AVENGER 500 Clinical Trial Shows No Overall Survival Benefit

NIAID; Flickr

The goal of phase III clinical trials is to prove that the new treatment is more effective than existing treatments. If that goal is not met, a drug will not get approved.

In 2021 it was announced that the AVENGER 500 trial did not meet its primary endpoint over overall survival. Now we are learning more details. According to data published in August 2024 in Journal of Clinical Oncology, the phase III AVENGER 500 trial did not significantly improve short- or long-term outcomes over standard treatment. The trial compared the combination of CPI-613 (devimistat) and modified FOLFIRINOX (mFFX) with standard FOLFIRINOX in patients with metastatic pancreatic cancer.

Looking at the Results

The findings showed that the median overall survival was 11.10 months with devimistat plus mFFX compared with 11.73 months with FOLFIRINOX.

Devimistat is designed to target the mitochondria of cancer cells in order to disrupt their energy production, cutting off the fuel for disease growth, according to Cornerstone Pharmaceuticals (formerly Rafael Pharmaceuticals), which sponsored the study. But the researchers concluded and wrote: “. . . there was no benefit with the addition of devimistat to mFFX in patients with metastatic pancreatic cancer.” And although targeting altered metabolism is both “rational” as well as “an attractive hypothetical approach,” it was ultimately not successful in this patient population. But there remains “. . . an urgent need to develop better strategies that can be explored preclinically, especially combinations that would mitigate the metabolic adaptations of cancer cell resistance to a single enzyme/pathway blockade,” they wrote.

About the Study

The open-label trial included 528 patients from six countries in North America, Europe, and Asia. To participate, patients had to have stage IV pancreatic cancer that had not previously been treated or had previous treatment that ended more than six months prior to joining the trial. Participants also had to be reasonably active and able to care for themselves.

Of the 266 patients randomly assigned to the devimistat/mFFX arm, 259 received treatment. At the time of data cutoff, 23 were still receiving the regimen, while 236 had discontinued the regimen. The most common reason for discontinuation was disease progression. Other reasons included toxicities, patient withdrawal, a decision made by a physician, or death of the patient, among other reasons. Of the 262 patients assigned to the control arm, 235 received treatment and 16 were still receiving treatment. A total of 219 patients discontinued treatment due to disease progression, patient withdrawal, adverse effects, physician decision, and other reasons.

Devimistat has been granted orphan drug designation by the U.S. Food and Drug Administration for the following indications: pancreatic cancer, acute myeloid leukemia, Burkitt’s lymphoma, biliary tract cancer, soft tissue sarcoma, myelodysplastic syndrome, and peripheral T-cell lymphoma, according to Cornerstone Pharmaceuticals.

Research into devimistat continues. A phase I study of the drug in combination with gemcitabine and radiation in patients with pancreatic cancer is recruiting participants at Froedtert & Medical College of Wisconsin, in Milwaukee.

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