Study of RMC-6291 in Combination With RMC-6236 in Participants With Advanced KRAS G12C Mutant Solid Tumors

Study Overview
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Brief Summary
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This study is to evaluate the safety, tolerability, and PK profiles of RMC-6291 and RMC-6236 in adults with KRAS G12C-mutated solid tumors.

Detailed Description
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This is an open-label, multicenter, Phase 1b study of RMC-6291 in combination with RMC-6236 in participants with advanced KRAS G12C-mutated solid tumors, to identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose and schedule (RP2DS) and provide a preliminary assessment of the antitumor activity of RMC-6291 in participants with KRASG12C tumors. The study consists of two parts: Part 1 - Dose-Escalation and Part 2 Dose-Expansion.

Official Title
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Phase 1b, Multicenter, Open-Label, Dose Escalation and Dose Expansion Study of RMC-6291 in Combination With RMC-6236 in Participants With Advanced KRAS G12C Mutant Solid Tumors

Conditions
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Non-Small Cell Lung Cancer (NSCLC), Colorectal Cancer, Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: Assigned interventions


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age Histology: pathologically documented, KRAS G12C-mutated, advanced or metastatic solid tumors not amendable to curative therapy Part 1. Dose Escalation: solid tumors, previously treated Part 2. Dose Expansion: i. NSCLC, previously treated with immunotherapy, chemotherapy, and KRAS G12C (OFF) inhibitors, ii. NSCLC, previously treated with immunotherapy and chemotherapy, naïve to KRAS G12C (OFF) inhibitors, iii. NSCLC, previously treated with immunotherapy, chemotherapy, with untreated, asymptomatic central nervous system (CNS) metastases <2 cm in size iv. Solid tumors, previously treated, naïve to KRAS G12C (OFF) inhibitors. ECOG performance status 0 or 1 Adequate organ function Exclusion Criteria: Primary central nervous system (CNS) tumors Active brain metastases Known impairment of GI function that would alter the absorption Major surgical procedures within 28 days or non-study related minor procedures within 7 days of treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 125 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RMC-6291 and RMC-6236<br>Dose escalation and Dose expansion | Drug: Assigned interventions<br>* Drug: RMC-6291 and RMC-6236 Oral tablets<br>|

What is the study measuring?
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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 vitals signs | up to 3 years | 
| Dose Limiting Toxicities | Number of participants with dose limiting toxicities | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Blood Concentration of RMC-6291 and RMC-6236 | Cmax | up to 21 weeks | 
| Time to Reach Maximum Blood Concentration of RMC-6291 and RMC-6236 | Tmax | up to 21 weeks | 
| Area Under Blood Concentration Time Curve of RMC-6291 and RMC-6236 | AUC | up to 21 weeks | 
| Elimination Half-Life of RMC-6291 and RMC-6236 | t1/2 | up to 21 weeks | 
| Ratio of accumulation of RMC-6291 and RMC-6236 from a single dose to steady state with repeated dosing | accumulation ratio | up to 21 weeks | 
| Overall Response Rate (ORR) | Overall response rate RECIST v1.1 | up to 3 years | 
| Duration of Response (DOR) | Duration of response per RECIST v1.1 | up to 3 years | 
| Disease Control Rate | Disease Control rate per RECIST v1.1 | up to 3 years | 
| Time to Response (TTR) | Time to response per RECIST v1.1 | up to 3 years | 
| Progression-Free Survival (PFS) | Progression-free survival per RECIST v1.1 | up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PDAC, NSCLC, RMC-6291, RAS (ON), KRAS, KRASG12C, KRASG12C (ON), Targeted therapy, Metastatic Cancer, Lung Cancer, Lung Neoplasms, Thoracic Neoplasms, Non-small Cell Lung Cancer, Carcinoma, Non-Small Cell Lung, Colorectal Cancer, Colonic Neoplasms, CRC, Appendiceal Cancer, KRAS mutation, STK11/LKB1, KEAP1, Bronchial neoplasms, Respiratory tract neoplasms, Neoplasms by site, Neoplasms, Colon Cancer, Rectal Cancer, Lung disease, Respiratory tract diseases, Pancreatic Cancer, Carcinoma, Pancreatic Ductal, Gastrointestinal Neoplasms, Intestinal Neoplasms, Esophageal Cancer, Ampullary Cancer, Gastric Cancer, Gynecological Cancer, Ovarian Cancer, Endometrial Cancer, RMC-6236