Study of RAS(ON) Inhibitor Combinations in Patients with Advanced RAS-mutated NSCLC

Phase 1

Recruiting

• Conditions: Non-Small Cell Lung Cancer, NSCLC; KRAS, NRAS, HRAS-mutated NSCLC; KRAS G12C-mutated Solid Tumors, Lung Cancer; Lung Cancer Stage IV, Advanced Solid Tumor, Cancer; RAS G12D-mutated NSCLC
• Interventions: Drug: RMC-6291; Drug: RMC-6236; Drug: Pembrolizumab; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Drug: RMC-9805

• Registration Number: NCT06162221
• Lead Sponsor: Revolution Medicines, Inc.

Brief Summary

The purpose of this platform study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors combined with Standard(s) of Care (SOC) or with each other.

The first three subprotocols include the following:

Subprotocol A: RMC-6291 +/- RMC-6236 + SOC Subprotocol B: RMC-6236 + SOC Subprotocol C: RMC-9805 +/- RMC-6236 + SOC

Detailed Description

The platform study design allows combinations of RAS(ON) inhibitors with other anticancer agents to be evaluated in patients with RAS-mutated solid tumors with a focus on NSCLC.

This is an open-label platform Phase 1b/2 study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors combined with Standard of Care (SOC), and to define the Recommended Phase 2 Dose and Schedule (RP2DS). Enrollment of patients with KRAS or RAS mutations will be specified in each subprotocol.

Subprotocol A is an open-label, multicenter, Phase 1b/2 study of RMC-6291, with or without RMC-6236, in combination with pembrolizumab, with or without chemotherapy, in patients with KRAS G12C-mutated advanced solid tumors.

Subprotocol B is an open-label, multicenter, Phase1b/2 study of RMC-6236 in combination with pembrolizumab, with or without chemotherapy, in patients with RAS-mutated non-small cell lung cancer (NSCLC)

Subprotocol C is an open-label, multicenter, Phase1b/2 study of RMC-9805 with or without RMC-6236, in combination with other anticancer agents, in patients with RAS G12D-mutated non-small cell lung cancer (NSCLC)

Each subprotocol consists of two parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2023-11-30
• Study First Submitted QC: 2023-11-30
• Study First Posted: 2023-12-08
• Study Start: 2024-01-18
• Status Verified: 2024-05
• Last Update Submitted: 2025-01-03
• Last Update Posted: 2025-01-07
• Primary Completion: 2027-06
• Study Completion: 2028-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 484

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Subprotocol A: KRAS G12C-Mutated Solid Tumors	RMC-6291	RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol A: KRAS G12C-Mutated Solid Tumors	RMC-6236	RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol A: KRAS G12C-Mutated Solid Tumors	Pembrolizumab	RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol A: KRAS G12C-Mutated Solid Tumors	Cisplatin	RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol A: KRAS G12C-Mutated Solid Tumors	Carboplatin	RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol A: KRAS G12C-Mutated Solid Tumors	Pemetrexed	RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol B: RAS-mutated NSCLC	RMC-6236	RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol B: RAS-mutated NSCLC	Pembrolizumab	RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol B: RAS-mutated NSCLC	Cisplatin	RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol B: RAS-mutated NSCLC	Carboplatin	RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol B: RAS-mutated NSCLC	Pemetrexed	RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)
Subprotocol C: RAS G12D-mutated NSCLC	RMC-6236	RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).
Subprotocol C: RAS G12D-mutated NSCLC	Pembrolizumab	RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).
Subprotocol C: RAS G12D-mutated NSCLC	Cisplatin	RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).
Subprotocol C: RAS G12D-mutated NSCLC	Carboplatin	RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).
Subprotocol C: RAS G12D-mutated NSCLC	Pemetrexed	RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).
Subprotocol C: RAS G12D-mutated NSCLC	RMC-9805	RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).

Primary Outcome Measures

Name	Time	Method
Adverse events	Up to 5 years	Incidence and severity of treatment-emergent Adverse Events (AEs) and serious AEs and clinically significant changes in laboratory values, ECGs and vital signs
Dose limiting toxicities	21 days	Number of participants with dose limiting toxicities

Secondary Outcome Measures

Name	Time	Method
Drug concentrations over time	Up to 21 weeks
Cmax	Up to 21 weeks	Maximum observed blood concentration of each drug as applicable per subprotocol
Tmax	Up to 21 weeks	Time to reach maximum blood concentration of each drug as applicable per subprotocol
AUC	Up to 21 weeks	Area under the concentration-time curve of each drug as applicable per subprotocol
ORR	Up to 5 years	Objective Response Rate per RECIST v1.1
DOR	Up to 5 years	Duration of Response per RECIST v1.1

Trial Locations

Locations (49)

City of Hope - Duarte; 🇺🇸 Duarte, California, United States

New York University Langone Health; 🇺🇸 New York, New York, United States

IRCCS Instituto Nazionale tumori Ragina Elena; 🇮🇹 Rome, Italy

City of Hope - Lennar; 🇺🇸 Irvine, California, United States

UC Davis, Davis Comprehensive Cancer Center; 🇺🇸 Sacramento, California, United States

UCSF Medical Center - Mission Bay; 🇺🇸 San Francisco, California, United States

Stanford University; 🇺🇸 Stanford, California, United States

Georgetown University Medical Center; 🇺🇸 Washington, District of Columbia, United States

Boca Raton Clinical Research Associates; 🇺🇸 Plantation, Florida, United States

Cancer Specialists of North Florida; 🇺🇸 St Augustine, Florida, United States

Henry Ford Cancer - Detroit (Brigitte Harris Cancer Pavilion); 🇺🇸 Detroit, Michigan, United States

Intermountain Health - St. Vincent Frontier Cancer Center; 🇺🇸 Billings, Montana, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

Clinical Research Alliance; 🇺🇸 Westbury, New York, United States

University Hospitals Cleveland Medical Center; 🇺🇸 Cleveland, Ohio, United States

Hillman Cancer Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

NEXT Oncology Dallas; 🇺🇸 Irving, Texas, United States

NEXT Oncology Virginia; 🇺🇸 Fairfax, Virginia, United States

Hospices Civils de Lyon - Hôpital Louis Pradel; 🇫🇷 Bron, Auvergne-Rhône-Alpes, France

Centre Georges François Leclerc; 🇫🇷 Dijon, Bourgogne-Franche-Comté, France

CHU de Lille Institut Cœur Poumon; 🇫🇷 Lille, Hauts-de-France, France

CHU de Nantes; 🇫🇷 Nantes, Hauts-de-France, France

EDOG - Institut Bergonié; 🇫🇷 Bordeaux, Nouvelle-Aquitaine, France

Centre François Baclesse; 🇫🇷 Caen, France

Hopital Foch; 🇫🇷 Suresnes, France

Oncopole Claudius Regaud; 🇫🇷 Toulouse, France

Institut Curie; 🇫🇷 Paris, Île-de-France, France

Charite-Universitaetsmedizin Berlin - Campus Charite Mitte; 🇩🇪 Berlin, Germany

Universitätsklinikum Carl Gustav Carus an der TU Dresden; 🇩🇪 Dresden, Germany

Thoraxklinik Heidelberg gGmbH - Universitätsklinikum Heidelberg; 🇩🇪 Heidelberg, Germany

Lungenfachklinik Immenhausen; 🇩🇪 Immenhausen, Germany

Uniklinik Köln; 🇩🇪 Koln, Germany

Krankenhaus Bethanien Moers; 🇩🇪 Moers, Germany

Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST S.r.l; 🇮🇹 Meldola, Emilia-Romagna, Italy

A.O.U. San Luigi Gonzaga-Orbassano; 🇮🇹 Orbassano, Italy

Ospedale Santa Maria Delle Croci; 🇮🇹 Ravenna, Italy

Fondazione Policlinico Universitario A Gemelli-Rome; 🇮🇹 Rome, Italy

The Netherlands Cancer Institute (NKI); 🇳🇱 Amsterdam, Netherlands

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Comunidad de Madrid, Spain

Clinica Universidad de Navarra; 🇪🇸 Pamplona, Navarre, Spain

Complejo Hospitalario Universitario A Coruña; 🇪🇸 Coruña, Spain

Hospital Universitario Ramon y Cajal; 🇪🇸 Madrid, Spain

Hospital Clinico San Carlos; 🇪🇸 Madrid, Spain

Hospital Universitario Fundacion Jimenez Diaz; 🇪🇸 Madrid, Spain

Hospital Regional Universitario de Malaga - Hospital Civil; 🇪🇸 Malaga, Spain

Hospital Universitario Virgen del Rocio - PPDS; 🇪🇸 Sevilla, Spain

Fundacion Instituto Valenciano de Oncologia; 🇪🇸 Valencia, Spain

Hospital Universitari i Politecnic La Fe de Valencia; 🇪🇸 Valencia, Spain