Overview
This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C Non-Small Cell Lung Cancer (NSCLC) in patients who have been exposed to prior G12C inhibitor and those who have not been exposed to prior G12C inhibitor.
Description
This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety and tolerability and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C mutant NSCLC.
Eligibility
Inclusion Criteria:
- Male or female patients ≥ 18 years of age
- Histologic or cytologic evidence of NSCLC
- Known KRAS G12C mutation
- Have not received a KRAS inhibitor to be included in Part A (avutometinib + sotorasib) and Part B (avutometinib + sotorasib + defactinib), Cohort 1
- Received at least 1 dose of a G12C inhibitor to be included in Part A (avutometinib + sotorasib + defactinib) and Part B, Cohort 2
- Must have received appropriate treatment with at least one prior systemic regimen, but no more than 2 prior regimens, for Stage 3B-C or 4 NSCLC
- Measurable disease according to RECIST 1.1
- An Eastern Cooperative Group (ECOG) performance status ≤ 1
- Adequate organ function
- Adequate recovery from toxicities related to prior treatments
- Agreement to use highly effective method of contraceptive
Exclusion Criteria:
- Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy
- History of prior malignancy, with the exception of curatively treated malignancies
- Major surgery within 4 weeks, minor surgery within 2 weeks (excluding placement of vascular access)
- History of treatment with a direct and specific inhibitor of MEK
- Exposure to strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy
- Symptomatic brain metastases requiring steroids or other local interventions.
- Known SARS-Cov2 infection ≤28 days prior to first dose of study therapy
- Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active
- Active skin disorder that has required systemic therapy within the past year
- History of rhabdomyolysis
- Concurrent ocular disorders
- Concurrent heart disease or severe obstructive pulmonary disease
- Inability to swallow oral medications
- Female patients that are pregnant or breastfeeding
- Previously treated with sotorasib and were dose reduced due to toxicity