Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B/KEYMAKER-U03)
- Conditions
- Carcinoma, Renal Cell
- Interventions
- Registration Number
- NCT04626518
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 370
- Has a histologically confirmed diagnosis of locally advanced/metastatic clear cell renal cell carcinoma (ccRCC)
- Has experienced disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with a programmed cell death ligand 1 (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 Response Evaluation Criteria in Solid Tumors version 1.1 (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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Coformulation Favezelimab/Pembrolizumab 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). Pembrolizumab + MK-4830 Pembrolizumab 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). Coformulation Pembrolizumab/Quavonlimab 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). Pembrolizumab + MK-4830 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). Pembrolizumab + Belzutifan Pembrolizumab 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. Belzutifan + Lenvatinib Belzutifan Participants will receive Belzutifan 120 mg PLUS lenvatinib 20 mg. Both belzutifan and lenvatinib will be administered orally QD until progressive disease or discontinuation. Belzutifan + Lenvatinib 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. Pembrolizumab + Lenvatinib 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. Pembrolizumab + Lenvatinib Pembrolizumab 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. Pembrolizumab + Belzutifan 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.
- Primary Outcome Measures
Name Time Method 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.
Efficacy Phase: Number of participants who experience one or more AEs Up to ~56 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 ~56 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.
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 experienced 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: Objective response rate (ORR) Up to ~56 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
Name Time Method Efficacy Phase: Duration of response (DOR) Up to ~56 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.
Efficacy Phase: Progression-free survival (PFS) Up to ~56 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 ~56 months OS is defined as the time from randomization to death due to any cause.
Efficacy Phase: Clinical benefit rate (CBR) Up to ~56 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.
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Trial Locations
- Locations (51)
UTSW Medical Center ( Site 3003)
🇺🇸Dallas, Texas, United States
University of Chicago ( Site 3013)
🇺🇸Chicago, Illinois, United States
Yale-New Haven Hospital-Yale Cancer Center ( Site 3011)
🇺🇸New Haven, Connecticut, United States
University of California at San Francisco ( Site 3008)
🇺🇸San Francisco, California, United States
University of Iowa ( Site 3012)
🇺🇸Iowa City, Iowa, United States
Henry Ford Health System ( Site 3014)
🇺🇸Detroit, Michigan, United States
Laura and Isaac Perlmutter Cancer Center ( Site 3016)
🇺🇸New York, New York, United States
UPMC Cancer Center/Hillman Cancer Center ( Site 3017)
🇺🇸Pittsburgh, Pennsylvania, United States
Duke Cancer Institute ( Site 3015)
🇺🇸Durham, North Carolina, United States
Memorial Sloan Kettering Cancer Center ( Site 3002)
🇺🇸New York, New York, United States
Vanderbilt University Medical Center ( Site 3004)
🇺🇸Nashville, Tennessee, United States
Western Sydney Local Health District ( Site 3601)
🇦🇺Blacktown, New South Wales, Australia
St George Hospital ( Site 3602)
🇦🇺Kogarah, New South Wales, Australia
Royal Brisbane and Women s Hospital ( Site 3603)
🇦🇺Herston, Queensland, Australia
Bradfordhill-Clinical Area ( Site 4101)
🇨🇱Santiago, Region M. De Santiago, Chile
ONCOCENTRO APYS-ACEREY ( Site 4103)
🇨🇱Viña del Mar, Valparaiso, Chile
James Lind Centro de Investigación del Cáncer ( Site 4108)
🇨🇱Temuco, Araucania, Chile
CIDO SpA-Oncology ( Site 4106)
🇨🇱Temuco, Araucania, Chile
Institut de cancérologie Strasbourg Europe (ICANS) ( Site 3203)
🇫🇷Strasbourg, Alsace, France
Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 4301)
🇭🇺Budapest, Pest, Hungary
Gustave Roussy ( Site 3202)
🇫🇷Villejuif, Val-de-Marne, France
Samsung Medical Center ( Site 3801)
🇰🇷Seoul, Korea, Republic of
Sourasky Medical Center ( Site 3503)
🇮🇱Tel Aviv, Israel
Asan Medical Center ( Site 3800)
🇰🇷Songpagu, Seoul, Korea, Republic of
Auckland City Hospital ( Site 3700)
🇳🇿Auckland, New Zealand
Hospital Universitario Ramon y Cajal ( Site 3301)
🇪🇸Madrid, Spain
Hospital Universitari Vall d Hebron ( Site 3300)
🇪🇸Barcelona, Cataluna, Spain
The Beatson West of Scotland Cancer Centre ( Site 3405)
🇬🇧Glasgow, Glasgow City, United Kingdom
Royal Preston Hospital ( Site 3406)
🇬🇧Preston, Lancashire, United Kingdom
Barts Health NHS Trust ( Site 3401)
🇬🇧London, London, City Of, United Kingdom
Western General Hospital ( Site 3402)
🇬🇧Edinburgh, Midlothian, United Kingdom
Velindre Cancer Centre Hospital ( Site 3407)
🇬🇧Cardiff, Wales, United Kingdom
The Christie NHS Foundation Trust ( Site 3400)
🇬🇧Manchester, United Kingdom
Jewish General Hospital ( Site 3100)
🇨🇦Montreal, Quebec, Canada
Institut De Cancerologie De Lorraine ( Site 3204)
🇫🇷Vandoeuvre les Nancy, Ain, France
Hadassah Medical Center-Oncology ( Site 3504)
🇮🇱Jerusalem, Israel
FALP-UIDO ( Site 4100)
🇨🇱Santiago, Region M. De Santiago, Chile
Sheba Medical Center - Oncology Division ( Site 3501)
🇮🇱Ramat Gan, Israel
Rabin Medical Center ( Site 3502)
🇮🇱Petah Tiqwa, Israel
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 4200
🇵🇱Warszawa, Mazowieckie, Poland
Leicester Royal Infirmary ( Site 3408)
🇬🇧Leicester, Leicestershire, United Kingdom
Institut Claudius Regaud ( Site 3200)
🇫🇷Toulouse Cedex 9, Haute-Garonne, France
Erasmus Medisch Centrum ( Site 4401)
🇳🇱Rotterdam, Zuid-Holland, Netherlands
Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 4202)
🇵🇱Gdańsk, Pomorskie, Poland
Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 4402)
🇳🇱Amsterdam, Noord-Holland, Netherlands
Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 4201)
🇵🇱Bydgoszcz, Kujawsko-pomorskie, Poland
Rambam Health Care Campus-Oncology Division ( Site 3500)
🇮🇱Haifa, Israel
Princess Margaret Cancer Centre ( Site 3101)
🇨🇦Toronto, Ontario, Canada
Severance Hospital ( Site 3802)
🇰🇷Seoul, Korea, Republic of
Austin Health ( Site 3600)
🇦🇺Melbourne, Victoria, Australia
Southampton General Hospital ( Site 3403)
🇬🇧Southampton, England, United Kingdom