago, Region M. de Santiago, 8420383, Chile

Location

ONCOCENTRO APYS-ACEREY ( Site 2103)

Viña del Mar, Valparaiso, 2520598, Chile

Location

Clinica Colsanitas S.A, Sede Clínica Universitaria Colombia-Center Investigator ( Site 1900)

Bogotá, Bogota D.C., 111321, Colombia

Location

Sociedad De Oncologia Y Hematologia Del Cesar-Oncology ( Site 1905)

Valledupar, Cesar Department, 200001, Colombia

Location

Oncomédica S.A.S ( Site 1904)

Montería, Departamento de Córdoba, 230002, Colombia

Location

Fundación Valle del Lili ( Site 1901)

Cali, Valle del Cauca Department, 760032, Colombia

Location

Institut De Cancerologie De Lorraine ( Site 1204)

Vandœuvre-lès-Nancy, Ain, 54519, France

Location

Institut de cancérologie Strasbourg Europe (ICANS) ( Site 1203)

Strasbourg, Alsace, 67200, France

Location

Institut Claudius Regaud ( Site 1200)

Toulouse, Haute-Garonne, 31059, France

Location

Gustave Roussy ( Site 1202)

Villejuif, Val-de-Marne, 94800, France

Location

Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 2301)

Budapest, Pest County, 1122, Hungary

Location

Rambam MC ( Site 1500)

Haifa, 3525408, Israel

Location

Hadassah Medical Center-Oncology ( Site 1504)

Jerusalem, 9112001, Israel

Location

Rabin Medical Center ( Site 1502)

Petah Tikva, 4941492, Israel

Location

Sheba Medical Center - Oncology Division ( Site 1501)

Ramat Gan, 52621, Israel

Location

Sourasky Medical Center ( Site 1503)

Tel Aviv, 6423906, Israel

Location

Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 2402)

Amsterdam, North Holland, 1066CX, Netherlands

Location

Erasmus Medisch Centrum ( Site 2401)

Rotterdam, South Holland, 3015 GD, Netherlands

Location

Auckland City Hospital ( Site 1700)

Auckland, 1023, New Zealand

Location

Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 2201)

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

Location

Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 2200

Warsaw, Masovian Voivodeship, 02-781, Poland

Location

Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 2202)

Gdansk, Pomeranian Voivodeship, 80-952, Poland

Location

Asan Medical Center ( Site 1800)

Songpagu, Seoul, 05505, South Korea

Location

Severance Hospital ( Site 1802)

Seoul, 03722, South Korea

Location

Samsung Medical Center ( Site 1801)

Seoul, 06351, South Korea

Location

Hospital Universitari Vall d Hebron ( Site 1300)

Barcelona, Catalonia, 08035, Spain

Location

Hospital Universitario Ramon y Cajal ( Site 1301)

Madrid, 28034, Spain

Location

Southampton General Hospital ( Site 1403)

Southampton, England, SO16 6YD, United Kingdom

Location

The Beatson West of Scotland Cancer Centre ( Site 1405)

Glasgow, Glasgow City, G12 0YN, United Kingdom

Location

Royal Preston Hospital ( Site 1406)

Preston, Lancashire, PR2 9HT, United Kingdom

Location

Leicester Royal Infirmary ( Site 1408)

Leicester, Leicestershire, LE1 5WW, United Kingdom

Location

Barts Health NHS Trust ( Site 1401)

London, London, City of, EC1A 7BE, United Kingdom

Location

Western General Hospital ( Site 1402)

Edinburgh, Midlothian, EH4 2XU, United Kingdom

Location

Velindre Cancer Centre Hospital ( Site 1407)

Cardiff, Wales, CF14 2TL, United Kingdom

Location

The Christie NHS Foundation Trust ( Site 1400)

Manchester, M20 4BX, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 41115468 RESULT

Related Links

• Merck Oncology Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Carcinoma, Renal Cell; Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab; belzutifan; lenvatinib

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 10, 2020
• First Posted: November 12, 2020
• Study Start: December 16, 2020
• Primary Completion (Estimated): July 17, 2026
• Study Completion (Estimated): July 17, 2026
• Last Updated: May 6, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

IL (5); ES (2); GB (8); US (10); AU (4); NL (2); FR (4); NZ (1); HU (1); CA (2); CO (4); PL (3); KR (3); CL (6)