Abstract A018: Mitazalimab (CD40 agonist) in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Safety data and recommended dose for phase 2 (RP2D) from OPTIMIZE-1, a phase 1b/2 study
Authors: Van Laethem Jean-Luc , Borbath Ivan , Prenen Hans , Lambert Aurélien , Geboes Karen , Blanc Jean-Frédéric , de Coaña Yago Pico , Enell-Smith Karin , Schultz Lena , Nordbladh Karin , Ellmark Peter , Ambarkhane Sumeet , Carlsson Malin , Cassier Philippe 
Published: November 2022

Abstract
Mitazalimab is a human CD40 agonistic IgG1antibody being developed as 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 agonism activates myeloid cells and promotes the degradation of the desmoplastic tumor stroma, improving the 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. 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 mPDAC. The objective of the first (phase 1b) part of the study was to determine the RP2D of mitazalimab + mFOLFIRINOX. Mitazalimab was escalated from 450 µg/kg to 900 µg/kg following a Bayesian optimal interval design with at least 3 patients enrolled per dose level. In the first 21-day treatment cycle (Dose Limiting Toxicity assessment period), mitazalimab is administered intravenously on day 1 and 10 and mFOLFIRINOX 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. In part 2 of the study (phase 2), mitazalimab at the RP2D will be administered in combination with mFOLFIRINOX. Primary endpoint is RECIST-defined overall response rate. Progression-free survival and overall survival will be assessed as secondary endpoints. We report data from phase 1b (dose escalation) part of this study. As of March 9, 2022, 11 patients were treated with mitazalimab: 5 at 450 µg/kg and 6 at 900 µg/kg mitazalimab doses. One patient in the 900 µg/kg dose cohort withdrew from the trial for administrative reasons after the first mitazalimab infusion, prior to receiving mFOLFIRINOX and was not included in RP2D determination. Key baseline characteristics included: 7 female, 4 male; median age 63 (range 57-70); ECOG 0-1; median time since mPDAC diagnosis, 25 days. Mitazalimab related AEs were reported in 9/11 patients. Treatment related AEs occurring in &gt;1 patient were fever (60%), muscle pain (50%) and fatigue (20%). At the 450 µg/kg dose, all mitazalimab related AEs were grade 1-2. At the 900 µg/kg dose, 4 patients (67%) experienced grade 1-2 mitazalimab related AEs. One patient in the 900 µg/kg dose experienced mitazalimab related grade 3 fatigue and grade 3 headache that led to treatment discontinuation after the first cycle. There were no mitazalimab related grade 4 or 5 AEs. 1/10 patients required mFOLFIRINOX dose reduction and, at the cutoff date, the range of treatment length was 1-14 weeks. Mitazalimab combined with mFOLFIRINOX is safe and well tolerated. The 900 µg/kg dose of mitazalimab was selected as the RP2D. Phase 2 of the OPTIMIZE-1 trial is currently enrolling patients.
Citation Format: Jean-Luc Van Laethem, Ivan Borbath, Hans Prenen, Aurélien Lambert, Karen Geboes, Jean-Frédéric Blanc, Yago Pico de Coaña, Karin Enell-Smith, Lena Schultz, Karin Nordbladh, Peter Ellmark, Sumeet Ambarkhane, Malin Carlsson, Philippe Cassier. Mitazalimab (CD40 agonist) in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Safety data and recommended dose for phase 2 (RP2D) from OPTIMIZE-1, a phase 1b/2 study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A018.