Selective Dismutase Mimetic/SBRT Improves OS in Locally Advanced Pancreatic Cancer

Pipeline Report | <b>Pipeline Report: November 2020</b>

The addition of avasopasem manganese to stereotactic body radiation therapy led to a significant improvement in overall survival and favorable progression-free survival versus SBRT plus placebo in patients with locally advanced pancreatic cancer.

The addition of avasopasem manganese (GC4419) to stereotactic body radiation therapy (SBRT) led to a significant improvement in overall survival (OS) and favorable progression-free survival (PFS) versus SBRT plus placebo in patients with locally advanced pancreatic cancer, according to interim data from a phase 1/2 trial (NCT03340974) that were presented virtually during the 2020 ASTRO Annual Meeting.1,2

In the intent-to-treat cohort (n = 19), with a median follow-up of at least 1 year, the median OS had not yet been reached with avasopasem manganese/SBRT (n = 11) compared with 40.4 weeks in the SBRT/placebo arm (n = 8; HR, 0.30; P = .046). The median PFS was 29.3 months and 12.7 months, respectively (HR, 0.40; P = .078).

“This is the first clinical data assessing the anti-cancer activity of one of our dismutase mimetics, and we are encouraged by this analysis of the initial cohort which suggests a meaningful survival benefit in pancreatic cancer,” said Mel Sorensen, MD, President and CEO of Galera.2 

Superoxide is involved in normal metabolism but can lead to cell damage or cell death at high levels. Through the production of superoxide dismutase enzymes, superoxide is converted to hydrogen peroxide, which is toxic to cancer cells. However, radiotherapy can lead to an overproduction of superoxide, overwhelming superoxide dismutase enzymes and resulting in oral mucositis.

Avasopasem manganese is a highly selective small molecule superoxide dismutase mimetic that is designed to convert superoxide to hydrogen peroxide and oxygen. In preclinical models, these agents have demonstrated anticancer activity.

In March 2018, the FDA granted fast track and breakthrough therapy designations to avasopasem manganese for the reduction of radiotherapy-induced severe oral mucositis.

The trial enrolled patients with locally advanced or borderline resectable pancreatic cancer who had completed initial chemotherapy. Patients were randomized to 90 mg of intravenous (IV) avasopasem manganese plus SBRT (n = 24) or SBRT plus an IV placebo (n = 24). The following SBRT doses were assigned in real-time by 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).

Regarding baseline characteristics, patients in the investigational arm were slightly older, with a median age of 72 years versus 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 manganese/SBRT arms, respectively. Across both arms, the median CA19-9 level was approximately 27, and few patients were smokers. 

The primary end point was the first recommended dose of SBRT with avasopasem manganese or placebo based on grade 3/4 gastrointestinal toxicity or death within 90 days following SBRT and the 90-day rate of local stable disease or better following SBRT. Secondary end points consisted of 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. The single-center cohort was the focus of this presentation. 

Results also showed that the best response rate was 54% with avasopasem manganese versus 13% with SBRT/placebo. 

The median duration of local regional control was not reached (NR) with avasopasem manganese/SBRT versus 15 weeks with SBRT/placebo (HR, 0.10; P = .051). Moreover, the time to distant metastasis was more than doubled with the addition of avasopasem manganese, at 34.7 weeks versus 12.7 weeks with SBRT/placebo (HR, 0.40; P = .068).

Among patients who underwent surgical resection (n = 5 with avasopasem manganese/SBRT; n = 2 with SBRT/placebo), all patients who received avasopasem manganese/SBRT achieved clear margins (R0) versus 1 in the SBRT-alone arm. 

Among all patients who had been randomized in both the single-center and multicenter cohorts (n = 42), the median PFS estimates in resected patients, censoring for surgery, were 29.3 weeks versus 30.6 weeks in the avasopasem manganese/SBRT (n = 24) and SBRT/placebo (n = 18) arms, respectively (HR, 0.60; 95% CI, 0.23-1.56; P = .2852). The median OS estimates were NR versus 38.7 weeks with SBRT/placebo (HR, 0.40; 95% CI, 0.12-1.11; P = .0643).

Regarding safety, the incidence of acute (≤90 days) or late (91-365 days) grade 3 or higher acute adverse effects (AEs) post SBRT was comparable between arms, occurring in approximately 5% and 8% of patients, respectively. 

“LAPC is a devastating diagnosis with limited treatment options. By combining our investigational dismutase mimetics with SBRT, we believe we have an opportunity to improve tumor response and survival outcomes,” concluded Sorensen.

References

  1. 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.
  2. 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 October 29, 2020.