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.

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).

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