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)

Official title

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

Overview

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

Interventions

• Drug Belzutifan
  Oral Tablet
• Drug Zanzalintinib
  Oral Tablet

Primary outcome measures

• Safety Lead In Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs) [Time frame: Up to approximately 21 days]
• Safety Lead In Phase: Number of participants who experience one or more adverse events (AEs) [Time frame: Up to approximately 74 months]
• Safety Lead In Phase: Number of participants who discontinue study treatment due to an AE [Time frame: Up to approximately 74 months]
• Efficacy Phase: Number of participants who experience one or more DLTs [Time frame: Up to approximately 21 days]
• Efficacy Phase: Number of participants who experience one or more AEs [Time frame: Up to approximately 74 months]
• Efficacy Phase: Number of participants who discontinue study treatment due to an AE [Time frame: Up to approximately 74 months]
• Efficacy Phase: Objective Response Rate (ORR) [Time frame: Up to approximately 74 months]

Secondary outcome measures (4)

• Efficacy Phase: Duration of response (DOR) [Time frame: Up to approximately 74 months]
• Efficacy Phase: Progression-free survival (PFS) [Time frame: Up to approximately 74 months]
• Efficacy Phase: Overall survival (OS) [Time frame: Up to approximately 74 months]
• Efficacy Phase: Clinical benefit rate (CBR) [Time frame: Up to approximately 74 months]

Eligibility 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 7 centers

• UCSF Medical Center at Mission Bay ( Site 5008) — San Francisco
• Perlmutter Cancer Center at NYU Langone Hospital - Long Island ( Site 5026) — Mineola
• Laura and Isaac Perlmutter Cancer Center ( Site 5016) — New York
• Memorial Sloan Kettering Cancer Center ( Site 5002) — New York
• Duke Cancer Institute ( Site 5015) — Durham
• UPMC Cancer Center/Hillman Cancer Center ( Site 5017) — Pittsburgh
• Vanderbilt University Medical Center ( Site 5004) — Nashville

France · 5 centers

• C.H.U. de Strasbourg Hopital de Hautepierre ( Site 5203) — Strasbourg
• Institut Claudius Regaud ( Site 5200) — Toulouse
• Centre Eugene Marquis ( Site 5205) — Rennes
• Institut De Cancerologie De Lorraine ( Site 5204) — Vandœuvre-lès-Nancy
• Gustave Roussy ( Site 5202) — Villejuif

United Kingdom · 5 centers

• Western General Hospital ( Site 5402) — Edinburgh
• The Beatson West of Scotland Cancer Centre ( Site 5405) — Glasgow
• St Bartholomew's Hospital ( Site 5401) — London
• Velindre Cancer Centre ( Site 5407) — Cardiff
• The Christie NHS Foundation Trust ( Site 5400) — Manchester

Israel · 4 centers

• Rambam Health Care Campus ( Site 5500) — Haifa
• Rabin Medical Center ( Site 5502) — Petah Tikva
• Sheba Medical Center ( Site 5501) — Ramat Gan
• Sourasky Medical Center ( Site 5503) — Tel Aviv

South Korea · 3 centers

• Severance Hospital ( Site 5802) — Seoul
• Asan Medical Center ( Site 5800) — Seoul
• Samsung Medical Center ( Site 5801) — Seoul

Chile · 2 centers

• Centro de Estudios Clínicos SAGA ( Site 6110) — Santiago
• Bradfordhill ( Site 6101) — Santiago

Poland · 2 centers

• Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 6201) — Bydgoszcz
• Uniwersyteckie Centrum Kliniczne ( Site 6202) — Gdansk

Spain · 2 centers

• Hospital Universitario Ramon y Cajal ( Site 5301) — Madrid
• Hospital Universitari Vall d'Hebron ( Site 5300) — Barcelona

Identifiers

NCT: NCT07049926 · 3475-03C · MK-3475-03C · 2024-516437-12-00 · U1111-1310-6076 · KEYMAKER-U03

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗