Background: SEA-CD40 is an investigational non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40, a co-stimulatory receptor expressed on antigen-presenting cells (APCs). Activation of CD40 on APCs upregulates cytokine production and co-stimulatory receptors, enhancing tumor antigen presentation to T cells. Preclinical data indicate that treatment of PDAC with chemotherapy in conjunction with a CD40 agonist could enhance antigen presentation and initiate an antitumor immune response (Byrne KT and Vonderheide RH, Cell Rep 2016;15, 2719–2732). A Phase 1 study (SGNS40-001) is evaluating SEA-CD40 monotherapy and in combination with other agents in pts with advanced solid or hematologic malignancies. A cohort is enrolling to evaluate the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in PDAC. Methods: The cohort consists of pts with metastatic PDAC who have had no prior therapy for metastatic disease. Pts must be ≥18 years old, with (neo)adjuvant therapy completed > 4 months prior to enrollment; ECOG status ≤1; adequate renal, hepatic, and hematologic function; and measurable disease per RECIST v 1.1 criteria. A standard regimen of gemcitabine and nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle is administered with SEA-CD40 IV on Day 3. Pembrolizumab is administered every 42 days starting on Day 8. The primary objective is to evaluate antitumor activity; secondary objectives are to evaluate safety and tolerability and SEA-CD40 and pembrolizumab pharmacokinetics. Efficacy endpoints are confirmed RECIST objective response rate per investigator (primary), disease control rate (response or stable disease ≥16 weeks), duration of response, progression-free survival, and overall survival. Disease is assessed every 8 weeks using RECIST and immune-based RECIST (iRECIST). Treatment continues until unacceptable toxicity, progressive disease per iRECIST, consent withdrawal, or study closure, whichever occurs first. Assessment of dose-limiting toxicity will occur initially in groups of 6 pts to identify the recommended phase 2 dose of SEA-CD40 for the cohort. Enrollment to this cohort began in November 2019. Clinical trial information: NCT02376699