Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib in G12C NSCLC Patients

Study Overview
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Brief Summary
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This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with sotorasib in patients with 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.

Detailed Description
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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 in patients with KRAS G12C mutant NSCLC.

Official Title
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A Phase 1/2 Study of Avutometinib (VS-6766) in Combination With Sotorasib in Patients With KRAS G12C Mutant Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Non Small Cell Lung Cancer, KRAS Activating Mutation

Intervention / Treatment
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* Drug: avutometinib (VS-6766) and sotorasib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients ≥ 18 years of age Histologic or cytologic evidence of NSCLC Known G12C KRAS mutation Have not received a KRAS inhibitor to be included in Part A and Part B, Cohort 1 Received at least 1 dose of a G12C inhibitor to be included in Part A or 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 (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

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: avutometinib (VS-6766)+sotorasib<br>To determine the recommended phase 2 dose (RP2D) for avutometinib (VS 6766) in combination with sotorasib in G12C inhibitor naïve and exposed patients | Drug: avutometinib (VS-6766) and sotorasib<br>* The RP2D of avutometinib(VS-6766) + sotorasib determined in Part A will be used in Part B dose expansion<br>* Other names: LUMAKRAS™;|
| Experimental: avutometinib (VS-6766)+sotorasib - G12C inhibitor naïve<br>To determine the efficacy of the RP2D identified from Part A in G12C inhibitor naïve patients | Drug: avutometinib (VS-6766) and sotorasib<br>* The RP2D of avutometinib(VS-6766) + sotorasib determined in Part A will be used in Part B dose expansion<br>* Other names: LUMAKRAS™;|
| Experimental: avutometinib (VS-6766)+sotorasib - G12C inhibitor exposed<br>To determine the efficacy of the RP2D identified from Part A in G12C inhibitor exposed patients | Drug: avutometinib (VS-6766) and sotorasib<br>* The RP2D of avutometinib(VS-6766) + sotorasib determined in Part A will be used in Part B dose expansion<br>* Other names: LUMAKRAS™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: To determine RP2D for avutometinib(VS-6766) in combination with sotorasib | Assessment of Dose-limiting toxicities (DLTs) | From start of treatment to confirmation of RP2D; 28 days | 
| Part B: To determine the efficacy of the optimal regimen identified from Part A | Confirmed overall response rate per RECIST 1.1 | From start of treatment to confirmation of response; 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the safety and toxicity profile | Treatment emergent adverse events/ treatment emergent serious adverse events - their frequency, duration and severity, lab parameters, vital signs and ECG changes based on CTCAE | 24 months | 
| Duration of Response (DOR) | Time of first response to PD as assessed per RECIST 1.1 | Time from the first documentation of response to first documentation of progressive disease or death due to any cause, greater than or equal to 6 months | 
| Disease Control Rate (DCR) | CR and PR stable disease as assessed per RECIST 1.1 | Greater than or equal to 8 weeks | 
| Progression Free Survival (PFS) | From the time of first dose of study intervention to PD or death from any cause | 24 months | 
| Overall Survival (OS) | From time of first dose of study intervention to death | Up to 5 years | 
| Plasma Pharmacokinetics (PK) of VS 6766, sotorasib, and relevant metabolites - Tmax | time of Maximum concentration (Tmax) | 10 weeks | 
| Plasma Pharmacokinetics (PK) of VS 6766, sotorasib, and relevant metabolites -AUC | Area under plasma Concentration (AUC) 0 to t | 10 weeks | 
| Plasma Pharmacokinetics (PK) of VS 6766, sotorasib, and relevant metabolites half-life | concentration Half-life (T1/2) | 10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, KRAS G12C