PRIMARY OBJECTIVE:~I. Determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of olaparib in combination with durvalumab and radiation therapy (RT).~SECONDARY OBJECTIVES:~I. To observe and record anti-tumor activity. II. Correlate response with the circulating frequency and diversity of T cells within the peripheral blood.~III. Evaluate the safety and toxicity of olaparib in combination with durvalumab and RT.~EXPLORATORY OBJECTIVES:~I. Evaluate the genetic and clinicopathologic markers of response and resistance including prior receipt of platinum therapy.~II. To correlate response with baseline tumoral immune infiltrate.~OUTLINE: This is a dose-escalation study of olaparib in combination with fixed dose durvalumab and radiation therapy.~Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 and durvalumab intravenously (IV) over 55-65 minutes on day 1 of each cycle. Beginning cycle 2, patients also undergo radiation therapy daily on weekdays for 3 weeks. Chemotherapy and immunotherapy cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up at 90 days and every 12 weeks thereafter for two years on until death, whichever occurs first.
This phase I trial tests the safety and tolerability of olaparib in combination with durvalumab and radiation therapy in patients with pancreatic cancer that has spread to nearby tissue or lymph nodes (locally advanced) and cannot be removed by surgery (unresectable). Olaparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. The combination of targeted therapy with olaparib, immunotherapy with durvalumab and radiation therapy may stimulate an anti-tumor immune response and promote tumor control in locally advanced unresectable pancreatic cancer.