A pivotal multicenter, open-label, randomized phase III trial has been initiated to evaluate the efficacy and safety of the novel mitochondrial inhibitor, devimistat in combination with a modified FOLFIRNOX regimen for the first-line treatment of patients with metastatic pancreatic cancer, according to a press release from Rafael Pharmaceuticals.
A pivotal multicenter, open-label, randomized phase III trial (AVENGER 500, NCT03504423) has been initiated to evaluate the efficacy and safety of the novel mitochondrial inhibitor, devimistat (CPI-613) in combination with a modified FOLFIRNOX regimen for the first-line treatment of patients with metastatic pancreatic cancer, according to a press release from Rafael Pharmaceuticals.1
Devimistat is a first-in-class agent that targets enzymes in the mitochondria of cancer cells that affect cancer cell energy metabolism, resulting in tumor cell apoptosis and necrosis. Based on the performance of the drug in multiple disease states, the FDA has granted it orphan drug designation in pancreatic cancer, acute myeloid leukemia, myelodysplastic syndrome, peripheral T-cell lymphoma, and Burkitt’s lymphoma. The drug also has orphan drug designation from the European Medicines Agency (EMA).
“Pancreatic cancer is one of the deadliest cancers in the world and patients with metastatic pancreatic cancer, specifically, have a very low 5-year survival rate of 3%,” Sanjeev Luther, president and CEO of Rafael Pharmaceuticals, said in the press release. The company hopes that the combination will show improved outcomes for patients with pancreatic cancer.
The 2 primary endpoints to measure these outcomes are overall response rate (ORR) and progression-free survival (PFS). The secondary endpoints are overall survival (OS) and duration of response (DOR).
The AVENGER 500 trial plans to enroll 500 patients and randomize them to FOLFIRNOX monotherapy or the combination for devimistat and FOLFIRNOX. In the experimental arm, patients will receive 500mg/m2of devimistat by IV infusion on days 1 and 3 of a 14-day cycle. Immediately after devimistat is administered, patients are given FOLFIRNOX (oxaliplatin 65 mg/m2, folinic acid 400 mg/m2, irinotecan 140 mg/m2, and fluorouracil 400 mg/m2).
In the comparator arm, patients will receive a higher dose of FOLFIRNOX (oxaliplatin 85 mg/m2, folinic acid 400 mg/m2, irinotecan 180 mg/m2, and fluorouracil 400 mg/m2).
The trial is recruiting patients between the ages of 18 and 75 with an ECOG performance status of 0 or 1 who have had no prior treatments for stage IV pancreatic cancer and who have adequate hepatic, renal, and coagulation function. Patients with known cerebral, central nervous, and epidural tumor metastases are excluded. Other important exclusion criteria include previous chemotherapy for pancreatic cancer and having received gemcitabine-based chemotherapy or neoadjuvant/adjuvant FOLFIRNOX within 6 months of starting the trial. Already 100 patients have been enrolled in the trial, which is a significant milestone.
AVENGER 500 follows a phase I dose-finding study (NCT01835041) of devimistat with FOLFIRNOX, in which the maximum-tolerated dose was found to be 500 mg/m2/day given at a rate of 4 mL/min on days 1 and 3.2Although the phase II trial (NCT03374852) never opened for accrual, other clinical trials have shown the potential of devimistat, according to Rafael Pharmaceuticals. A phase III trial is also being initiated to study devimistat in patients with acute myeloid leukemia, the ARMADA 2000 study.
The rationale and design for AVENGER 500 were developed by Philip A. Philip, MD, professor of oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University. Philip is the lead investigator for the study and believes the combination has strong potential for treating patients with metastatic pancreatic cancer.
“Pancreatic cancer has remained a difficult disease to treat, and I am hopeful that the data from this trial will demonstrate devimistat’s potential in treating metastatic pancreatic cancer,” Philip said in a statement.
The study is actively enrolling patients throughout the United States, France, Israel, and South Korea and has an estimated completion date of March 2022.