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

Carcinoma, Renal Cell Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04626518
• Other study ID #: 3475-03B
• Secondary ID: MK-3475-03B2019-
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: December 17, 2020
• Est. completion date: September 7, 2025

Study information

• Verified date: January 2024
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 370
• Est. completion date: September 7, 2025
• Est. primary completion date: September 7, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell

Intervention

Biological:
• 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

Drug:
• Belzutifan
Administered via oral tablet at a dose of 120 mg QD
• Lenvatinib
Administered via oral capsule at a dose of 20 mg QD

Biological:
• 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

Locations

Country	Name	City	State
Australia	Western Sydney Local Health District ( Site 3601)	Blacktown	New South Wales
Australia	Royal Brisbane and Women s Hospital ( Site 3603)	Herston	Queensland
Australia	St George Hospital ( Site 3602)	Kogarah	New South Wales
Australia	Austin Health ( Site 3600)	Melbourne	Victoria
Canada	Jewish General Hospital ( Site 3100)	Montreal	Quebec
Canada	Princess Margaret Cancer Centre ( Site 3101)	Toronto	Ontario
Chile	Bradfordhill-Clinical Area ( Site 4101)	Santiago	Region M. De Santiago
Chile	FALP-UIDO ( Site 4100)	Santiago	Region M. De Santiago
Chile	CIDO SpA-Oncology ( Site 4106)	Temuco	Araucania
Chile	James Lind Centro de Investigación del Cáncer ( Site 4108)	Temuco	Araucania
Chile	ONCOCENTRO APYS-ACEREY ( Site 4103)	Viña del Mar	Valparaiso
France	Institut de cancérologie Strasbourg Europe (ICANS) ( Site 3203)	Strasbourg	Alsace
France	Institut Claudius Regaud ( Site 3200)	Toulouse Cedex 9	Haute-Garonne
France	Institut De Cancerologie De Lorraine ( Site 3204)	Vandoeuvre les Nancy	Ain
France	Gustave Roussy ( Site 3202)	Villejuif	Val-de-Marne
Hungary	Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 4301)	Budapest	Pest
Israel	Rambam Health Care Campus-Oncology Division ( Site 3500)	Haifa
Israel	Hadassah Medical Center-Oncology ( Site 3504)	Jerusalem
Israel	Rabin Medical Center ( Site 3502)	Petah Tiqwa
Israel	Sheba Medical Center - Oncology Division ( Site 3501)	Ramat Gan
Israel	Sourasky Medical Center ( Site 3503)	Tel Aviv
Korea, Republic of	Samsung Medical Center ( Site 3801)	Seoul
Korea, Republic of	Severance Hospital ( Site 3802)	Seoul
Korea, Republic of	Asan Medical Center ( Site 3800)	Songpagu	Seoul
Netherlands	Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 4402)	Amsterdam	Noord-Holland
Netherlands	Erasmus Medisch Centrum ( Site 4401)	Rotterdam	Zuid-Holland
New Zealand	Auckland City Hospital ( Site 3700)	Auckland
Poland	Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 4201)	Bydgoszcz	Kujawsko-pomorskie
Poland	Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 4202)	Gdansk	Pomorskie
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 4200	Warszawa	Mazowieckie
Spain	Hospital Universitari Vall d Hebron ( Site 3300)	Barcelona	Cataluna
Spain	Hospital Universitario Ramon y Cajal ( Site 3301)	Madrid
United Kingdom	Velindre Cancer Centre Hospital ( Site 3407)	Cardiff	Wales
United Kingdom	Western General Hospital ( Site 3402)	Edinburgh	Midlothian
United Kingdom	The Beatson West of Scotland Cancer Centre ( Site 3405)	Glasgow	Glasgow City
United Kingdom	Leicester Royal Infirmary ( Site 3408)	Leicester	Leicestershire
United Kingdom	Barts Health NHS Trust ( Site 3401)	London	London, City Of
United Kingdom	The Christie NHS Foundation Trust ( Site 3400)	Manchester
United Kingdom	Royal Preston Hospital ( Site 3406)	Preston	Lancashire
United Kingdom	Southampton General Hospital ( Site 3403)	Southampton	England
United States	University of Chicago ( Site 3013)	Chicago	Illinois
United States	UTSW Medical Center ( Site 3003)	Dallas	Texas
United States	Henry Ford Health System ( Site 3014)	Detroit	Michigan
United States	Duke Cancer Institute ( Site 3015)	Durham	North Carolina
United States	University of Iowa ( Site 3012)	Iowa City	Iowa
United States	Vanderbilt University Medical Center ( Site 3004)	Nashville	Tennessee
United States	Yale-New Haven Hospital-Yale Cancer Center ( Site 3011)	New Haven	Connecticut
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	UPMC Cancer Center/Hillman Cancer Center ( Site 3017)	Pittsburgh	Pennsylvania
United States	University of California at San Francisco ( Site 3008)	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Chile,  France,  Hungary,  Israel,  Korea, Republic of,  Netherlands,  New Zealand,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	Efficacy Phase: Overall survival (OS)	OS is defined as the time from randomization to death due to any cause.	Up to ~56 months
Secondary	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

External Links

•   Merck Clinical Trials Information
•   Plain Language Summary