A Study of Avutometinib (VS-6766) + Defactinib in Recurrent KRAS G12V, Other KRAS and BRAF Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This study will assess the safety and efficacy of avutometinib (VS-6766) monotherapy or VS-6766 in combination with defactinib in subjects with recurrent Non-small cell lung cancer.

Detailed Description
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This is a multicenter, open-label Phase 2 study designed to evaluate safety and tolerability and efficacy of avutometinib (VS-6766) versus avutometinib (VS-6766) in combination with defactinib in subjects with KRAS and BRAF mutant NSCLC following treatment with an appropriate platinum-based regimen and an approved immune checkpoint inhibitor (CPI).

Official Title
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A Phase 2 Study of Avutometinib (VS-6766) (Dual RAF/MEK Inhibitor) as a Single Agent and In Combination With Defactinib (FAK Inhibitor) in Recurrent KRAS-Mutant (KRAS-MT) and BRAF-Mutant (BRAF-MT) Non-Small Cell Lung Cancer (NSCLC) (RAMP 202)

Conditions
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Non Small Cell Lung Cancer, KRAS Activating Mutation

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects ≥ 18 years of age Histologic or cytologic evidence of NSCLC Known KRAS or BRAF mutation The subject must have received appropriate prior therapy 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, KRAS or BRAF except for treatment of BRAF V-600E mutant NSCLC Exposure to strong CYP2C9 and CYP3A4 inhibitors or inducers within 7 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 Active skin disorder that has required systemic therapy within the past 1 year History of rhabdomyolysis Concurrent ocular disorders Concurrent heart disease or severe obstructive pulmonary disease Subjects with the inability to swallow oral medications

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: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: avutometinib (VS-6766) monotherapy<br>in patients with NSCLC KRAS-G12V tumor | Drug: avutometinib (VS-6766)<br>* Monotherapy<br>|
| Experimental: Arm 2: avutometinib (VS-6766) in combination with defactinib<br>in patients with a NSCLC KRAS-G12V tumor | Drug: avutometinib (VS-6766) and Defactinib<br>* Combination therapy<br>* Other names: avutometinib (VS-6766) and VS-6063;|
| Experimental: Arm 3: avutometinib (VS-6766) in combination with defactinib<br>in patients with a NSCLC KRAS-other (non-G12V) tumor | Drug: avutometinib (VS-6766) and Defactinib<br>* Combination therapy<br>* Other names: avutometinib (VS-6766) and VS-6063;|
| Experimental: Arm 4: avutometinib (VS-6766) in combination with defactinib<br>in patients with a NSCLC BRAF-V600E tumor | Drug: avutometinib (VS-6766) and Defactinib<br>* Combination therapy<br>* Other names: avutometinib (VS-6766) and VS-6063;|
| Experimental: Arm 5:avutometinib (VS-6766) in combination with defactinib<br>in patients with a NSCLC BRAF-non-V600E tumor | Drug: avutometinib (VS-6766) and Defactinib<br>* Combination therapy<br>* Other names: avutometinib (VS-6766) and VS-6063;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the optimal regimen, either avutometinib (VS-6766) monotherapy or avutometinib (VS-6766) in combination with defactinib, in KRAS-G12V NSCLC | Confirmed overall response rate per RECIST 1.1 | From start of treatment to confirmation of response; 24 weeks | 
| To evaluate the initial efficacy of avutometinib (VS-6766) in combination with defactinib in BRAF-MT NSCLC | Confirmed overall response rate per RECIST 1.1 | From start of treatment to confirmation of response; 24 weeks | 
| To determine efficacy in KRAS-other (non-G12V) NSCLC | Confirmed overall response rate per RECIST 1.1 | From start of treatment to confirmation of response; 24 weeks | 
| To determine the efficacy of avutometinib (VS-6766) in combination with defactinib in BRAF-MT NSCLC | Confirmed overall response rate per RECIST 1.1 | From start of treatment to confirmation of response; 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the safety and toxicity profile of VS-6766 as a monotherapy and in combination with defactinib in KRAS-MT NSCLC and in BRAF-MT NSCLC | Adverse events (AEs), serious AEs (SAEs), vital signs, physical examinations, clinical laboratory values, and tolerability (dose interruptions/reductions) | 24 weeks | 
| Overall Response Rate per RECIST 1.1 as assessed by Investigator | Proportioned subjects achieving a CR or PR as assess by the investigator | From start of treatment to confirmation of response; 24 weeks | 
| Duration of Response (DOR) | Time of first response to PD as assessed by the IRC | 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 by the IRC | 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 | Up to 5 years | 
| Overall Survival (OS) | From time of first dose of study intervention to death | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, KRAS-G12V, G12V, BRAF, V600E, KRAS