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

Carcinoma, Renal Cell Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04626479
• Other study ID #: 3475-03A
• Secondary ID: MK-3475-03A2023-
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: December 16, 2020
• Est. completion date: May 31, 2026

Study information

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

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 400
• Est. completion date: May 31, 2026
• Est. primary completion date: May 31, 2026
• 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 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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell

Intervention

Biological:
• Pembrolizumab
Administered via IV infusion at a dose of 400 mg Q6W
• Favezelimab/Pembrolizumab
Administered via IV infusion at a dose of 800 mg/200 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

Drug:
• Vibostolimab/Pembrolizumab
Administered via IV infusion at a dose of 200 mg/200 mg Q6W

Locations

Country	Name	City	State
Australia	Western Sydney Local Health District ( Site 1601)	Blacktown	New South Wales
Australia	Austin Health ( Site 1600)	Heidelberg	Victoria
Australia	Royal Brisbane and Women s Hospital ( Site 1603)	Herston	Queensland
Australia	St George Hospital ( Site 1602)	Kogarah	New South Wales
Canada	Jewish General Hospital ( Site 1100)	Montreal	Quebec
Canada	Princess Margaret Cancer Centre ( Site 1101)	Toronto	Ontario
Chile	Bradfordhill-Clinical Area ( Site 2101)	Santiago	Region M. De Santiago
Chile	FALP-UIDO ( Site 2100)	Santiago	Region M. De Santiago
Chile	Oncovida ( Site 2107)	Santiago	Region M. De Santiago
Chile	CIDO SpA-Oncology ( Site 2106)	Temuco	Araucania
Chile	James Lind Centro de Investigación del Cáncer ( Site 2108)	Temuco	Araucania
Chile	ONCOCENTRO APYS-ACEREY ( Site 2103)	Viña del Mar	Valparaiso
Colombia	Clinica Colsanitas S.A, Sede Clínica Universitaria Colombia-Center Investigator ( Site 1900)	Bogota	Distrito Capital De Bogota
Colombia	Fundación Valle del Lili ( Site 1901)	Cali	Valle Del Cauca
Colombia	Oncomédica S.A.S ( Site 1904)	Montería	Cordoba
Colombia	Sociedad De Oncologia Y Hematologia Del Cesar-Oncology ( Site 1905)	Valledupar	Cesar
France	Institut de cancérologie Strasbourg Europe (ICANS) ( Site 1203)	Strasbourg	Alsace
France	Institut Claudius Regaud ( Site 1200)	Toulouse Cedex 9	Haute-Garonne
France	Institut De Cancerologie De Lorraine ( Site 1204)	Vandoeuvre les Nancy	Ain
France	Gustave Roussy ( Site 1202)	Villejuif	Val-de-Marne
Hungary	Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 2301)	Budapest	Pest
Israel	Rambam MC ( Site 1500)	Haifa
Israel	Hadassah Medical Center-Oncology ( Site 1504)	Jerusalem
Israel	Rabin Medical Center ( Site 1502)	Petah Tiqwa
Israel	Sheba Medical Center - Oncology Division ( Site 1501)	Ramat Gan
Israel	Sourasky Medical Center ( Site 1503)	Tel Aviv
Korea, Republic of	Samsung Medical Center ( Site 1801)	Seoul
Korea, Republic of	Severance Hospital ( Site 1802)	Seoul
Korea, Republic of	Asan Medical Center ( Site 1800)	Songpagu	Seoul
Netherlands	Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 2402)	Amsterdam	Noord-Holland
Netherlands	Erasmus Medisch Centrum ( Site 2401)	Rotterdam	Zuid-Holland
New Zealand	Auckland City Hospital ( Site 1700)	Auckland
Poland	Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 2201)	Bydgoszcz	Kujawsko-pomorskie
Poland	Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 2202)	Gdansk	Pomorskie
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 2200	Warszawa	Mazowieckie
Spain	Hospital Universitari Vall d Hebron ( Site 1300)	Barcelona	Cataluna
Spain	Hospital Universitario Ramon y Cajal ( Site 1301)	Madrid
United Kingdom	Velindre Cancer Centre Hospital ( Site 1407)	Cardiff	Wales
United Kingdom	Western General Hospital ( Site 1402)	Edinburgh	Midlothian
United Kingdom	The Beatson West of Scotland Cancer Centre ( Site 1405)	Glasgow	Glasgow City
United Kingdom	Leicester Royal Infirmary ( Site 1408)	Leicester	Leicestershire
United Kingdom	Barts Health NHS Trust ( Site 1401)	London	London, City Of
United Kingdom	The Christie NHS Foundation Trust ( Site 1400)	Manchester
United Kingdom	Royal Preston Hospital ( Site 1406)	Preston	Lancashire
United Kingdom	Southampton General Hospital ( Site 1403)	Southampton	England
United States	University of Chicago ( Site 1013)	Chicago	Illinois
United States	UTSW Medical Center ( Site 1003)	Dallas	Texas
United States	Henry Ford Health System ( Site 1014)	Detroit	Michigan
United States	Duke Cancer Institute ( Site 1015)	Durham	North Carolina
United States	University of Iowa ( Site 1012)	Iowa City	Iowa
United States	Yale-New Haven Hospital-Yale Cancer Center ( Site 1011)	New Haven	Connecticut
United States	Laura and Isaac Perlmutter Cancer Center ( Site 1016)	New York	New York
United States	Memorial Sloan Kettering Cancer Center ( Site 1002)	New York	New York
United States	UPMC Cancer Center/Hillman Cancer Center ( Site 1017)	Pittsburgh	Pennsylvania
United States	University of California at San Francisco ( Site 1008)	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Chile,  Colombia,  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 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
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 ~43 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 ~43 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 ~43 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 ~43 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 ~43 months
Secondary	Efficacy Phase: Overall survival (OS)	OS is defined as the time from randomization to death due to any cause.	Up to ~43 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 ~43 months

External Links

•   Merck Oncology Clinical Trials Information
•   Plain Language Summary