Background: Transforming growth factor-β (TGF-β) can suppress adaptive and innate anti-tumor immune responses. G (LY2157299) is an oral small molecule inhibitor of TGF-β receptor I kinase that down-regulates phosphorylation of SMAD2, abrogating activation of the canonical pathway. Programmed cell death-ligand 1 (PD-L1) is upregulated in a broad range of cancers including pancreatic; expression of PD-L1 helps tumors evade immune system detection through binding to PD-1 on cytotoxic T lymphocytes. D (MEDI4736) is an anti-PD-L1 monoclonal antibody that blocks PD-L1/PD-1 interactions. Blockade of both TGF-β and PD-L1 pathways could reverse immunosuppression associated with these molecules by activating adaptive and innate anti-tumor immune responses. Methods: This two part phase 1b open-label study will enroll patients (pts) with recurrent or refractory metastatic pancreatic cancer. Part 1 is a 3+3 dose-escalation assessment of the safety and tolerability of G (4 escalating doses) and D (constant dose). After dose-limiting toxicity evaluation, cohort expansion with approximately 25 pts at the dose determined in the dose escalation portion will occur. Eligible pts have recurrent or refractory metastatic pancreatic cancer ( ≤ 2 prior systemic regimens) regardless of PD-L1 status; ECOG PS 0-1. Pts who have received prior therapy targeting T-cell costimulation or checkpoint pathways, or have received a TGF-β R1 kinase inhibitor are not eligible. Pretreatment and on-treatment biopsies will be obtained. The primary objective is to assess safety and tolerability of G in combination with D by identifying dose-limiting toxicities and to assess safety of the combination at the dose-escalation-established dose. Secondary objectives are pharmacokinetics; immunogenicity; preliminary anti-tumor activity; overall survival. Exploratory objectives are to examine biomarkers relevant to G, D, and the disease state. Enrollment began on 15-June-2016; as of 13-Sep-2016, 1 pt entered treatment. Clinical trial information: NCT02734160