Study of RMC-5127 in Patients With Advanced KRAS G12V-Mutant Solid Tumors

This is an open-label, multicenter, Phase 1/1b study of RMC-5127 in adults with advanced KRAS G12V-mutant solid tumors to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity. The study consists of three arms: RMC-5127 monotherapy arm, RMC-5127 plus daraxonrasib combination arm, and RMC-5127 plus cetuximab combination arm. All arms consist of two parts: Part 1- dose exploration and Part 2- dose expansion. Both parts of the monotherapy arm may include Food Effect Cohorts.

• RMC-5127 (Drug): oral tablets
• daraxonrasib (Drug): oral tablets
• cetuximab (Drug): IV infusion

Primary outcomes

• Number of patients with adverse events (AEs) [Up to approximately 3 years]: Number of patients with AEs as assessed by Common Terminology Criteria for Adverse Events CTCAE v5
• Changes in vital signs [Up to approximately 3 years]: Number of patients with changes from baseline in vital signs
• Changes in electrocardiogram (ECG) test values [Up to approximately 3 years]: Number of patients with changes from baseline in ECG test values
• Changes in clinical laboratory test values [Up to approximately 3 years]: Number of patients with changes from baseline in clinical laboratory test values
• Dose Limiting Toxicities [Up to 28 days]: Number of patients with dose limiting toxicities

Secondary outcomes

• Cmax concentrations of RMC-5127 and daraxonrasib [Up to Cycle 5 Day 1 (each cycle is up to 28 days)]: Maximum blood concentration (Cmax) of RMC-5127 as monotherapy and in combination with daraxonrasib or cetuximab, and Cmax of daraxonrasib in combination with RMC-5127 over time as applicable
• Tmax concentration of RMC-5127 and daraxonrasib [Up to Cycle 5 Day 1 (each cycle is up to 28 days)]: Time to reach maximum blood concentration (Tmax) of RMC-5127 as monotherapy and in combination with daraxonrasib or cetuximab, and Tmax of daraxonrasib in combination with RMC-5127 over time as applicable
• AUC concentrations of RMC-5127 and daraxonrasib [Up to Cycle 5 Day 1 (each cycle is up to 28 days)]: Area under the blood concentration time curve (AUC) of RMC-5127 as monotherapy and in combination with daraxonrasib or cetuximab, and AUC of daraxonrasib in combination with RMC-5127 over time as applicable
• Ratio of accumulation of RMC-5127 [Up to Cycle 5 Day 1 (each cycle is up to 28 days)]: Ratio of accumulation of RMC-5127 from a single dose to steady state with repeated dosing as monotherapy and in combination with darabxrasib or cetuximab over time as applicable
• Half-Life of RMC-5127 and daraxonrasib [Up to Cycle 5 Day 1 (each cycle is up to 28 days)]: Elimination Half-Life (t1/2) of RMC-5127 as monotherapy and in combination with daraxonrasib or cetuximab, and t1/2 of daraxonrasib in combination with RMC-5127 over time as applicable
• Objective Response Rate (ORR) [Up to approximately 3 years]: ORR per response evaluation criteria in solid tumors (RECIST) v1.1
• Duration of Response (DOR) [Up to approximately 3 years]: DOR per RECIST v1.1

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* At least 18 years old and has provided informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Pathologically documented, locally advanced or metastatic KRAS G12V-mutated solid tumor malignancy.
* Received and progressed or been intolerant to prior standard therapy (including targeted therapy) appropriate for tumor type and stage.
* Measurable per RECIST v1.1
* Adequate organ function (bone marrow, liver, kidney, coagulation).
* Able to take oral medications.

Exclusion Criteria:

* Primary central nervous system (CNS) tumors
* Prior therapy with KRAS G12V inhibitor or direct RAS-targeted therapy (eg. degraders and/or inhibitors).
* Any conditions that may affect the ability to take or absorb study drug.
* Major surgery within 28 days prior to receiving study drug(s).
* Patient is unable or unwilling to comply with protocol-required study visits or procedures.