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

Study Overview
=================
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 two subprotocols include the following: Subprotocol A: RMC-6291 + SOC Subprotocol B: 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 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.

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

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: RMC-6291
* Drug: RMC-6236
* Drug: Pembrolizumab
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Pemetrexed


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NSCLC, KRAS G12C, RAS Mutation, KRAS G12X, Non-Small Cell Lung Cancer, Lung Cancer, Lung Cancer Stage IV, Advanced Solid Tumor, Cancer