Devimistat, which is being evaluated in combination with modified FOLFIRINOX in the frontline treatment of patients with metastatic adenocarcinoma of the pancreas, failed to meet the primary end point of overall survival in the phase 3 AVENGER 500 trial.
Devimistat (CPI-613), which is being evaluated in combination with modified FOLFIRINOX in the frontline treatment of patients with metastatic adenocarcinoma of the pancreas, failed to meet the primary end point of overall survival (OS) in the phase 3 AVENGER 500 trial (NCT03504423).1
The agent has also been under investigation for use in those with relapsed/refractory acute myeloid leukemia (AML) as part of the phase 3 ARMADA 2000 trial (NCT03504410), which has been stopped due to lack of efficacy following a recommendation from an independent data monitoring committee.
“These cancers are incredibly difficult to treat, with few to no effective treatments available, but Rafael Pharmaceuticals, Inc. took the risk because we will always fight for our patients,” Sanjeev Luther, president and chief executive officer of Rafael Pharmaceuticals, stated in a press release. “While we are disappointed by the outcomes of these well-designed and well-executed studies, we remain committed to furthering our research and development in cancer metabolism for the treatment of hard-to-treat cancers, as our other studies continue.”
Devimistat is a first-in-class agent that targets enzymes that are involved in cancer cell energy metabolism and are in the mitochondria of cancer cells. The agent was developed to target the mitochondrial TCA cycle, which is a key process associated with tumor cell multiplication and survival. Devimistat significantly increases cellular stress and the sensitivity of cancer cells to a wide range of chemotherapeutic agents, and the synergy permits for potential combinations that are effective without the added cost of toxicity.
The multicenter, open-label AVENGER 500 enrolled a total of 528 patients with metastatic adenocarcinoma of the pancreas who had not previously received any treatment. To be eligible for enrollment, patients needed to be between the ages of 18 years and 75 years and an ECOG performance status of 0 or 1.2
Study participants were randomized 1:1 to receive devimistat at a dose of 500 mg/m2 on days 1 and 3 of a 14-day cycle followed by modified FOLFIRINOX, which consisted of a standard dose and schedule of 5-flourouracil and reduced doses of oxaliplatin (65 mg/m2) and irinotecan (140 mg/m2), or standard-of-care FOLFIRINOX.3
The primary end point of the trial was OS, and key secondary end points included progression-free survival, duration of response, and overall response rate.
Results indicated that when devimistat was given with modified FOLFIRINOX, it did not result in a statistically significant improvement in OS. The median OS with the addition of devimistat was 11.1 months vs 11.7 months with FOLFIRINOX (HR, 0.95; P = .66).
“Pancreatic cancer carries a high mortality rate and is extremely difficult to treat, but promising earlier clinical data encouraged us to move into this advanced phase trial with devimistat,” Philip Philip, MD, PhD, FRCP, principal investigator and medical oncologist at the Karmanos Cancer Institute at Wayne State University, stated in a press release. “We are working diligently to further analyze the data and determine the best plan of action to further assess the drug’s capabilities in the clinic.”
The open-label, multicenter, phase 3 ARMADA 200 trial evaluated the safety and efficacy of devimistat in combination with high-dose cytarabine and mitoxantrone in older patients with relapsed/refractory AML.4
Two cohorts were compared as part of a futility analysis: those who received the agent plus high-dose cytarabine and mitoxantrone or those given only high-dose cytarabine and mitoxantrone. The control subgroups included mitoxantrone, etoposide, and cytarabine, as well as a regimen composed of fludarabine, cytarabine, and filgrastim.
The primary end point of the trial was complete remission (CR), and secondary end points comprised OS and CR plus CR with incomplete hematologic recovery (CRh).
Previously, in July 2021, an independent data monitoring committee had recommended that ARMADA 200 continue as planned after they had convened for a meeting held on June 25, 2021. The meeting was part of the preplanned interim futility analysis, where they looked at data collected from 142 patients who made up the intent-to-treat population. They determined that the trial was non-futile.5
Prior data from a phase 1 study evaluating the agent in combination with cytarabine plus mitoxantrone showed that the triplet resulted in a CR rate of 50% in patients with relapsed/refractory AML. A combined phase 1/2 trial evaluated the agent delivered at a dose of 2000 mg/m2 in patients with relapsed/refractory disease. Results showed that the CR/CRh rate in these patients was 32% with the regimen, and the median OS was 12.4 months.
“Earlier clinical trial data demonstrated positive results, despite the challenges we face in treating AML,” Jorge Cortes, MD, director of the Georgia Cancer Center at Augusta University, stated in the press release. “We were all hoping for positive results and while this trial did not meet our expectations, we will continue to test devimistat in other studies.”
Rafael Pharmaceuticals are working with investigators to complete a full evaluation of the data produced on both trials of devimistat.