A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (KEYMAKER-U03): Substudy 03C in Participants With Recurrent Disease During or After Anti-PD-(L)1 Adjuvant Therapy
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 140
- Locations
- 43
- Primary Endpoint
- Safety Lead In Phase: Number of participants who experience one or more adverse events (AEs)
Study Overview
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
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Single (Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to 120 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
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
Arms & Interventions
Zanzalintinib at Dose Level 1 or 2 + Belzutifan
Participants will be allocated to receive zanzalintinib at dose level 1 or 2 + belzutifan daily until progressive disease or discontinuation
Intervention: Belzutifan (Drug)
Zanzalintinib at Dose Level 1 or 2 + Belzutifan
Participants will be allocated to receive zanzalintinib at dose level 1 or 2 + belzutifan daily until progressive disease or discontinuation
Intervention: Zanzalintinib (Drug)
Belzutifan
Participants will receive belzutifan daily until progressive disease or discontinuation
Intervention: Belzutifan (Drug)
Outcomes
Primary Outcomes
Safety Lead In Phase: Number of participants who experience one or more adverse events (AEs)
Time Frame: 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 dose-limiting toxicities (DLTs)
Time Frame: 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)
Time Frame: 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.
Safety Lead In Phase: Number of participants who discontinue study treatment due to an AE
Time Frame: 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
Time Frame: 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
Time Frame: 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 AEs
Time Frame: 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 Outcomes
- Efficacy Phase: Duration of response (DOR)(Up to approximately 74 months)
- Efficacy Phase: Clinical benefit rate (CBR)(Up to approximately 74 months)
- Efficacy Phase: Progression-free survival (PFS)(Up to approximately 74 months)
- Efficacy Phase: Overall survival (OS)(Up to approximately 74 months)