Study of Avutometinib (VS-6766) +Defactinib With Gemcitabine and Nab-paclitaxel in Patients With Pancreatic 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) and defactinib in combination with gemcitabine and nab-paclitaxel in patients with Pancreatic Ductal Adenocarcinoma (PDAC) who have been previously untreated.

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) and defactinib in combination with gemcitabine and nab-paclitaxel in patients previously untreated metastatic Pancreatic Ductal Adenocarcinoma (PDAC).

Official Title
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A Phase 1b/2a Study of Gemcitabine and Nab-paclitaxel in Combination With Avutometinib (VS-6766) and Defactinib in Patients With Previously Untreated Metastatic Adenocarcinoma of the Pancreas

Conditions
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KRAS Activating Mutation, Metastatic Cancer, Pancreas Cancer, Neoplasms Pancreatic, Malignant Neoplasm of Pancreas

Intervention / Treatment
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* Drug: avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel


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 metastatic pancreatic ductal adenocarcinoma. An Eastern Cooperative Group (ECOG) performance status ≤ 1 Measurable disease according to RECIST 1.1 Adequate organ function Adequate cardiac function Agreement to use highly effective method of contraceptive Exclusion Criteria: Patients with pancreatic neuroendocrine tumors Prior or concomitant treatment for metastatic pancreatic ductal adenocarcinoma Prior treatment with inhibitors of the RAS /MAPK pathway [e.g. MEK inhibitors] or inhibitors of FAK History of prior malignancy, with the exception of curatively treated malignancies Major surgery within 4 weeks (excluding placement of vascular access) Concurrent heart disease or severe obstructive pulmonary disease Concurrent ocular disorders Active skin disorder that has required systemic therapy within the past 1 year Patients with interstitial lung disease or pulmonary fibrosis or severe lung disease, pulmonary edema, and adult respiratory distress syndrome Known SARS-Cov2 infection ≤28 days prior to first dose of study therapy

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: Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib<br>To determine the recommended phase 2 dose (RP2D) for gemcitabine Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib in patients with untreated metastatic PDAC. | Drug: avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel<br>* The RP2D of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel determined in Part A will be used in Part B dose expansion.<br>* Other names: Abraxane;|
| Experimental: Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib RP2D<br>To determine the efficacy of the RP2D identified in Part A in untreated metastatic PDAC patients | Drug: avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel<br>* The RP2D of avutometinib (VS-6766) and defactinib in combination with gemcitabine and nab-paclitaxel determined in Part A will be used in Part B dose expansion.<br>* Other names: Abraxane;|

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) and defactinib in combination gemcitabine and nab-paclitaxel | Assessment of Dose-limiting toxicities (DLTs) | 28 days | 
| To determine the efficacy of the RP2D identified in Part A | Confirmed overall response rate (ORR) (partial response [PR] + complete response [CR] defined according to Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]) | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | Time of first response to PD as assessed per RECIST 1.1 | 24 months | 
| Disease Control Rate (DCR) | CR + PR + SD as assessed per RECIST 1.1 | 24 months | 
| Progression Free Survival (PFS) | From the time of first dose of study intervention to PD as assessed per RECIST 1.1 or death from any cause | 24 months | 
| Overall Survival (OS) | From the time of first dose of study intervention to PD as assessed per RECIST 1.1 or death from any cause | Up to 5 years | 
| Plasma Pharmacokinetics (PK) of avutometinib (VS-6766) and Defactinib and relevant metabolites, Tmax | Time to Maximum concentration (Tmax) | 10 weeks | 
| Plasma Pharmacokinetics (PK) of avutometinib (VS-6766) and Defactinib and relevant metabolites, AUC | Area under plasma Concentration (AUC) 0 to t | 10 Weeks | 
| Plasma Pharmacokinetics (PK) of avutometinib (VS-6766) and Defactinib and relevant metabolites, Half-life | concentration Half-life (T1/2) | 10 weeks | 
| Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs) | Count of AE and SAEs by grade, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale | 24 months | 
| Number of abnormal laboratory values | Count of abnormal laboratory values by grade | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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avutometinib (VS-6766), Metastatic Cancer, KRAS Mutation, Pancreatic Cancer