Background: PAC is an aggressive disease characterized by poor prognosis and is inadequately treated with available therapies. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase (BTK) that was shown to inhibit mast cell degranulation in the PAC tumor microenvironment with subsequent inhibition of tumor cell proliferation, angiogenesis, and collagen deposition (Chang, 2011; Masso-Valles, 2015). Durvalumab, a human IgG1 monoclonal antibody (mAb), binds PD-L1 with high affinity and prevents interaction with PD-1 and CD80 (IC₅₀values of 0.1 nM and 0.04 nM, respectively), facilitating antitumor T-cell responses (Stewart, 2015). Ibrutinib + anti-PD-L1 mAbs inhibited tumor cell growth and led to enhanced anti-tumor immune responses in mouse models (Sagiv-Barfi, 2015). This trial (PCYC-1135; NCT02403271) evaluates the safety and efficacy of ibrutinib + durvalumab in pts with PAC, breast cancer, and non-small cell lung cancer. Study details presented here focus on the cohort of pts with PAC. Methods: Key inclusion criteria include pathologically confirmed PAC, R/R disease (failed ≥ 1 prior systemic therapy), stage III-IV disease, ≥ 1 measurable lesion by RECIST 1.1 criteria, and adequate hematologic, renal, hepatic function. Key exclusion criteria include any history of central nervous system involvement; prior treatment with ibrutinib/BTK inhibitor or treatment with antibodies targeting PD-1, PD-L1, PD-L2, CD137, or CTLA-4; history of allogeneic organ transplant; or treatment with a strong cytochrome P450 3A inhibitor. Primary objectives are safety, tolerability, and efficacy of the combination; secondary objectives include pharmacokinetics and pharmacodynamic assessments of the combination. The phase 1b portion will assess the dose-limiting toxicities (DLTs) and determine the recommended phase 2 dose (RP2D). Ibrutinib will be administered at the standard dose with the potential for dose level reductions if DLTs occur in combination with durvalumab. After RP2D determination, enrollment in phase 2 will occur until a total of 130-160 pts (across all 3 disease cohorts) are treated. Enrollment for phase 1b began in March 2015. Clinical trial information: NCT02403271