GRECO-2: A Randomized, Phase 2 Study of Stereotactic Body Radiation Therapy (SBRT) in Combination with GC4711 in the Treatment of Unresectable or Borderline Resectable Nonmetastatic Pancreatic Cancer (PC)
Hoffe S, Kim DW, Malafa M, Costello J, Aguilera TA, Beg SM, Parikh PJ, Herman JM, Terry K, Holmlund J, and Moser EC. GRECO-2: A Randomized, Phase 2 Study of Stereotactic Body Radiation Therapy (SBRT) in Combination with GC4711 in the Treatment of Unresectable or Borderline Resectable Nonmetastatic Pancreatic Cancer (PC). Int J Radiat Oncol Biol Phys 2021; 111(3):e44-e45.
Int J Radiat Oncol Biol Phys
Purpose/Objective(s): New therapeutic approaches are needed to improve survival in PC. The GRECO-2 study is designed to examine survival benefit of adding GC4711 to multi-modality treatment in selected patients, responsive to first line (m)FOLFIRINOX. While systemic treatment of PC has improved, rates of surgical resection - considered optimum treatment - remain low due to toxicity and disease progression during induction chemotherapy. SBRT is practiced enhancing resection rates and 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 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 the anti-tumor activity of 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 with a selective dismutase mimetic 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.
Materials/Methods: GRECO-2 is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect on the overall survival of adding GC4711 to SBRT following 4 months of chemotherapy in subjects with unresectable or borderline nonmetastatic PC. Approximately 160 subjects will be randomized (20 sites) to receive GC4711 100 mg or placebo IV infusion over 15 min, prior to each SBRT (5×10Gy). All subjects will then complete 2 additional months of adjuvant chemotherapy. Subjects judged operable will be operated within 8 weeks after SBRT. Secondary endpoints address resection rates, local and distant disease progression, and safety, while exploratory studies include ctDNA, immune profiling, PRO-CTCAE, CA19.9 normalization, and radiomics.
Results: For trial progress, see NCT04698915.
Conclusion: GC4711 may improve the benefit-risk ratio of 5-fraction SBRT and drive survival benefit of local treatment of chemotherapy responsive PC patients.