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

A Platform Study of RAS(ON) Inhibitor Combinations in Patients With RAS-Mutated Non-Small Cell Lung Cancer (NSCLC)

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 two subprotocols include the following:

Subprotocol A: RMC-6291 + SOC Subprotocol B: RMC-6236 + SOC

Study Overview

• Status: 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
• Intervention / Treatment: Drug: Pemetrexed; Drug: Carboplatin; Drug: Pembrolizumab; Drug: Cisplatin; Drug: RMC-6291; Drug: RMC-6236

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 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)

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

• Study Type: Interventional
• Enrollment (Estimated): 352
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Revolution Medicines; Phone Number: (650)779-2300; Email: CT-inquiries@RevMed.com

Study Locations

• United States
  • Florida
    • Plantation, Florida, United States, 33322
      • Recruiting
      • Boca Raton Clinical Research Associates
  • New York
    • Westbury, New York, United States, 11590
      • Recruiting
      • Clinical Research Alliance
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
    • Irving, Texas, United States, 75039
      • Recruiting
      • NEXT Oncology Dallas
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • NEXT Oncology Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

All Patients (unless otherwise noted):

• ≥ 18 years of age
• ECOG PS is 0 to 1
• Adequate organ function as outlined by the study
• Received prior standard therapy appropriate for tumor type and stage
• Must have pathologically documented, locally advanced or metastatic KRAS G12C-mutated solid tumor malignancy (not amenable to curative surgery) (Subprotocol A)
• Must have pathologically documented, locally advanced or metastatic RAS-mutated NSCLC (Subprotocol B)

Exclusion criteria:

All Patients:

• Primary central nervous system (CNS) tumors
• Impaired gastrointestinal (GI) function that may significantly alter the absorption of RMC drugs
• Major surgery < 28 days of first dose
• Active or history of interstitial lung disease (ILD) or pneumonitis requiring steroids

Other inclusion/exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Subprotocol A: KRAS G12C-Mutated Solid Tumors; RMC-6291 (BID) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)	Drug: Pemetrexed; IV infusion; Drug: Carboplatin; IV Infusion; Drug: Pembrolizumab; IV Infusion; Drug: Cisplatin; IV Infusion; Drug: RMC-6291; Oral tablet
Experimental: Subprotocol B: RAS-mutated NSCLC; RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)	Drug: Pemetrexed; IV infusion; Drug: Carboplatin; IV Infusion; Drug: Pembrolizumab; IV Infusion; Drug: Cisplatin; IV Infusion; Drug: RMC-6236; Oral tablet

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax	Maximum observed blood concentration of each drug per subprotocol	Up to 21 weeks
Tmax	Time to reach maximum blood concentration of each drug per subprotocol	Up to 21 weeks
AUC	Area under the concentration-time curve of each drug per subprotocol	Up to 21 weeks
ORR	Overall Response Rate per RECIST v1.1	Up to 5 years
DOR	Duration of Response per RECIST v1.1	Up to 5 years

Collaborators and Investigators

• Sponsor: Revolution Medicines, Inc.
• Investigators: Study Director: Revolution Medicines, Revolution Medicines

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2024
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: November 30, 2023
• First Submitted That Met QC Criteria: November 30, 2023
• First Posted (Actual): December 8, 2023

Study Record Updates

• Last Update Posted (Estimated): May 15, 2024
• Last Update Submitted That Met QC Criteria: May 13, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Cancer; Lung Cancer; NSCLC; Non-Small Cell Lung Cancer; KRAS G12C; Advanced Solid Tumor; RAS Mutation; KRAS G12X; Lung Cancer Stage IV
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Folic Acid Antagonists; Carboplatin; Pembrolizumab; Pemetrexed
• Other Study ID Numbers: RMC-LUNG-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No