Efficacy observed with the combination of devimistat and modified FOLFIRINOX in patients with metastatic pancreatic cancer has lead to a negative result in the phase 3 AVENGER 500 clinical trial.
The combination of devimistat (CPI-613) in combination with the combination of folinic acid, fluorouracil, irinotecan, and oxaliplatin (modified FOLFIRINOX; mFFX) showed no improvement in overall survival (OS) in patients with metastatic adenocarcinoma of the pancreas compared with mFFX alone, missing the primary end point of the phase 3 AVENGER 500 clinical trial.1
According to a press release issued by Rafael Pharmaceuticals, Inc, developer of devimistat, the median OS observed with devimistat plus mFFX was 11.1 months compared with 11.7 months in the mFFX-only arm (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. While these are not the results, we all hoped for, we will not give up, and we are hopeful that devimistat with its novel mechanism of action will demonstrate efficacy in other studies,” said Philip Philip, MD, PhD, FRCP, principal investigator and medical oncologist at the Karmanos Cancer Institute at Wayne State University, in the 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.”
AVENGER 500 is a multicenter, open-label, randomized phase 3 study in which 528 patients with metastatic pancreatic cancer were randomized 1:1 to receive either devimistat 500 mg/m2 by intravenous infusion plus mFFX consisting of oxaliplatin 85 mg/m2, folic acid 400 mg/m2, irinotecan 180 mg/m2, and fluorouracil 400 mg/m2 administered immediately after devimistat in the experimental or standard dose FFX in the control arm.2,3
The study was conducted to address the low median survival of 11.1 months and 8.5 months observed, respectively, with standards of care FFX and the combination of gemcitabine and nab-paclitaxel. The combination of devimistat and mFFX has already shown the ability to induce responses in patients with metastatic pancreatic cancer in a phase 1 study and was deemed safe to assess in patient at the maximum tolerated dose of 500 mg/m2.3,4 At a median follow up of 378 days (interquartile range, 250-602) in 20 patients, the ORR was 61% included complete and partial responses.4
No deaths resulting from adverse events (AEs) were reported in the study. The most common grade 3 or 4 non-hematologic AEs observed were hyperglycemia (55%), hypokalemia (33%), peripheral sensory neuropathy (28%), diarrhea (28%), and abdominal pain (22%). The most common grade 3 or 4 hematologic AEs in the study were neutropenia (28%). lymphopenia (28%), anemia (22%), and thrombocytopenia (17%). Cases of grade 1 to 3 sensory neuropathy was also reported in 94% of patients.
Investigators hypothesized that the combination could improve other outcomes, like survival.3
The primary end point of OS was defined as the duration from the date of randomization to the date of death of any cause. The study also explored progression-free survival, duration of response, and overall response rate as secondary end points. Outcomes were compared using the
National Comprehensive Cancer Network - Hepatibiliary Symptom Index Questionnaire. A hazard ratio of less than .48 was required for devimistat plus mFFX to be considered efficacious.
“These cancers are incredibly difficult to treat, with few to no effective treatments available, but Rafael took the risk because we will always fight for our patients,” said Sanjeev Luther, president,, and chief executive officer of Rafael Pharmaceuticals, in the press release.1 “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. I personally want to express my heartfelt appreciation to the patients, their loved ones, the researchers, and principal investigators for their trust and support. I am also incredibly grateful to my team, who works tirelessly for the patients we treat.”
1. Rafael Pharmaceuticals provides update on pivotal phase 3 clinical trial in patients with metastatic pancreatic cancer and interim analysis of pivotal phase 3 clinical trial in patients with relapsed or refractory acute myeloid leukemia. News release. Rafael Pharmaceuticals. October 28, 2021. Accessed October 28, 2021. https://bit.ly/3jGb7On
2. Phillip PA, Buyse ME, Alistar AT, et al. Avenger 500, a phase III open-label randomized trial of the combination of CPI-613 with modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas. J Clin Oncol. 2019;37(4). doi: 10.1200/JCO.2019.37.4_suppl.TPS479
3. Study evaluating efficacy and safety of FFX versus combination of CPI-613 With mFFX in patients with metastatic adenocarcinoma of the pancreas. Clinicaltrials.gov. Accessed October 28, 201
4. Alistar A, Morris BB, Desnoyer R, et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2017;18(6):770-778. doi: 10.1016/S1470-2045(17)30314-5