Immune Checkpoint Inhibition (Tremelimumab and/or MEDI4736) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer

Background: \- Stereotactic body radiation therapy (SBRT) is used to treat cancer. It is a way of giving very focused beams of radiation to tumors. Researchers think that the drugs being used in this study might work better when combined with SBRT in people with pancreatic cancer. Objective: \- To study the safety and effectiveness of Durvalumab (MEDI4736) and/or tremelimumab with SBRT. Eligibility: \- People 18 and older who have pancreatic cancer that has not responded or to chemotherapy. They must be candidates for radiation but not resection. Design: * Participants will be screened with medical history and physical exam. They will have blood tests. Their tumor will be measured using computerized tomography (CT) or magnetic resonance imaging (MRI). * Participants will have their tumor biopsied with a needle. They will have also have a biopsy after cycle 1. * Participants will get 1 or 2 drugs in combination with the SBRT. * For MEDI4736, the duration of each cycle will be 28-days. Participants will get the drug through an intravenous (IV) infusion twice in each cycle (Days 1 and 15). * For tremelimumab, the duration of the first 6 cycles will each last 28 days. Then the duration of the last 3 cycles will change to 12 weeks. Participants will get the drug through an IV once in each cycle. * All participants will have SBRT. Some will get 1 dose of radiation and some will get 5. CT scans will map their tumor. * Participants will have medical history, physical exam, and blood tests in each cycle. They will have a CT scan or MRI every 8 weeks. Cycles will continue for up to 12 months. * Participants will be contacted yearly for follow-up.

Background: Tremelimumab is a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Anti-CTLA4 therapy has been shown to enhance anti-tumor immunity by blocking tumor-induced immune suppression of cytotoxic T cells. Durvalumab is a human monoclonal antibody directed against Programmed death-ligand 1 (PD-L1). Blockage of ligation between PD-L1 and Programmed cell death protein 1 (PD1) induces local immune activation and prevent anergy and exhaustion of effectors T-cells. Several studies have documented an increase in peripheral antitumor immunity following radiation. This effect is evidently too weak to be clinically relevant, but has the potential to be boosted by immune modulation. The underlying hypothesis of this study is that the effect of Immune Checkpoint inhibitor (Durvalumab with or without Tremelimumab) treatment can be enhanced by radiation in patients with advanced pancreatic carcinoma. Objective: To determine the safety, tolerability and feasibility of immune checkpoint inhibition \[comprising either Durvalumab alone, or combined Durvalumab and Tremelimumab\] in combination with stereotactic body radiation therapy (SBRT) in patients with unresectable pancreatic cancer. Eligibility: Histologically confirmed metastatic pancreatic cancer with primary in-situ (or locally-recurrent) with at least 1 measurable metastatic lesion by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and accessible for biopsy. There is no limit to the number of prior chemotherapy regimens received. Patients must be greater than or equal to 18 years of age and have a performance status (Eastern Cooperative Oncology Group (ECOG)) less than or equal to 1 Life expectancy of greater than 3 months. Acceptable organ and bone marrow function. Patients must not have had standard of care chemotherapy, radiotherapy, or major surgery within the last 2 weeks prior to entering the study. For recent experimental therapies a 28 day period of time must have elapsed before commencing protocol treatment. No active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome; Hashimoto syndrome; Graves disease; rheumatoid arthritis, hypophysitis, uveitis, etc.) within the past 3 years prior to the start of treatment. No active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. No active or history of systemic lupus erythematosus, Wegeners granulomatosis. Design: Subjects will be assigned to 4 arms Anti-PDL1 (Durvalumab) in combination with radiation (8 Gray (Gy) in fraction) \- Anti-PDL1 (Durvalumab) in combination with radiation (5 Gy in 5 fractions) Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with radiation (8 Gy in 1 fractions) \- Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with radiation (5 Gy in 5 fractions).