Background: Local progression causes up to 30% of deaths from pancreatic cancer (PC) and is also a significant source of morbidity. Stereotactic body radiotherapy (SBRT) offers the potential for improved therapeutic index over standard fractionation, but current regimens of 5-7 Gy/fraction x 5 are constrained by nearby organ tolerance and offer only palliation without improving survival. Safe dose escalation is necessary to improve SBRT efficacy. GC4419, a superoxide dismutase mimetic, selectively converts superoxide (O2•-) to hydrogen peroxide (H2O2) and oxygen. O2•-initiates normal tissue damage due to RT. GC4419 is in a Phase 3 trial (NCT03689712) to reduce RT-induced oral mucositis in head and neck cancer, based on positive results in a randomized Phase 2 trial for that indication (Anderson, ASCO 2018). GC4419 improved the survival of mice receiving 8.5 Gy x 5 to the upper abdomen. Cancer cells are less tolerant to elevated H2O2, and more tolerant to elevated O2•-, than normal cells, and GC4419 demonstrated mechanism-dependent synergy with high dose-fraction RT in a human tumor xenograft with inducible expression of catalase (Sishc, AACR 2018). Thus, adding GC4419 to SBRT may increase both the efficacy and the safety of the latter. Methods: 48 patients with localized, unresectable PC without frank duodenal invasion, who have received 3+ cycles of induction chemotherapy, are to be randomized 1:1 to placebo or GC4419, 90 mg IV, prior to each of 5 consecutive daily (M-F) SBRT fractions. A phase I/II Late Onset Efficacy/ Toxicity tradeoff (LO-ET) based adaptive design adaptive model drives SBRT dose escalation in each arm based on a dual endpoint (Gr 3-4 GI toxicity or death ;stable disease or better) by 90 days post SBRT. The planned dose levels are 10, 11 and 12Gy x 5 fractions (BED10=100,112.5 and 132Gy, respectively) as an integrated boost to the gross tumor volume (GTV). Primary endpoint: Maximum tolerated dose of SBRT with GC4419 or placebo. Exploratory endpoints include change in tumor radiographic resectability, correlative studies (ctDNA, exosomal DNA, tumor exome/transcriptome sequencing, immune profiling). Supported by Galera Therapeutics, Inc. Clinical trial information: NCT03340974