Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients

Purpose

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.

Conditions

  • Non Small Cell Lung Cancer
  • KRAS Activating Mutation

Eligibility

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

Inclusion Criteria

  • Male or female patients ≥ 18 years of age - Histologic or cytologic evidence of NSCLC - Known KRAS G12C mutation - Either exposed or not exposed to a KRAS inhibitor to be included in Part A (avutometinib + sotorasib + defactinib) and not exposed to KRAS inhibitor to be included in Part B (avutometinib + sotorasib + defactinib), Cohort 1 - Received at least 1 dose of a G12C inhibitor to be included in Part B, Cohort 2 (avutometinib + sotorasib + defactinib) - 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

Study Design

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

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
avutometinib (VS-6766)+sotorasib 		To determine the recommended phase 2 dose (RP2D) for avutometinib (VS 6766) in combination with sotorasib in KRAS G12C inhibitor naïve and exposed patients
  • Drug: avutometinib and sotorasib
    The RP2D of avutometinib + sotorasib determined in Part A will be used in Part B dose expansion
    Other names:
    • AMG 510
    • LUMAKRAS™
    • VS-6766
Experimental
avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïve 		To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients
  • Drug: avutometinib and sotorasib
    The RP2D of avutometinib + sotorasib determined in Part A will be used in Part B dose expansion
    Other names:
    • AMG 510
    • LUMAKRAS™
    • VS-6766
Experimental
avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposed 		To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients
  • Drug: avutometinib and sotorasib
    The RP2D of avutometinib + sotorasib determined in Part A will be used in Part B dose expansion
    Other names:
    • AMG 510
    • LUMAKRAS™
    • VS-6766
Experimental
avutometinib (VS-6766)+sotorasib+defactinib 		To determine the recommended phase 2 dose (RP2D) for avutometinib (VS-6766) in combination with sotorasib and defactinib in KRAS G12C inhibitor exposed patients
  • Drug: avutometinib and sotorasib and defactinib
    The RP2D of avutometinib + sotorasib + defactinib determined in Part A will be used in Part B dose expansion
    Other names:
    • AMG 510
    • LUMAKRAS™
    • VS-6766
    • VS-6063
Experimental
avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naive 		To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients
  • Drug: avutometinib and sotorasib and defactinib
    The RP2D of avutometinib + sotorasib + defactinib determined in Part A will be used in Part B dose expansion
    Other names:
    • AMG 510
    • LUMAKRAS™
    • VS-6766
    • VS-6063
Experimental
avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposed 		To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients
  • Drug: avutometinib and sotorasib and defactinib
    The RP2D of avutometinib + sotorasib + defactinib determined in Part A will be used in Part B dose expansion
    Other names:
    • AMG 510
    • LUMAKRAS™
    • VS-6766
    • VS-6063

More Details

Status
Active, not recruiting
Sponsor
Verastem, Inc.

Study Contact

Detailed 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.