Mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (PDAC): Safety data from part of the OPTIMIZE-1 study.

e16237 Background: Mitazalimab is a human CD40 agonistic IgG1antibody being developed for cancer immunotherapy. Targeting CD40 kickstarts the cancer immunity cycle by licensing DCs leading to tumor-specific T cell priming and activation. Furthermore, in PDAC CD40 agonists on myeloid cells promote degradation of the desmoplastic tumor stroma, improving influx of T cells and chemotherapeutic agents into the tumor. Mitazalimab has shown to be safe and well tolerated (at doses up to 1200 μg/kg), with signs of clinical activity in solid tumors in a Phase I study (NCT02829099). Most drug related adverse events (AE) were grade 1 or 2. Methods: OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open-label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with mFOLFIRINOX in adults diagnosed with previously untreated metastatic PDAC. In the first 21-day treatment cycle (Dose Limiting Toxicity (DLT) assessment period), mitazalimab is administered intravenously on day 1 and 10 and mFOLFIRINOX infusion starts on day 8. In the second and subsequent cycles, treatment follows a 14-day cycle schedule where mitazalimab is administered 2 days after mFOLFIRINOX. The primary objective of the first part of the study (Phase 1b) is to determine the recommended Phase 2 Dose (RP2D) of mitazalimab in combination with mFOLFIRINOX. Mitazalimab will be escalated from 450 µg/kg to 900 µg/kg following a Bayesian optimal interval design with at least 3 patients enrolled per dose level. A minimum of 6 patients will be evaluated at the RP2D. In Part 2 of the study, mitazalimab at the RP2D will be administered in combination with mFOLFIRINOX. The primary endpoint is RECIST-defined overall response rate. Progression-free survival and overall survival will be assessed as secondary endpoints. Here we report data from the Phase 1b (dose escalation) part of this study. Results: Five patients with histologically confirmed, previously untreated metastatic PDAC were treated at the 450 µg/kg dose level. Key baseline characteristics included: 2 female, 3 male; median age 65 (range 60-68); ECOG score of 0 or 1; median time since primary diagnosis 13 days (range 7-82). Treatment related AEs were only grade 1 or 2 (reported in 4 of 5 patients). Treatment related AEs occurring in > 1 patient were fever, muscle pain and nausea. No DLTs were reported. No patients required dose interruption/reduction with mitazalimab or mFOLFIRINOX. Two patients discontinued treatment due to disease progression and three remain on study. The study continues and patients are currently being enrolled at the 900 µg/kg mitazalimab dose in combination with mFOLFIRINOX. Conclusions: Mitazalimab at 450 µg/kg dose combined with mFOLFIRINOX is safe and well tolerated. Enrollment at the 900 µg/kg dose is ongoing for this Phase 1b/2 study. Updated data from part 1 of the study will be presented. Clinical trial information: NCT04888312.