The Miami "EMPIRE" Trial - Eradication of Metastatic Pancreatic Cancer With Immuno-Radiation

The purpose of this study is to assess if radiation therapy (which uses high-energy radiation to damage or destroy cancer cells) combined with immune checkpoint inhibitors (medications that helps the body recognize and attack cancer cells) will be beneficial for patients with metastatic pancreatic ductal adenocarcinoma.

Inclusion Criteria: 1. ≥18 years old 2. Histologically or cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma. 3. Microsatellite stable (MSS) disease by pathologic assessment. 4. Patients must have measurable disease as defined by RECIST 1.1. 5. Progression on ≥1 line of systemic therapy. 6. No concomitant therapy with any of the following: interleukin (IL)-2, interferon, non study immunotherapy regimens, cytotoxic chemotherapy, immunosuppressive agents, other investigational therapies, and/or chronic use of systemic corticosteroids. 7. No known infection with human immunodeficiency virus (HIV) or active infection with Hepatitis B. 8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 9. Life expectancy ≥3 months. 10. Patients must have the following lab values obtained \ 10 mg daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses (≤ 10 mg daily prednisone equivalent) are permitted in the absence of active autoimmune disease. 5. Previous external beam radiation therapy to the liver or radioisotope therapy directed to the liver or any liver embolization. 6. Clinically significant ascites requiring a paracentesis in the last 4 weeks, or clinically significant history of liver failure defined as any prior episode of hepatic encephalopathy and/or any prior history of an elevated serum ammonia level. 7. Partial or complete bowel obstruction within the last 3 months prior to study enrollment, signs/symptoms of bowel obstruction, or known radiologic evidence of impending obstruction. 8. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of study enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication. a. QT interval corrected using Fridericia's formula (QTcF) of \> 480 ms. 9. Prior allogeneic organ transplantation. 10. Treatment with chemotherapy or targeted therapy within 2 weeks prior to initiating EMPIRE treatment. 11. Persistent grade ≥2 adverse events (aEs) from prior therapy (except neuropathy). 12. Known additional malignancy requiring active treatment. 13. History of non-infectious pneumonitis. 14. Active infection requiring antibiotic. 15. Live vaccine within 30 days of protocol treatment. 16. Severe acute respiratory syndrome (SARS) coronavirus 2 (CoV 2) (SARS-CoV-2) vaccine or booster \< 7 days before Cycle 1 Day 1 (C1D1). For vaccines requiring more than 1 dose, the full series should be completed prior to C1D1, when feasible. Booster shot not required but also must be administered \> 7 days from C1D1 or \> 7 days from future cycle on study. 17. History of severe hypersensitivity reaction to monoclonal antibody. 18. Participants with impaired decision-making capacity.