Background: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options and is thought to be a “cold” tumor that does not respond to immunotherapy, due to a tumor microenvironment (TME) consisting of a desmoplastic stroma and poor T cell infiltrate. BXCL701 is an oral synthetic dipeptide that competitively inhibits dipeptidyl peptidases DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). BXCL701 exerts antitumor activity via inhibition of DPP8/9, which is associated with induction of proinflammatory cytokines, as well as inhibition of FAP, which disrupts tumor-stromal interactions. Preclinical xenograft models demonstrate synergy between BXCL701 and an anti-PD-1 monoclonal antibody, reducing tumor growth and promoting an increase in intratumoral CD4+ and CD8+ T cells and NK cells. The combination of BXCL701 and pembrolizumab is already being studied in a phase II trial in patients with prostate cancer (NCT03910660) and a multi-cohort basket study (NCT04171219). Methods: This is a phase II trial of BXCL701 administered at 0.2 mg PO BID days 1-7 and 0.3 mg BID days 8-14 during cycle 1 (21 days) followed by 0.3 mg BID days 1-14 every 21 days in all subsequent cycles, given with pembrolizumab 200 mg IV every 21 days (all cycles). The primary objective is to determine the 18-week progression-free survival rate (PFS18weeks) in patients with metastatic PDAC treated in the second-line setting. We estimate that historical 2^nd-line PFS18weeks is 30% or less; using a Simon’s two-stage (minimax) design, a type I error rate of 0.05 and power of 80% when the true response rate of 50%, we will need 19 patients in stage 1 and 20 in stage 2 (a total of 39). We plan to enroll 43 patients to account for a predicted 10% drop out of unevaluable patients. Eligible patients must have metastatic PDAC and disease progression or intolerance to only 1 line of therapy for metastatic disease, without exposure to prior immunotherapy. Patients must have measurable disease amenable to serial biopsies. Correlative pharmacodynamic studies include imaging mass cytometry to examine 34 markers of the PDAC TME in tissue biopsies, as well as blood-based analyses of KRAS circulating tumor DNA, circulating markers of fibrosis, and IL-6. Enrollment began in Q1 2023. Clinical trial information: NCT05558982.