Stereotactic body radiotherapy plus rucosopasem in locally advanced or borderline resectable pancreatic cancer: GRECO-2 phase II study design

Abstract

Ablative doses of stereotactic body radiotherapy (SBRT) may improve pancreatic cancer outcomes but may carry greater potential for gastrointestinal toxicity. Rucosopasem, an investigational selective dismutase mimetic that converts superoxide to hydrogen peroxide, can potentially increase tumor control of SBRT without compromising safety. GRECO-2 is a phase II, multicenter, randomized, double-blind, placebo-controlled trial of rucosopasem in combination with SBRT in locally advanced or borderline resectable pancreatic cancer. Patients will be randomized to rucosopasem 100 mg or placebo via intravenous infusion over 15 min, before each SBRT fraction (5 × 10 Gy). The primary end point is overall survival. Secondary end points include progression-free survival, locoregional control, time to metastasis, surgical resection rate, best overall response, in-field local response and acute and long-term toxicity.

Trial registration: ClinicalTrials.gov NCT04698915.

Keywords: pancreatic cancer; rucosopasem; stereotactic body radiation therapy; superoxide dismutase mimetic.

Figure 1.. Mechanism of action for dismutase mimetics.

Selective dismutase mimetics rapidly and specifically convert superoxide to hydrogen peroxide. Normal cells tolerate hydrogen peroxide fluxes better than cancer cells. DM: Dismutase mimetic; SOD: Superoxide dismutase.

Figure 2.. Synergy of dismutase mimetic and stereotactic body radiation therapy on tumor control.

In an H1299 xenograft model, the selective dismutase mimetic, avasopasem, increased tumor growth delay when given 30 to 60 min before SBRT and daily for 4 days after SBRT. Enhancement of SBRT-mediated tumor growth delay increased with increasing radiation dose per fraction. Average tumor volumes (left column), individual tumor volumes (middle column), and Kaplan–Meier analysis using the IACUC threshold of 1000 mm³ tumor volume as a proxy for survival are shown. Eight to ten animals were included per cohort. AAAS: American Association for the Advancement of Science; AVA: Avasopasem; Avg.: Average; Ind.: Individual; SBRT: Stereotactic body radiation therapy. From [29] www.science.org/doi/10.1126/scitranslmed.abb3768. Reprinted with permission from AAAS.

Figure 3.. GRECO-2 study design.

¹At least 6 weeks of either (m) FOLFIRINOX or gemcitabine-based chemotherapy. There is no upper limit on the number of chemotherapy cycles administered prior to SBRT. ²Patients who remain free of metastases following induction chemotherapy will be eligible for randomization. ³Randomization stratified by disease status at diagnosis (borderline resectable vs locally advanced) as determined by a multidisciplinary tumor review group. Patients may receive additional chemotherapy following randomization and prior to SBRT treatment. ⁴SBRT should not be initiated until at least 1 week following the end of the last chemotherapy cycle. ⁵Surgical exploration within 8 weeks following SBRT. Approximately 160 patients with borderline resectable or locally advanced pancreatic cancer following initial chemotherapy will be randomized to receive rucosopasem 100 mg or placebo via iv. infusion prior to each SBRT fraction. At randomization, patients who are eligible for SBRT and do not have distant metastases will be stratified based on disease status, borderline resectable or unresectable, at diagnosis. Patients judged to be technically and medically resectable after SBRT will be surgically explored. All patients will be followed every 3 months from the completion of SBRT for 2 years and every 6 months thereafter, for a total of up to 3 years. iv.: Intravenous; PBO: Placebo; QD: Once daily; RUCO: Rucosopasem; SBRT: Stereotactic body radiation therapy.