Background: Gemcitabine (GEM) and Nab-Paclitaxel (Nab-P) has become a standard 1^st line therapy for advanced PDAC based on the MPACT Trial.Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor (PD-1). Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Monotherapy with immune checkpoint inhibitors has thus far demonstrated limited activity in PDAC. This may be partly related to the activity of cancer associated fibroblasts (CAF) in promoting an immunosuppressive tumoural microenvironment in PDAC. GEM and Nab-P treatment may deplete stroma and CAFs, release neo-antigens and increase the immunogenicity of PDAC. This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to GEM/Nab-P increases treatment efficacy. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) will assess the efficacy and safety of GEM/Nab-P vs. GEM/Nab-P/D/T in patients (pts) with metastatic PDAC (n = 190). Good performance status pts (ECOG < 2) with untreated metastatic PDAC will be eligible. Prior adjuvant therapy is allowed provided recurrence is > 6 months post-completion. There is a safety lead in of 10 pts receiving GEM/Nab-P/D/T. Assuming no safety concerns the study will go on to randomize pts in a 2:1 ratio to receive GEM (1000mg/m² D1, 8, 15)/Nab-P (125mg/m² D1, 8, 15) with/without D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is overall survival; secondary endpoints include progression free survival, safety, overall response rate and quality of life. Analysis will be according to randomized group stratified by ECOG PS and receipt of prior adjuvant chemotherapy. Blood, plasma, and archival tissue will be collected and assessed for potential prognostic and predictive biomarkers. As of February 1 2017, 11 pts have been enrolled and the initial safety analysis is ongoing. Clinical trial information: NCT02879318