Background: While systemic treatment of PC has improved, rates of surgical resection - considered optimum treatment - remain low. Patients with un-resectable or borderline PC still have poor outcomes, with both toxicity and disease progression during induction chemotherapy limiting the number eligible for surgery. SBRT practice to enhance margin negative resection or to provide local control, if inoperable after neoadjuvant therapy, has shifted to higher dose delivery (Mellon 2015, Colbert 2018), but timing and appropriate patient selection are under constant debate. SBRT delivery over 50Gy exhibits superior cell killing compared to conventionally fractionated RT but carries potential GI toxicity risk (Zhong 2017). GC4711 is a selective superoxide dismutase mimetic that converts superoxide to hydrogen peroxide. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control without compromising radiation safety (Sishc, AACR 2019). GC4711 consistently augmented tumor control by SBRT in PC experimental xenograft mouse models. In a pilot phase 1/2 trial (GC4419-101), subjects with locally advanced PC were randomized to receive SBRT plus either the selective dismutase mimetic GC4419 or placebo. This pilot trial has demonstrated acceptable safety with SBRT (5 × 10-11Gy), as well as apparent improvements in survival, surgical resection, locoregional control, and time to distant metastases. Altogether, these data support the hypothesis that GC4711 may improve tumor outcomes and the benefit-risk ratio of 5-fraction SBRT delivering 50Gy by improving efficacy without increasing GI-toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study to determine the effect on overall survival of adding GC4711 to SBRT following 4 months of chemotherapy in subjects with un-resectable or borderline non-metastatic PC. Approximately 160 subjects will be enrolled at over 20 sites to receive GC4711 100 mg or placebo IV given as IV infusion over 15 min, prior to each of 5 SBRT fractions of 10Gy). Subjects judged operable will be explored within 8 weeks after SBRT. All subjects will complete 2 additional months of adjuvant chemotherapy. Primary end point is overall survival and secondary endpoints address resection rates, local and distant disease progression, and safety, while exploratory studies include ctDNA, tumor exome/transcriptome sequencing, and immune profiling, patient-reported symptoms (PRO-CTCAE), CA19.9 normalization, and radiomics. Colbert L, Rebueno N, Moningi S et al Advances in Radiation Oncology (2018) 3, 693-700 Mellon EA, Hoffe SE, Springett GM, et al Acta Oncologica, 2015;54:7 Zhong J, Patel K, Switchenko J, et al. Cancer. 2017 Sep 15;123(18):3486-3493. Sishc BJ, Saha D, Story MD. AACR PADC 2019 C52. Clinical trial information: NCT04698915