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)
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)
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
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
Kidney (Renal Cell)
Phase I/II
Adults
Mol. targeted/Immunotherapy/Biologics
Belzutifan,
Zanzalintinib
Rini, Brian
International
Vanderbilt University
05-19-2026
Eligibility
18 Years to 120 Years
ALL
false
Inclusion 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
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
