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

Revolution Medicines

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Lung Cancer Stage IV, Advanced Solid Tumor, Cancer; Non-Small Cell Lung Cancer, NSCLC; KRAS, NRAS, HRAS-mutated NSCLC; KRAS G12C-mutated Solid Tumors, Lung Cancer

Treatments: Drug: Pembrolizumab; Drug: RMC-6291; Drug: Pemetrexed; Drug: Cisplatin; Drug: Carboplatin; Drug: RMC-6236

Study type: Interventional

Funder types: Industry

Identifiers

NCT06162221

RMC-LUNG-101

Details and patient eligibility

About

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 +/- RMC-6236 + SOC Subprotocol B: RMC-6236 + SOC

Full 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)

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

Enrollment: 484 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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484 participants in 2 patient groups

Subprotocol A: KRAS G12C-Mutated Solid Tumors

Experimental group

Description:

RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)

Treatment:

Drug: RMC-6236

Drug: Carboplatin

Drug: Cisplatin

Drug: Pemetrexed

Drug: RMC-6291

Drug: Pembrolizumab

Subprotocol B: RAS-mutated NSCLC

Experimental group

Description:

RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W-Q4W)

Treatment:

Drug: RMC-6236

Drug: Carboplatin

Drug: Cisplatin

Drug: Pemetrexed

Drug: Pembrolizumab