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

Purpose

The purpose of this platform study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of novel RAS(ON) inhibitors as a monotherapy or combined with Standard(s) of Care (SOC) or with each other. The first four subprotocols include the following: Subprotocol A: RMC-6291 +/- RMC-6236 + SOC Subprotocol B: RMC-6236 + SOC Subprotocol C: RMC-9805 +/- RMC-6236 + SOC Subprotocol D: RMC-9805

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

Eligibility

Eligible Ages
Over 18 Years
Eligible Sex
All
Accepts Healthy Volunteers
No

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) - Must have pathologically documented, locally advanced or metastatic RAS G12D-mutated NSCLC (Subprotocol C and Subprotocol D)

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 Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Subprotocol A: KRAS G12C-Mutated Solid Tumors 		RMC-6291 (BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W)
  • Drug: RMC-6291
    Oral tablet
  • Drug: RMC-6236
    Oral tablet
  • Drug: Pembrolizumab
    IV Infusion
  • Drug: Cisplatin
    IV Infusion
  • Drug: Carboplatin
    IV Infusion
  • Drug: Pemetrexed
    IV infusion
Experimental
Subprotocol B: RAS-mutated NSCLC 		RMC-6236 (QD) and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W)
  • Drug: RMC-6236
    Oral tablet
  • Drug: Pembrolizumab
    IV Infusion
  • Drug: Cisplatin
    IV Infusion
  • Drug: Carboplatin
    IV Infusion
  • Drug: Pemetrexed
    IV infusion
Experimental
Subprotocol C: RAS G12D-mutated NSCLC 		RMC-9805 (QD or BID), RMC-6236 (QD), and Pembrolizumab (Q3W) with or without Chemotherapy (Q3W).
  • Drug: RMC-6236
    Oral tablet
  • Drug: Pembrolizumab
    IV Infusion
  • Drug: Cisplatin
    IV Infusion
  • Drug: Carboplatin
    IV Infusion
  • Drug: Pemetrexed
    IV infusion
  • Drug: RMC-9805
    Oral Tablet
Experimental
Subprotocol D: RAS G12D-mutated NSCLC 		RMC-9805 (QD)
  • Drug: RMC-9805
    Oral Tablet

Recruiting Locations

Georgetown University Medical Center
Washington, District of Columbia 20007
Contact:
Shannon Raue
202-784-5097
sr1657@georgetown.edu

More Details

Status
Recruiting
Sponsor
Revolution Medicines, Inc.

Study Contact

Revolution Medicines
1-844-2-REVMED
medinfo@RevMed.com

Detailed Description

The platform study design allows combinations of RAS(ON) inhibitors with other anticancer agents or as a monotherapy 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), or as a monotherapy 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) Subprotocol D is a Phase 2, Open-label, Multicenter Study of Zoldonrasib (RMC-9805) in Previously Treated Patients with RAS G12D-Mutant Non-Small Cell Lung Cancer (NSCLC) Subprotocols A, B, and C consist of two parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion. Subprotocol D consists of only one part.