Study of Avutometinib (VS-6766) + Adagrasib in KRAS 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 adagrasib in patients with G12C Non-Small Cell Lung Cancer (NSCLC) who have been exposed to prior G12C inhibitor and experienced progressive disease.

Detailed Description
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This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety, tolerability and efficacy of avutometinib (VS-6766) in combination with adagrasib in patients with KRAS G12C mutant NSCLC who have been exposed to prior G12C inhibitor and experienced progressive disease.

Official Title
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A Phase 1/2 Study of Avutometinib (VS-6766) in Combination With Adagrasib in Patients With KRAS G12C Mutant Non-Small Cell Lung Cancer (NSCLC) (RAMP 204)

Conditions
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Advanced Cancer, Non Small Cell Lung Cancer, KRAS Activating Mutation, Metastatic Cancer, Malignant Neoplasm of Lung, Malignant Neoplastic Disease

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


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 G12C mutation The subject must have received prior therapy with a KRAS G12C inhibitor and experienced progression Must have received appropriate treatment with at least one prior systemic regimen, but no more than 3 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: Prior chemotherapy, targeted therapies, radiotherapy, immunotherapy or treatment with an investigational agent within 14 days of receipt of study drug (within 6 weeks for nitrosoureas, mitomycin C and chest radiation; within 6 months prior to Cycle 1 Day 1 for chest radiation > 30Gy) History of prior malignancy, with the exception of curatively treated malignancies Major surgery within 4 weeks (excluding placement of vascular access) Exposure to strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy Exposure to strong inhibitors of breast cancer resistance protein (BCRP) within 14 days prior to the first dose and during the course of therapy Symptomatic brain metastases requiring steroids or other local interventions within the 2 weeks prior to initiation of therapy 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 1 year History of rhabdomyolysis or interstitial lung disease 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

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

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 adagrasib | Assessment of Dose-limiting toxicities (DLTs) | From start of treatment to confirmation of RP2D; 28 days | 
| 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: | Incidence of Adverse events (AEs) and Serious Adverse Events (SAEs) assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0) Severity of Adverse events (AEs) and Serious Adverse Events (SAEs) by toxicity grade assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0) Duration of Adverse events (AEs) and Serious Adverse Events (SAEs) Incidence of clinically significant changes in lab parameters Incidence of abnormal vital signs (including systolic and diastolic blood pressure in mmHg) | 24 Months | 
| ECG QT Interval | Corrected ECG QT interval by Fredericia (QTcF) | 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 avutometinib(VS 6766), adagrasib, and relevant metabolites - Tmax | time of Maximum concentration (Tmax) | 10 weeks | 
| Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - AUC | Area under plasma Concentration (AUC) 0 to t | 10 weeks | 
| Plasma Pharmacokinetics (PK) of avutometinib(VS 6766), adagrasib, and relevant metabolites - Half-life | concentration Half-life (T1/2) | 10 weeks | 
| Clinical Benefit Rate | defined as Complete Response+Partial Response +Stable Disease | ≥ 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, KRAS G12C, Non Small Cell Lung Cancer, Metastatic Cancer, Adagrasib, Avutometinib (VS-6766)