Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B)

A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (U03): Substudy 03B

Substudy 03B 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 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Renal Cell
• Intervention / Treatment: Drug: Lenvatinib; Biological: Pembrolizumab/Quavonlimab; Biological: Favezelimab/Pembrolizumab; Drug: Belzutifan; Biological: Pembrolizumab; Biological: MK-4830

• Study Type: Interventional
• Enrollment (Estimated): 370
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Toll Free Number; Phone Number: 1-888-577-8839; Email: Trialsites@merck.com

Study Locations

• Australia
  • New South Wales
    • Blacktown, New South Wales, Australia, 2148
      • Western Sydney Local Health District ( Site 3601)
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital ( Site 3602)
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane and Women s Hospital ( Site 3603)
  • Victoria
    • Melbourne, Victoria, Australia, 3084
      • Austin Health ( Site 3600)
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1Z5
      • Princess Margaret Cancer Centre ( Site 3101)
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital ( Site 3100)
• Chile
  • Araucania
    • Temuco, Araucania, Chile, 4800827
      • James Lind Centro de Investigación del Cáncer ( Site 4108)
    • Temuco, Araucania, Chile, 4810148
      • CIDO SpA-Oncology ( Site 4106)
  • Region M. De Santiago
    • Santiago, Region M. De Santiago, Chile, 7500921
      • FALP-UIDO ( Site 4100)
    • Santiago, Region M. De Santiago, Chile, 8420383
      • Bradfordhill-Clinical Area ( Site 4101)
  • Valparaiso
    • Viña del Mar, Valparaiso, Chile, 2520598
      • ONCOCENTRO APYS-ACEREY ( Site 4103)
• France
  • Ain
    • Vandoeuvre les Nancy, Ain, France, 54519
      • Institut De Cancerologie De Lorraine ( Site 3204)
  • Alsace
    • Strasbourg, Alsace, France, 67033
      • Institut de cancérologie Strasbourg Europe (ICANS) ( Site 3203)
  • Haute-Garonne
    • Toulouse Cedex 9, Haute-Garonne, France, 31059
      • Institut Claudius Regaud ( Site 3200)
  • Val-de-Marne
    • Villejuif, Val-de-Marne, France, 94800
      • Gustave Roussy ( Site 3202)
• Hungary
  • Pest
    • Budapest, Pest, Hungary, 1122
      • Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 4301)
• Israel
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus-Oncology Division ( Site 3500)
  • Jerusalem, Israel, 9112001
    • Hadassah Medical Center-Oncology ( Site 3504)
  • Petah Tiqwa, Israel, 4941492
    • Rabin Medical Center ( Site 3502)
  • Ramat Gan, Israel, 52621
    • Sheba Medical Center - Oncology Division ( Site 3501)
  • Tel Aviv, Israel, 6423906
    • Sourasky Medical Center ( Site 3503)
• Korea, Republic of
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital ( Site 3802)
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center ( Site 3801)
  • Seoul
    • Songpagu, Seoul, Korea, Republic of, 05505
      • Asan Medical Center ( Site 3800)
• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1066 CX
      • Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 4402)
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
      • Erasmus Medisch Centrum ( Site 4401)
• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland City Hospital ( Site 3700)
• Poland
  • Kujawsko-pomorskie
    • Bydgoszcz, Kujawsko-pomorskie, Poland, 85-796
      • Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 4201)
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-781
      • Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 4200
  • Pomorskie
    • Gdańsk, Pomorskie, Poland, 80-952
      • Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 4202)
• Spain
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal ( Site 3301)
  • Cataluna
    • Barcelona, Cataluna, Spain, 08035
      • Hospital Universitari Vall d Hebron ( Site 3300)
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation Trust ( Site 3400)
  • England
    • Southampton, England, United Kingdom, SO16 6YD
      • Southampton General Hospital ( Site 3403)
  • Glasgow City
    • Glasgow, Glasgow City, United Kingdom, G12 0YN
      • The Beatson West of Scotland Cancer Centre ( Site 3405)
  • Lancashire
    • Preston, Lancashire, United Kingdom, PR2 9HT
      • Royal Preston Hospital ( Site 3406)
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary ( Site 3408)
  • London, City Of
    • London, London, City Of, United Kingdom, EC1A 7BE
      • Barts Health NHS Trust ( Site 3401)
  • Midlothian
    • Edinburgh, Midlothian, United Kingdom, EH42XU
      • Western General Hospital ( Site 3402)
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 2TL
      • Velindre Cancer Centre Hospital ( Site 3407)
• United States
  • California
    • San Francisco, California, United States, 94158
      • University of California at San Francisco ( Site 3008)
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale-New Haven Hospital-Yale Cancer Center ( Site 3011)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago ( Site 3013)
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa ( Site 3012)
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System ( Site 3014)
  • New York
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center ( Site 3016)
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center ( Site 3002)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute ( Site 3015)
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Center/Hillman Cancer Center ( Site 3017)
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center ( Site 3004)
  • Texas
    • Dallas, Texas, United States, 75390-7208
      • UTSW Medical Center ( Site 3003)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has a histologically confirmed diagnosis of locally advanced/metastatic ccRCC
• Has experienced disease progression on or after having received systemic. treatment for locally advanced or metastatic RCC with a 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 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 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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Biological: Pembrolizumab/Quavonlimab; Administered via IV infusion at a dose of 400 mg/25 mg Q6W; Other Names: MK-1308A
Experimental: 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).	Biological: Favezelimab/Pembrolizumab; Administered via IV infusion at a dose of 800 mg/200 mg Q3W; Other Names: MK-4280A
Experimental: 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).	Biological: Pembrolizumab; Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W; Other Names: MK-3475; KEYTRUDA®; Biological: MK-4830; Administered via IV infusion at a dose of 800 mg Q3W
Experimental: 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.	Drug: Belzutifan; Administered via oral tablet at a dose of 120 mg QD; Other Names: MK-6482; WELIREG™; Biological: Pembrolizumab; Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W; Other Names: MK-3475; KEYTRUDA®
Experimental: 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.	Drug: Lenvatinib; Administered via oral capsule at a dose of 20 mg QD; Other Names: E7080; MK-7902; LENVIMA®; Drug: Belzutifan; Administered via oral tablet at a dose of 120 mg QD; Other Names: MK-6482; WELIREG™
Experimental: 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.	Drug: Lenvatinib; Administered via oral capsule at a dose of 20 mg QD; Other Names: E7080; MK-7902; LENVIMA®; Biological: Pembrolizumab; Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W; Other Names: MK-3475; KEYTRUDA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 experienced 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 ~56 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 ~56 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 ~56 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to ~56 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.	Up to ~56 months
Efficacy Phase: Overall survival (OS)	OS is defined as the time from randomization to death due to any cause.	Up to ~56 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.	Up to ~56 months

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2020
• Primary Completion (Estimated): September 7, 2025
• Study Completion (Estimated): September 7, 2025

Study Registration Dates

• First Submitted: November 10, 2020
• First Submitted That Met QC Criteria: November 10, 2020
• First Posted (Actual): November 12, 2020

Study Record Updates

• Last Update Posted (Actual): January 26, 2024
• Last Update Submitted That Met QC Criteria: January 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: receptor tyrosine kinase inhibitor; programmed cell death 1 (PD-1, PD1); programmed cell death ligand 1 (PD-L1, PDL1)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Pembrolizumab; Lenvatinib; Belzutifan
• Other Study ID Numbers: 3475-03B; MK-3475-03B (Other Identifier: Merck); 2019-003610-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No