Background: Combinatorial strategies aimed at priming tumor antigen-specific T cells while simultaneously blocking negative immune checkpoints may improve immunotherapy for immune tolerant cancers such as pancreatic adenocarcinoma (PDA). In a previously reported trial, concurrent administration of an allogeneic GM-CSF transfected pancreatic tumor vaccine and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody, ipilimumab (IPI), which blocks an inhibitory signal on T cells resulted in both CT scan regressions and CA19-9 declines in heavily preteated patients. This proposal will test vaccine + IPI in patients with metastatic PDA who have stable disease (SD) with upfront FOLFIRINOX (5-FU/irinotecan/oxaliplatin) chemotherapy. Integrating immunotherapy after upfront chemotherapy has several advantages. Chemotherapy can debulk the tumor and predispose cancer cells to cell death mediated by immune cells. Immunotherapy can take weeks to months to be effective and is therefore more likely to work in patients with SD. Vaccine + IPI showed promise in heavily pre-treated patients and giving it immediately after front line chemotherapy may improve activity. Methods: This is a phase 2, multicenter, randomized, controlled, open-label trial in patients with metastatic PDA who have SD after 8-12 doses of FOLFIRINOX. 92 patients will be randomized 1:1 to Arm A (vaccine + IPI) or Arm B (continue chemotherapy per standard of care). Patients on Arm A will receive vaccine + IPI (10mg/kg) every 3 weeks for 4 doses then every 8 weeks. The primary objective of the study is to compare the overall survival (OS) of Arm A vs Arm B. Secondary objectives include: assessment of safety, progression-free survival (PFS), immune-related PFS, duration of response, objective response rate by RECIST and immune-related response criteria, and tumor marker kinetics (CA 19-9). Exploratory objectives include: identification of predictors of response and toxicity using proteomic techniques, assessment of T cell responses and genomic and IHC analyses of tumor tissue. (FDA Office of Orphan Products Development, R01FD004819-01). Clinical trial information: NCT01896869.