Dismutase Mimetic/SBRT Continues to Impress in Locally Advanced Pancreatic Cancer

The dismutase mimetic avasopasem manganese (GC4419) was found to improve overall survival (OS), progression-free survival (PFS), local disease control, time to metastases, and tumor response rate compared with placebo in patients with unresectable or borderline resectable locally advanced pancreatic cancer who were undergoing stereotactic body radiation (SBRT), according to data from a phase 1/2b pilot trial (NCT03340974).¹

At a minimum of 1 year of follow-up, improvements were observed across all efficacy parameters in the 42 patients enrolled to the double-blind, multicenter, placebo-controlled, proof-of-concept trial. Specifically, the hazard ratio (HR) for OS with the agent was 0.48 (95% CI, 0.20-1.14; P = .090). The HRs for PFS, local tumor control, and time to distant metastases were 0.46 (95% CI, 0.22-0.98; P = .040), 0.30 (95% CI, 0.08-1.10; P = .055), and 0.39 (95% CI, 0.16-0.93; P = .028), respectively.

Moreover, the agent was found to have favorable tolerability, with similar rates of early and late adverse effects (AEs) in both treatment arms.

“We are very pleased with the survival and tumor outcome benefits observed in the final analysis of this proof-of-concept trial,” Mel Sorensen, MD, president and chief executive officer of Galera Therapeutics, Inc., stated in the press release. “The improvements across multiple efficacy parameters, together with the safety data, are encouraging and underpin the rationale for our 160-patient blinded, randomized GRECO-2 trial of GC4711 with SBRT in pancreatic cancer, where the primary end point is OS.”

Avasopasem manganese is a highly selective small molecule superoxide dismutase mimetic that is designed to convert superoxide to hydrogen peroxide and oxygen.

The phase 1/2b trial enrolled patients with locally advanced or borderline resectable pancreatic cancer who had finished initial chemotherapy. Participants were randomized to 90 mg of intravenous (IV) avasopasem manganese with SBRT (n = 24) or SBRT plus an IV placebo (n = 24).2,3 The following SBRT doses were assigned in real-time via adaptive Bayesian model: 10 Gy x 5 (BED10 = 100 Gy), 11 Gy x 5 (BED10 = 116 Gy), and 12 Gy x 5 (BED10 = 132 Gy).

Patients enrolled to the investigational arm were slightly older, with a median age of 72 years vs 68 years in the control arm. The duration of prior chemotherapy was a median 21.9 weeks and 17.9 weeks in the placebo and avasopasem/SBRT arms, respectively. Across the arms, the median CA19-9 level was approximately 27, and few patients were smokers.

The primary end point of the trial was the first recommended dose of SBRT with avasopasem or placebo based on grade 3/4 gastrointestinal toxicity or death within 90 days after SBRT and the 90-day rate of local stable disease or better after SBRT. Key secondary end points comprised PFS, OS, local control, distant metastasis rate, objective response rate, and resectability.

The trial was divided into single-center and multicenter (n = 23) cohorts, the latter of which also included patients with borderline resectable disease. Data from the single-center cohort were previously presented during the 2020 ASTRO Annual Meeting and demonstrated that with a median follow-up of at least 1 year, the median OS had not yet been reached in the investigative arm (n = 11) vs 40.4 weeks in the SBRT-alone arm (n = 8; HR, 0.30; P = .046). Moreover, the median PFS was 29.3 months with avasopasem/SBRT vs 12.7 months with SBRT alone (HR, 0.40; P = .078).

Additionally, thebest response rate achieved with avasopasem manganese/SBRT was 54% vs 13% with SBRT/placebo. The median duration of local regional control was not reached with avasopasem/SBRT compared with 15 weeks with SBRT/placebo (HR, 0.10; P = .051). The time to distant metastasis was more than doubled with the addition of avasopasem, at 34.7 weeks vs 12.7 weeks with SBRT/placebo (HR, 0.40; P = .068).

Data from the pilot trial have reinforced the rationale for the double-blind, placebo-controlled, phase 2b GRECO-2 trial (NCT04698915), in which investigators are comparing the safety and efficacy of avasopasem with placebo in patients with locally advanced pancreatic cancer who are undergoing SBRT.

To be eligible for enrollment, patients need to be at least 18 years of age, have histological or biopsy-proven adenocarcinoma of the pancreas, have newly diagnosed pancreatic cancer that has been judged by a tumor board to be feasible for mFOLFIRINOX and SBRT, and have nonmetastatic disease following 3 months of chemotherapy.4 Moreover, patients needed to have an ECOG performance status of 0 to 2 and acceptable end-organ function.

If patients had documented metastatic disease, received frontline chemotherapy other than (m)FOLFIRINOX and/or chemotherapy given for a total period of longer than 4 months before the start SBRT, had previously received abdominal radiotherapy with substantial overlap in radiation fields, have not recovered from treatment-related AEs, or an uncontrolled malignancy other than prostate cancer, they were excluded.

The primary end point of the trial is OS, and key secondary end points include PFS, local tumor control, time to distant metastases, surgical resection rate, and safety.

GRECO-2 was initiated in May 2021 and is anticipated to enroll about 160 patients.

“We are excited to see the final results from this trial and enthusiastic to participate in the phase 2b GRECO-2 trial,” Sarah Hoffe, MD, section head of GI radiation oncology at H. Lee Moffitt Cancer Center and Research Institute, stated in a press release. “These observed OS rates are particularly encouraging in pancreatic cancer, as this patient population faces a difficult diagnosis with high rates of distant metastasis and low rates of cure.”

References

1. Galera announces final results from pancreatic cancer trial showing improvements on all efficacy parameters. News release. Galera Therapeutics. September 8, 2021. Accessed September 14, 2021. https://bit.ly/3hrJFCT
2. Hoffe SE, Frakes J, Aguilera TA, et al. Randomized, double-blinded, placebo-controlled multicenter adaptive phase 1-2 trial of GC4419, a dismutase mimetic, in combination with high dose stereotactic body radiation therapy (SBRT) in locally advanced pancreatic cancer (PC). Presented at: 62nd Annual ASTRO Meeting; October 25-28, 2020; virtual. Abstract LBA5.
3. Galera Therapeutics announces positive interim data from first cohort of patients in pilot phase 1/2 clinical trial of GC4419 in pancreatic cancer. Galera Therapeutics, Inc. News release. October 23, 2020. Accessed September 14, 2021. https://bit.ly/2XjrMPb
4. Phase 2b study of GC4711 in combination with SBRT for nonmetastatic pancreatic cancer. ClinicalTrials.gov. Updated July 6, 2021. Accessed September 14, 2021. https://clinicaltrials.gov/ct2/show/NCT04698915