In a phase Ib/II trial reported in The Lancet Oncology, Cullen M. Taniguchi, MD, and colleagues found that the addition of the selective dismutase mimetic avasopasem to stereotactic body radiotherapy (SBRT) produced promising results in patients with localized pancreatic adenocarcinoma.
Cullen M. Taniguchi, MD
Study Details
The double-blind trial included 42 eligible patients from six U.S. centers with borderline resectable or locally advanced disease who had received at least 3 months of chemotherapy. They were randomly assigned between January 2018 and April 2020 to receive intravenous avasopasem at 90 mg (n = 28) or placebo (n = 14) directly prior to (ie, within 180 minutes) each fraction of SBRT at 50, 55, or 60 Gy in five fractions (adaptively assigned in real time by Bayesian estimates of 90-day safety and efficacy).
The primary objective was to identify the optimal dose of SBRT with avasopasem or placebo as determined by the late-onset EffTox method; this method determines an optimal dose on the basis of both efficacy and toxicity (not necessarily the maximum tolerated dose). Analyses were performed in the intention-to-treat population.
Key Findings
The placebo (control) group was terminated early after failing to meet prespecified efficacy parameters. At data cutoff at the end of June 2021, the avasopasem group satisfied boundaries for both efficacy and toxicity.
Late-onset EffTox efficacy responses were observed in 16 (89%) of 18 patients at 50 Gy and in 6 (100%) of 6 patients at 55 Gy in the avasopasem group; response was observed in 3 (50%) of 6 patients at 50 Gy and 9 (75%) of 12 at 55 Gy in the control group. The Bayesian model used for analysis recommended a regimen of SBRT at 50 Gy or 55 Gy in five fractions with avasopasem for further study.
Safety
Serious adverse events occurred in 25% of patients in the avasopasem group and 17% of the control group. In the placebo group, grade 3 adverse events occurring within 90 days of SBRT included abdominal pain, acute cholangitis, pyrexia, increased blood lactic acid, and increased lipase in one patient (6%) each; no grade 4 events reported. In the avasopasem group, grade 3 or 4 adverse events within 90 days of SBRT included acute kidney injury, increased blood alkaline phosphatase, hematoma, colitis, gastric obstruction, lung infection, abdominal abscess, postsurgical atrial fibrillation, and pneumonia leading to respiratory failure in one patient (4%) each.
No treatment-related deaths were reported. However, one late death in the avasopasem group due to sepsis in a patient with duodenal obstruction after off-study treatment was reported as potentially related to SBRT.
The investigators concluded, “SBRT that uses 50 or 55 Gy in five fractions can be considered for patients with localized pancreatic ductal adenocarcinoma. The addition of avasopasem might further enhance disease outcomes. A larger phase II trial (GRECO-2, [ClinicalTrials.gov identifier NCT04698915) is underway to validate these results.”
Sarah E. Hoffe, MD, of the Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Galera Therapeutics. For full disclosures of the study authors, visit thelancet.com.
