A Study of Avutometinib (VS-6766) v. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation

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 and in combination with defactinib in subjects with recurrent Low-Grade Serous Ovarian Cancer (LGSOC)

Detailed Description
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This is a multicenter, randomized, open-label Phase 2 study designed to evaluate safety and tolerability and preliminary efficacy of avutometinib (VS-6766) versus avutometinib (VS-6766) in combination with defactinib in subjects with molecularly profiled recurrent LGSOC.

Official Title
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A Phase 2 Study of Avutometinib (VS-6766) (Dual RAF/MEK Inhibitor) Alone and In Combination With Defactinib (FAK Inhibitor) in Recurrent Low-Grade Serous Ovarian Cancer (LGSOC)

Conditions
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Low Grade Ovarian Serous Adenocarcinoma, Ovarian Cancer

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: Histologically proven LGSOC (ovarian, peritoneal) Progression or recurrence of LGSOC after at least one prior systemic therapy for metastatic disease. 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, if necessary Exclusion Criteria: Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy Co-existing high-grade ovarian cancer or another histology History of prior malignancy with recurrence <3 years from the time of enrollment Major surgery within 4 weeks Symptomatic brain metastases requiring steroids or other interventions Known SARS-Cov2 infection (clinical symptoms) ≤28 days prior to first dose of study therapy For subjects with prior MEK exposure, Grade 4 toxicity deemed related to the MEK inhibitor 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 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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Female

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>To determine the optimal regimen, either avutometinib(VS-6766) monotherapy or avutometinib (VS-6766) in combination with defactinib, for subsequent evaluation for efficacy in the Expansion Phase (Part B) | Drug: avutometinib (VS-6766)<br>* avutometinib (VS-6766) monotherapy<br>Drug: avutometinib (VS-6766) and defactinib<br>* avutometinib (VS-6766) and defactinib combination<br>* Other names: avutometinib (VS-6766) and VS-6063;|
| Experimental: Part B<br>To determine the efficacy of the optimal regimen identified from Part A | Drug: avutometinib (VS-6766)<br>* avutometinib (VS-6766) monotherapy<br>Drug: avutometinib (VS-6766) and defactinib<br>* avutometinib (VS-6766) and defactinib combination<br>* Other names: avutometinib (VS-6766) and VS-6063;|
| Experimental: Part C:<br>To evaluate additional efficacy parameters for the optimal regimen identified in Part A. | Drug: avutometinib (VS-6766) and defactinib<br>* avutometinib (VS-6766) and defactinib combination<br>* Other names: avutometinib (VS-6766) and VS-6063;|
| Experimental: Part D<br>To evaluate additional efficacy parameters for a lower dose of avutometinib in combination with defactinib | Drug: avutometinib (VS-6766) and defactinib<br>* avutometinib (VS-6766) and defactinib combination<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 |
| --- | --- | --- |
| Part A: Determine optimal regimen of avutometinib (VS-6766) monotherapy or in combination with defactinib | Confirmed overall response rate per RECIST 1.1 | From start of treatment to confirmation of response; 24 weeks | 
| 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; 24 weeks | 
| Part C: To evaluate additional efficacy parameters for the optimal regimen identified in Part A | Confirmed overall response rate per RECIST 1.1 | From start of treatment to confirmation of response; 24 weeks | 
| Part D:To evaluate additional efficacy parameters for a lower dose of avutometinib in combination with defactinib | Confirmed ORR defined according to RECIST 1.1 | From start of treatment to confirmation of response; 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate 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) | From time of first response to PD as assessed by the BIRC | 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+PR+stable disease | Greater than or equal to 8 weeks | 
| Progression Free Survival (PFS) | From time of first dose of study intervention to PD or death for 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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Low Grade Serous Ovarian Cancer, KRAS, KRAS wt