Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients (RAMP203)

Verastem

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: KRAS Activating Mutation; Non Small Cell Lung Cancer

Treatments: Drug: avutometinib and sotorasib and defactinib; Drug: avutometinib and sotorasib

Study type: Interventional

Funder types: Industry

Identifiers

NCT05074810

VS-6766-203

Details and patient eligibility

About

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.

Full 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.

Enrollment: 153 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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153 participants in 6 patient groups

avutometinib (VS-6766)+sotorasib

Experimental group

Description:

To determine the recommended phase 2 dose (RP2D) for avutometinib (VS 6766) in combination with sotorasib in KRAS G12C inhibitor naïve and exposed patients

Treatment:

Drug: avutometinib and sotorasib

avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïve

Experimental group

Description:

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients

Treatment:

Drug: avutometinib and sotorasib

avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposed

Experimental group

Description:

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients

Treatment:

Drug: avutometinib and sotorasib

avutometinib (VS-6766)+sotorasib+defactinib

Experimental group

Description:

To determine the recommended phase 2 dose (RP2D) for avutometinib (VS-6766) in combination with sotorasib and defactinib in KRAS G12C inhibitor exposed patients

Treatment:

Drug: avutometinib and sotorasib and defactinib

avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naive

Experimental group

Description:

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients

Treatment:

Drug: avutometinib and sotorasib and defactinib

avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposed

Experimental group

Description:

To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients

Treatment:

Drug: avutometinib and sotorasib and defactinib