Devimistat Moves Into Phase 3 Testing for Metastatic Pancreatic Cancer

Philip A. Philip, MD

AVENGER 500, a pivotal phase 3 clinical trial evaluating the efficacy and safety of devimistat for patients with metastatic pancreatic cancer, has achieved its target enrollment of 500 patients. However, enrollment will remain open for the time being, according to principal investigator Philip A. Philip, MD, who added that he hopes that preliminary results will be available early next year.

Rafael Pharmaceuticals developed devimistat, formerly CPI-613, for use in combination with modified FOLFIRINOX in the first-line setting. Devimistat is a first-in-class agent that selectively targets the mitochondrial tricarboxylic acid (TCA) cycle in tumor cells, which is essential to tumor cell multiplication and survival. The novel lipoate analog simultaneously inhibits pyruvate dehydrogenase (PDH) and a-ketoglutarate dehydrogenase (KGDH), thereby blocking the entry of either glucose- or glutamine-derived carbons into the TCA cycle.

Philip, a professor of oncology at the Barbara Ann Karmanos Cancer Institute at Wayne State University, told OncLive that the drug substantially increases the sensitivity of cancer cells to a diverse range of chemotherapeutic agents. This synergy may mean that combinations containing devimistat will be effective at lower doses, reducing the risk for toxicity.

“Currently, this is the only [ongoing] phase 3 trial [of a novel agent] in frontline pancreatic cancer in the world,” Philip said. “There is a lot of hope and anticipation of some good results.”

AVENGER 500 (NCT03504423) is an international, open-label randomized trial in which investigators are examining devimistat plus modified FOLFIRINOX versus FOLFIRINOX alone in treatment-naïve adults with stage IV metastatic pancreatic cancer between the ages of 18 and 75 years. Participants in the experimental arm are administered 500 mg/m2 of devimistat on days 1 and 3 of a 14-day cycle. They will then receive standard dose and schedule of 5-fluorouracil, but reduced doses of oxaliplatin (65 mg/m²) and irinotecan (140 mg/m²). Patients in the control arm will receive standard-dose FOLFIRINOX. Patients will be randomly assigned 1:1 between the treatment arms.

Investigators will conduct an interim analysis after 167 patients are evaluable for response.

The coprimary end points of the trial are overall response rate (ORR) and progression-free survival (PFS). An independent, blinded, central review will assess best response within the first 12 cycles to determine ORR. Secondary end points include overall survival (OS), duration of response, and safety.

“I feel like sometime in the first half of 2021 we will have some results,” Philip said. He added that the novel coronavirus 2019 pandemic slowed medical research in general, but strong support from Rafael and key opinion leaders, along with the excitement generated by previous results, helped investigators recruit patients to AVENGER 500.

The current standard therapy for this patient population is gemcitabine plus nab-paclitaxel or FOLFIRINOX. However, the median survival for these regimens is 8.5 months and 11.1 months, respectively.^1,2

Investigators evaluated the safety and efficacy of devimistat plus modified FOLFIRINOX in CCCWFU 57112 (NCT01835041), a single-center, open-label, dose-escalation study (n = 20). The maximum-tolerated dose (MTD) of devimistat was 500 mg/m².³

Among the 18 patients who received the MTD, the ORR was 61%, with a median OS of 19.9 months and a median PFS of 9.9 months. The ORR with standard FOLFIRINOX is 31.6% versus 24% with standard gemcitabine plus nab-paclitaxel.

Philip added that duration of survival with the combination was longer than investigators had anticipated.

“The objective shrinkage of the tumor was about what was expected from the chemotherapy alone, despite the fact that the doses of the drugs were somewhat lower,” Philip explained. “Three patients achieved a complete response, which is very rarely seen with chemotherapy in pancreatic cancer.”

Investigators determined that the treatment was well tolerated, overall. No deaths due to adverse events were reported and no patients died while on active treatment.

The FDA has granted devimistat orphan drug status for the treatment of patients with pancreatic cancer, acute myeloid leukemia (AML), myelodysplastic syndrome, Burkitt lymphoma, and peripheral T-cell lymphoma. The agent is also being examined in patients with AML in the phase 3 ARMADA 2000 trial (NCT03504410).

References

1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923
2. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703. doi:10.1056/NEJMoa1304369
3. 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