CA-4948 Added to Standard Chemotherapy to Treat Metastatic or Unresectable Pancreatic Cancer

PRIMARY OBJECTIVE: I. To assess dose limiting toxicities and determine the recommended phase 2 dose of emavusertib (CA--4948) in combination with chemotherapy in patients with pancreatic ductal adenocarcinoma. SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. II. To evaluate the safety and tolerability of the combination of CA-4948 and chemotherapy. III. To determine preliminary signals of efficacy, as measured by objective response rate (ORR), CA-4948 response, progression free survival (PFS), and overall survival (OS). EXPLORATORY OBJECTIVES: I. To evaluate pharmacodynamic effect of CA-4948 in combination with chemotherapy. II. To evaluate pharmacokinetics of CA-4948 in combination with chemotherapy. III. To explore biomarkers and genomic alterations associated with treatment response. OUTLINE: This is a dose-escalation study of CA-4948 in combination with fixed-dose gemcitabine and nab-paclitaxel followed by a dose-expansion study. Patients receive CA-4948 orally (PO) twice daily (BID) on days 1-21 or 1-28 of each cycle, gemcitabine intravenously (IV) over 30-60 minutes on days 1 and 8 or 1, 8, and 15 of each cycle, and nab-paclitaxel IV over 30-40 minutes on days 1 and 8 or 1, 8, and 15 of each cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT), tumor biopsies, and blood sample collection throughout the trial. After completion of study treatment, patients are followed every 3 months for 1 year.