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

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04626479

Collaborator

(none)

400

Enrollment

Locations

Arms

62.9

Anticipated Duration (Months)

11.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Renal Cell	Biological: Pembrolizumab Biological: Favezelimab/Pembrolizumab Drug: Belzutifan Drug: Lenvatinib Biological: Pembrolizumab/Quavonlimab Drug: Vibostolimab/Pembrolizumab	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

400 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 16, 2020

Anticipated Primary Completion Date :

Mar 16, 2026

Anticipated Study Completion Date :

Mar 16, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib 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 Administered via oral capsule at a dose of 20 mg QD Other Names: MK-7902 E7080 LENVIMA® Biological: Pembrolizumab/Quavonlimab Administered via IV infusion at a dose of 400 mg/25 mg Q6W Other Names: MK-1308A
Experimental: Coformulation Favezelimab/Pembrolizumab+ Lenvatinib 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 Administered via IV infusion at a dose of 800 mg/200 mg Q3W Other Names: MK-4280A Drug: Lenvatinib Administered via oral capsule at a dose of 20 mg QD Other Names: MK-7902 E7080 LENVIMA®
Experimental: Pembrolizumab + Belzutifan + Lenvatinib 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 Administered via IV infusion at a dose of 400 mg Q6W Other Names: MK-3475 KEYTRUDA® Drug: Belzutifan Administered via oral tablet at a dose of 120 mg QD Other Names: MK-6482 WELIREG™ Drug: Lenvatinib Administered via oral capsule at a dose of 20 mg QD Other Names: MK-7902 E7080 LENVIMA®
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.	Biological: Pembrolizumab Administered via IV infusion at a dose of 400 mg Q6W Other Names: MK-3475 KEYTRUDA® Drug: Lenvatinib Administered via oral capsule at a dose of 20 mg QD Other Names: MK-7902 E7080 LENVIMA®
Experimental: Coformulation Vibostolimab/Pembrolizumab+Belzutifan 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 Administered via oral tablet at a dose of 120 mg QD Other Names: MK-6482 WELIREG™ Drug: Vibostolimab/Pembrolizumab Administered via IV infusion at a dose of 200 mg/200 mg Q6W Other Names: MK-7684A

Outcome Measures

Primary Outcome Measures

Safety Lead-in Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs) [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) [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 [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 [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 [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 [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) [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).

Secondary Outcome Measures

Efficacy Phase: Duration of response (DOR) [Up to ~43 months]
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.
Efficacy Phase: Progression-free survival (PFS) [Up to ~43 months]
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.
Efficacy Phase: Overall survival (OS) [Up to ~43 months]
OS is defined as the time from randomization to death due to any cause.
Efficacy Phase: Clinical benefit rate (CBR) [Up to ~43 months]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago ( Site 1013)	Chicago	Illinois	United States	60637
2	Henry Ford Health System ( Site 1014)	Detroit	Michigan	United States	48202
3	Laura and Isaac Perlmutter Cancer Center ( Site 1016)	New York	New York	United States	10016
4	Memorial Sloan Kettering Cancer Center ( Site 1002)	New York	New York	United States	10065
5	Duke Cancer Institute ( Site 1015)	Durham	North Carolina	United States	27710
6	UPMC Cancer Center/Hillman Cancer Center ( Site 1017)	Pittsburgh	Pennsylvania	United States	15232
7	UTSW Medical Center ( Site 1003)	Dallas	Texas	United States	75390
8	Western Sydney Local Health District ( Site 1601)	Blacktown	New South Wales	Australia	2148
9	St George Hospital ( Site 1602)	Kogarah	New South Wales	Australia	2217
10	Royal Brisbane and Women s Hospital ( Site 1603)	Herston	Queensland	Australia	4029
11	Austin Health ( Site 1600)	Heidelberg	Victoria	Australia	3084
12	Princess Margaret Cancer Centre ( Site 1101)	Toronto	Ontario	Canada	M5G 1Z5
13	Jewish General Hospital ( Site 1100)	Montreal	Quebec	Canada	H3T 1E2
14	Institut De Cancerologie De Lorraine ( Site 1204)	Vandoeuvre les Nancy	Ain	France	54519
15	Institut de cancérologie Strasbourg Europe (ICANS) ( Site 1203)	Strasbourg	Alsace	France	67033
16	Institut Claudius Regaud ( Site 1200)	Toulouse Cedex 9	Haute-Garonne	France	31059
17	Gustave Roussy ( Site 1202)	Villejuif	Val-de-Marne	France	94800
18	Rambam MC ( Site 1500)	Haifa		Israel	3525408
19	Hadassah Medical Center-Oncology ( Site 1504)	Jerusalem		Israel	9112001
20	Rabin Medical Center ( Site 1502)	Petah Tiqwa		Israel	4941492
21	Sheba Medical Center - Oncology Division ( Site 1501)	Ramat Gan		Israel	52621
22	Sourasky Medical Center ( Site 1503)	Tel Aviv		Israel	6423906
23	Asan Medical Center ( Site 1800)	Songpagu	Seoul	Korea, Republic of	05505
24	Severance Hospital ( Site 1802)	Seoul		Korea, Republic of	03722
25	Samsung Medical Center ( Site 1801)	Seoul		Korea, Republic of	06351
26	Auckland City Hospital ( Site 1700)	Auckland		New Zealand	1023
27	Hospital Universitari Vall d Hebron ( Site 1300)	Barcelona	Cataluna	Spain	08035
28	Hospital Universitario Ramon y Cajal ( Site 1301)	Madrid		Spain	28034
29	Western General Hospital ( Site 1402)	Edinburgh	Edinburgh, City Of	United Kingdom	EH4 2XU
30	Southampton General Hospital ( Site 1403)	Southampton	Hampshire	United Kingdom	SO16 6YD
31	Royal Preston Hospital ( Site 1406)	Preston	Lancashire	United Kingdom	PR2 9HT
32	Leicester Royal Infirmary ( Site 1408)	Leicester	Leicestershire	United Kingdom	LE1 5WW
33	Barts Health NHS Trust ( Site 1401)	London	London, City Of	United Kingdom	EC1A 7BE
34	The Christie NHS Foundation Trust ( Site 1400)	Manchester		United Kingdom	M20 4BX