This study is evaluating the drugs nab-paclitaxel and gemcitabine in combination with avutometinib (VS-6766) and defactinib for patients with pancreatic ductal adenocarcinoma.

Nab-paclitaxel and gemcitabine are anti-cancer chemotherapy drugs used to kill cancer cells by stopping cell division and causing cell death. Nab-paclitaxel in combination with gemcitabine is approved by the U.S. Food and Drug Administration (FDA) for the first-line treatment  for patients with pancreatic ductal adenocarcinoma. Both nab-paclitaxel and gemcitabine are given intravenously (through a vein in the arm) or through a port (small device implanted beneath the skin to make intravenous treatments easier). A central line, which is a bigger catheter that’s put into a large vein in the chest or arm, may also be placed depending on a participant’s circumstances.

VS-6766 (avutometinib) and defactinib  are a type of drug called kinase inhibitors. Kinase inhibitors block cancer growth by disrupting signals that tell the cancer cells to divide. Both are given in pill form and are taken by mouth.

The combination of these 4 study drugs is considered investigational, which means the combination has not yet been approved by the FDA.

This study is trying to find out what the best dose of each study drug in combination will be. Another goal of the study is to see if the combination will provide a treatment benefit to participants with your diagnosis.

There are 3 possible dose combinations. The study team will discuss the assigned doses with each participant.

• Dose level -1: VS-6766 (avutometinib) 2.4 mg dose twice per week and defactinib 200 mg twice daily in combination with gemcitabine 800 mg/m2 once weekly and nab-paclitaxel 100 mg/m2 once weekly (mg/m2 means that the dose is calculated based on your body weight).
• Dose level 1: VS-6766 (avutometinib) 2.4 mg dose twice per week and defactinib 200 mg twice daily in combination with gemcitabine 800 mg/m2 once weekly and nab-paclitaxel 125 mg/m2 once weekly.  
• Dose level 2: VS-6766 (avutometinib) 3.2 mg dose twice per week and defactinib 200 mg twice daily in combination with gemcitabine 1000 mg/m2 once weekly and nab-paclitaxel 125 mg/m2 once weekly.

Total study participation depends on how well each participant responds to the treatments.