Substudy 03C: A Study of Combination Therapies in Participants With Renal Cell Carcinoma With Recurrent Disease During or After Anti-PD-(L)1 Therapy (MK-3475-03C/KEYMAKER-U03)

Not Applicable

Not yet recruiting

• Conditions: Renal Cell Carcinoma
• Interventions: Drug: Belzutifan; Drug: Zanzalintinib

• Registration Number: NCT07049926
• Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary

Substudy 03C 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 03C is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with clear cell renal cell carcinoma (ccRCC) who have recurrent disease during or after anti-programmed cell death 1/programmed cell death ligand 1 (PD-\[L\]1) adjuvant therapy.

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

Study Timeline

• Status Verified: 2025-06
• Study First Submitted: 2025-06-25
• Study First Submitted QC: 2025-06-25
• Last Update Submitted: 2025-06-25
• Study First Posted: 2025-07-03
• Last Update Posted: 2025-07-03
• Study Start: 2025-08-04
• Primary Completion: 2031-10-26
• Study Completion: 2031-10-26

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Zanzalintinib at Dose Level 1 + Belzutifan	Belzutifan	Participants will receive zanzalintinib at dose level 1 + belzutifan daily until progressive disease or discontinuation
Zanzalintinib at Dose Level 1 + Belzutifan	Zanzalintinib	Participants will receive zanzalintinib at dose level 1 + belzutifan daily until progressive disease or discontinuation
Zanzalintinib at Dose Level 2 + Belzutifan	Belzutifan	Participants will receive zanzalintinib at dose level 2 + belzutifan daily until progressive disease or discontinuation
Zanzalintinib at Dose Level 2 + Belzutifan	Zanzalintinib	Participants will receive zanzalintinib at dose level 2 + belzutifan daily 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 approximately 21 days	DLTs are defined as any of a pre-specified list of toxicities if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration, excluding toxicities clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc.
Efficacy Phase: Objective Response Rate (ORR)	Up to approximately 74 months	ORR is defined as the percentage of participants with 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) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.
Efficacy Phase: Number of participants who experience one or more AEs	Up to approximately 74 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Safety Lead In Phase: Number of participants who experience one or more adverse events (AEs)	Up to approximately 74 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Safety Lead In Phase: Number of participants who discontinue study treatment due to an AE	Up to approximately 74 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
Efficacy Phase: Number of participants who experience one or more DLTs	Up to approximately 21 days	DLTs are defined as any of a pre-specified list of toxicities if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration, excluding toxicities clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc.
Efficacy Phase: Number of participants who discontinue study treatment due to an AE	Up to approximately 74 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. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

Secondary Outcome Measures

Name	Time	Method
Efficacy Phase: Duration of response (DOR)	Up to approximately 74 months	For participants who demonstrate a confirmed CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.
Efficacy Phase: Clinical benefit rate (CBR)	Up to approximately 74 months	CBR is defined as the percentage of participants who have achieved stable disease (SD: Neither sufficient shrinkage to qualify for PR \[at least a 30% decrease in the sum of diameters of target lesions\] nor sufficient increase to qualify for PD) of ≥6 months or confirmed CR (disappearance of all target lesions) or PR per RECIST 1.1. PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. The CBR as assessed by BICR will be presented.
Efficacy Phase: Progression-free survival (PFS)	Up to approximately 74 months	PFS is defined as the time from first dose of study treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurs first as assessed by RECIST 1.1. PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by BICR will be presented.
Efficacy Phase: Overall survival (OS)	Up to approximately 74 months	OS is defined as time from first dose of study treatment to death due to any cause.