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

Study Overview
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Brief Summary
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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.

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

Conditions
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Carcinoma, Renal Cell

Intervention / Treatment
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* Biological: Pembrolizumab
* Biological: MK-4830
* Drug: Belzutifan
* Drug: Lenvatinib
* Biological: Pembrolizumab/Quavonlimab
* Biological: Favezelimab/Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Coformulation Pembrolizumab/Quavonlimab<br>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<br>* Administered via IV infusion at a dose of 400 mg/25 mg Q6W<br>* Other names: MK-1308A;|
| Experimental: Coformulation Favezelimab/Pembrolizumab<br>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<br>* Administered via IV infusion at a dose of 800 mg/200 mg Q3W<br>* Other names: MK-4280A;|
| Experimental: Pembrolizumab + MK-4830<br>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<br>* Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W<br>* Other names: KEYTRUDA®;Biological: MK-4830<br>* Administered via IV infusion at a dose of 800 mg Q3W<br>|
| Experimental: Pembrolizumab + Belzutifan<br>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. | Biological: Pembrolizumab<br>* Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W<br>* Other names: KEYTRUDA®;Drug: Belzutifan<br>* Administered via oral tablet at a dose of 120 mg QD<br>* Other names: WELIREG™;|
| Experimental: Belzutifan + Lenvatinib<br>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: Belzutifan<br>* Administered via oral tablet at a dose of 120 mg QD<br>* Other names: WELIREG™;Drug: Lenvatinib<br>* Administered via oral capsule at a dose of 20 mg QD<br>* Other names: LENVIMA®;|
| Experimental: Pembrolizumab + Lenvatinib<br>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<br>* Administered via IV infusion at a dose of 200 mg Q3W or 400 mg Q6W<br>* Other names: KEYTRUDA®;Drug: Lenvatinib<br>* Administered via oral capsule at a dose of 20 mg QD<br>* Other names: LENVIMA®;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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receptor tyrosine kinase inhibitor, programmed cell death 1 (PD-1, PD1), programmed cell death ligand 1 (PD-L1, PDL1)