Background: SEA-CD40 is an investigational nonfucosylated IgG1 monoclonal agonistic antibody targeted to CD40, expressed on antigen-presenting cells. SEA-CD40 binds with increased affinity to FcγRIIIa resulting in enhanced effector function and CD40 agonism, allowing amplification of immune stimulation and antitumor activity. PDAC can be treated with gemcitabine + nab-paclitaxel (GnP), often with poor survival. Combining chemotherapeutic agents with SEA-CD40 could facilitate robust antigen release and amplified presentation to CD8+ T cells. In preclinical models, the combination of SEA-CD40 and chemotherapy resulted in significant antitumor activity which is further enhanced with anti-PD1 treatment. We present data from an ongoing Phase 1 study (SGNS40-001) in a PDAC cohort evaluating the combination of SEA-CD40, GnP, and pembrolizumab (pembro). Methods: Patients (pts) ≥18 years old with untreated metastatic PDAC and Eastern Cooperative Oncology Group performance scores of 0 or 1 were enrolled. GnP were administered on Days 1, 8, and 15 of each 28-day cycle with 10 or 30 μg/kg SEA-CD40 IV on Day 3. Pembro was administered every 42 days starting on Day 8. Results: As of July 9, 2021, 61 pts were treated: 40 and 21 pts at 10 and 30 μg/kg SEA-CD40, respectively. Minimum follow-up was 5 months. The most frequent treatment-emergent adverse events (TEAEs) are shown in Table. 5 (8%) pts experienced an AE leading to treatment (tx) discontinuation (3 and 2 in 10 and 30 μg/kg SEA-CD40 dose, respectively), 35 (57%) pts experienced a serious TEAE (22 and 13 pts in 10 and 30 μg/kg, respectively). Two tx-related deaths occurred: colitis attributed to pembro, and septic shock attributed to GnP. Pts had transient increases in circulating cytokines and chemokines associated with immune activation and trafficking as well as increases in markers of activation on peripheral NK cells and T cells. Conclusions: The combination of SEA-CD40 + GnP + pembro demonstrated a tolerable safety profile. Evidence of immune activation was observed, consistent with the proposed mechanism of action. Follow-up for response and survival are ongoing. Clinical trial information: NCT02376699.