Background: The prognosis for advanced metastatic pancreatic adenocarcinoma remains dismal, highlighting the need for novel therapeutic agents. FOLFIRINOX (5-Fluorouracil + Oxaliplatin + Irinotecan) remains the standard of care frontline therapy for advanced disease, with historical objective response rate (ORR) of ~31%. Eryaspase is an investigational red blood cell product encapsulating L-asparaginase, which hydrolyzes and reduces asparagine levels in plasma, leading to cancer cell death. A phase III trial (Trybeca-1), which compared chemotherapy with or without eryaspase in the second line setting, did not reach its primary efficacy endpoint. However, there was a trend towards improved survival in the group receiving 5-fluorouracil and irinotecan plus eryaspase. We herein report the final results from our phase I front-line study of mFOLFIRINOX plus eryaspase. Methods: Patients with locally advanced or metastatic biopsy-proven pancreatic adenocarcinoma were treated with mFOLFIRINOX plus eryaspase in a standard 3 +3 dose escalation trial design. mFOLFIRINOX was given as 5-Fluorouracil 2400 mg/m2 over 46 hours, Oxaliplatin 85 mg/m2, Irinotecan 150 mg/m2 plus eryaspase 75 units/kg at dose level 0 or 100 units/kg at dose level 1. Key eligibility criteria included performance status of 0 or 1, locally advanced or metastatic disease, and adequate organ function. The primary objectives were to determine the maximum tolerated dose (MTD) and to determine the safety of this combination. Results: At completion of trial, eighteen patients were enrolled. Three patients were enrolled at dose level 0 and fifteen at dose level 1, with no dose limiting toxicities. Seventeen patients had imaging to evaluate best response: 24% (N=4) had partial response (PR), 65% (N=11) had stable disease (SD), and 11% (N=2) had progressive disease. The disease control rate (PR +SD) was 89%. Progression free survival (PFS) was 6.4 months (95% CI 3.21 – 16.79) and overall survival (OS) was 10.1 months (95% CI 7.18 – NR). There were select patients with very durable response (PFS>12 months and OS >18 months). There was one grade 5 (G5) sepsis adverse event (AE) and one G4 thromboembolic AE. G3 AEs were hypokalemia (22%), fatigue (11%), anemia (6%), hypotension (6%), diarrhea (6%), syncope (6%), and atrial fibrillation (6%). Pharmacokinetic and pharmacodynamic data are in process. Conclusions: The novel combination of mFOLFIRINOX plus eryaspase was well tolerated with no DLT and demonstrated signals of clinical activity in select patients. The MTD was declared with 5-FU 2400 mg/2, Oxaliplatin 85 mg/2, Irinotecan 150 mg/m2, and eryaspase 100 units/kg. Although the phase III Trybeca-1 trial did not meet the primary OS endpoint, both trials may suggest enhanced activity of eryaspase with regimens containing 5-Fluorouracil and Irinotecan. Clinical trial information: NCT04292743.