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)

Merck Sharp & Dohme (MSD)

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Renal Cell Carcinoma

Treatments: Drug: Zanzalintinib; Drug: Belzutifan

Study type: Interventional

Funder types: Industry

Identifiers

NCT07049926

U1111-1310-6076 (Registry Identifier)

MK-3475-03C (Other Identifier)

KEYMAKER-U03 (Other Identifier)

2024-516437-12-00 (Registry Identifier)

3475-03C

Details and patient eligibility

About

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

Enrollment: 140 estimated patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

The main inclusion criteria include but are not limited to the following:

• Has a histologically confirmed diagnosis of unresectable locally advanced/metastatic renal cell carcinoma (RCC) with clear cell component
• Has received no other prior systemic therapy for treatment of advanced/metastatic clear cell renal cell carcinoma (ccRCC) except for adjuvant programmed cell death ligand 1 (PD-(L)1) therapy
• Has disease recurrence during adjuvant anti- PD-(L)1 therapy or ≤24 months following the last dose of adjuvant anti-PD-(L)1 therapy
• Is able to swallow oral medication
• Submits an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Participants receiving bone resorptive therapy (must have therapy initiated at least 2 weeks before allocation/randomization)
• Has adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤140/90 mm Hg with no change in antihypertensive medications within 1 week before allocation/randomization
• Has adequate organ function

The main exclusion criteria include but are not limited to the following:

• Has clinically significant hematuria, hematemesis, or hemoptysis of (>2.5 mL) of red blood, or other history of significant bleeding
• Has clinically significant cardiovascular disease within 12 months from first dose of study intervention
• Has deep vein thrombosis within 3 months before allocation/randomization unless stable, asymptomatic, and treated with therapeutic anticoagulation for at least 4 weeks before allocation/randomization
• Has history of idiopathic pulmonary fibrosis, organizing pneumonia, or evidence of active pneumonitis
• Has serious wound, ulcer or bone fracture or has had major surgery within 8 weeks before first dose of study intervention
• Has symptomatic pleural effusion (for example cough, dyspnea, pleuritic chest pain), ascites, or pericardial fluid requiring drainage in the last 4 weeks before allocation/randomization
• Has gastrointestinal (GI) disorders, including those associated with a high risk of perforation or fistula formation
• Has malabsorption due to prior GI surgery or GI disease
• Has moderate to severe hepatic impairment
• Has received colony-stimulating factors within 28 days prior to intervention allocation/randomization
• Has received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids
• Is currently receiving strong inhibitors of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for the duration of the study
• Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention
• Is currently receiving anticoagulants or platelet inhibitors that cannot be discontinued for the duration of the study
• Have been previously allocated/randomized to study intervention in any sub study of protocol MK-3475-U03
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
• Has active autoimmune disease that has required systemic treatment in the past 2 years
• Has an active infection requiring systemic therapy
• Has history of human immunodeficiency virus (HIV) infection
• Has hepatitis B or hepatitis C virus infection

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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140 participants in 2 patient groups

Zanzalintinib at Dose Level 1 or 2 + Belzutifan

Experimental group

Description:

Participants will be allocated to receive zanzalintinib at dose level 1 or 2 + belzutifan daily until progressive disease or discontinuation

Treatment:

Drug: Belzutifan

Drug: Zanzalintinib

Belzutifan

Experimental group

Description:

Participants will receive belzutifan daily until progressive disease or discontinuation

Treatment:

Drug: Belzutifan