Large Phase III Global Trial Targets Cancer Metabolism

Disrupting a cancer cell’s ability to grow and spread by targeting its metabolism is an area of research gaining significant momentum.

Rafael Pharmaceuticals announced on October 28, 2021 that the AVENGER 500 clinical trial failed to meet its primary endpoint of overall survival. Trial data is still being evaluated. 

One novel drug currently in a Phase III global trial called AVENGER 500 is dubbed devimistat (CPI-613). The drug targets enzymes (ketoglutarate dehydrogenase and pyruvate dehydrogenase) that are involved in cancer cell energy metabolism. These enzynes are located in the mitochondria of cancer cells. Mitochondria are membrane-bound cell organelles that generate most of the chemical energy needed to power the cells’ biochemical reactions.

Devimistat has received so-called Fast Track designation from the U.S. Food and Drug Administration (FDA) for the treatment of metastatic pancreatic cancer. Put simply, that means the drug will receive expedited review by the FDA. The designation is given to drugs that treat a serious or life-threatening condition and fill an unmet medical need.

The drug’s novel mode of action—targeting the complex cycle of metabolism rather than a genetic mutation—is intriguing to scientists who have seen the promise of drugs or treatment strategies that have improved outcomes in other cancers fail to produce robust results in pancreas cancer.

Metabolism May Be Key

Pancreatic cancer does not—as of yet—have an established early detection strategy. And although surgery can be curative, most patients experience recurrence due to micrometastases (small cancer cells from the primary tumor that travel through the blood or lymph system and spread the disease to other parts of the body). Genomic profiling, so far, has only been beneficial for a very small number of patients. Immunotherapy strategies have not yet been effective in pancreatic cancer.

“There has been progress in all areas [of pancreatic cancer treatment], but the progress has been really quite modest in the sense that we are inching forward,” says lead investigator Philip Philip, M.D., Ph.D., F.R.C.P., who serves as the Kathryn Cramer, M.D., Endowed Chair in Cancer Research and leader of the Gastrointestinal and Neuroendocrine Multidisciplinary Team at the Barbara Ann Karmanos Cancer Institute in Detroit, Michigan. “So, as scientists and as physicians who treat patients, we need to develop new strategies and start to really look at areas that haven’t been tested before. That’s where cancer metabolism comes into play.”

One reason that physician-scientists are hopeful about targeting cancer metabolism is that most drugs being tested for cancer treatment are cytotoxic, meaning they not only kill cancerous cells but healthy cells, too. That results in too many adverse events for patients, many of whom get too sick to complete treatment.

But devimistat has been shown to increase the sensitivity of cancer cells to different chemotherapy agents, meaning that, potentially, chemotherapy could be given at lower doses. Plus, devimistat itself is well tolerated. “Being able to reduce toxicity for our patients while increasing the sensitivity of cancer cells to those therapies could potentially be a game changer,” says Philip, who also serves as professor of hematology and oncology at Detroit’s Wayne State University School of Medicine. “I am hopeful, very hopeful. But I won’t get excited until I see the data. Right now, in frontline pancreatic cancer treatment, this [AVENGER 500] is one of the largest, most novel, trials in the world. I really hope that things shake out well because we desperately need better treatments for this disease.”

The novel drug actually targets two enzymes in what is called the Krebs cycle in the mitochondria. The Krebs cycle is basically the cycle of chemical reactions that serves as the major source of energy in living organisms. “It [devimistat] shuts down an important pathway for the cancer cells, and how they use glucose,” Philip adds. “Cancer cells will take the glucose, the sugar, and metabolize it. Devimistat targets those enzymes whose jobs it is to work on that pathway. If you start to chip away and shut off that energy source the cancer cells can’t grow or divide.”

About AVENGER 500

AVENGER 500 enrolled patients in 75 sites around the world, in countries including the United States, South Korea, Israel, Belgium, France, and Germany. It reached target enrollment quickly, “which shows just how much new treatments are needed and that patients are willing to try something that could potentially lengthen their lives,” posits Philip. “The fact that it accrued so rapidly during a pandemic reinforces that there really is an unmet need for these patients.”

In June 2021, due to rapid accrual, the researchers were able to change the trial design to the primary endpoint of “overall survival” (OS) versus the initial endpoint of “progression free survival” (PFS). OS measures how long patients who undergo a certain treatment regimen live compared to patients who are in a control group. If a clinical trial demonstrates improved OS, it provides evidence of the drug’s value in prolonging a cancer patient’s life. PFS measures how long a person lives without the disease worsening. “In a cancer trial, the gold standard really is overall survival and we were in a position, because of how quickly this trial accrued, to pivot and get that kind of data,” Philip says. The study start date was November 9, 2018, and the expected study primary endpoint readout is in fourth quarter 2021.

Room for More Investigation

Devimistat is also being studied in early phase trials in pancreatic cancer combining it with gemcitabine and nab-paclitaxel. It is also being investigated as a neoadjuvant agent combined with chemotherapy, according to Philip.

“I think that as we move forward we will start to look at potential biomarkers that could potentially tell us what patients may benefit most from the drug,” Philip says. “We might try to see if this will help with immunotherapy. There is so much room for investigation and to design intelligent clinical trials.”

Devimistat has been granted orphan drug status by the FDA for the treatment of pancreatic cancer, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), Burkitt’s lymphoma, peripheral T-cell lymphomas, soft tissue sarcoma, and biliary cancer.

Because almost all pancreatic cancer patients have metastases or micrometastatic disease, it’s important “that discoveries be made on both ends of the spectrum,” Philip adds. “On one end we absolutely need earlier detection and at the other end we need better systemic drugs for pancreatic cancer,” he says.