Phase 3 ARMADA 2000 Trial of Devimistat in Relapsed/Refractory AML to Continue

An independent data monitoring committee has recommended that the phase 3 ARMADA 200 trial (NCT03504410) examining devimistat (CPI-613) plus high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia (AML) continue as planned.¹

The committee met on June 25, 2021, and as part of the preplanned interim futility analysis, they looked at 142 patients who comprised the intention-to-treat population and determined the trial to be non-futile.

“The findings from this interim futility analysis further solidify the potential that devimistat holds in safely and effectively treating AML and other hard-to-treat cancers,” Sanjeev Luther, president and chief executive officer of Rafael Pharmaceuticals, stated in a press release. “As we continue to advance devimistat through clinical trials, we remain hopeful for the cancer community.”

An intravenously administered, novel lipoate analog, devimistat was designed to inhibit 2 key tricarboxcylic acid (TCA) cycle enzymes: pyruvate dehydrogenase and α-ketoglutarate dehydrogenase complexes.² The former complex controls TCA cycle entry of glucose, while the latter controls entry of glutamine-derived carbons. DNA damaging agents cause AML cells to upregulate the TCA cycle and devimistat is known to increase sensitivity to them.

Data from a phase 1 study examining the agent in combination with cytarabine plus mitoxantrone showed that the regimen elicited a complete remission (CR) rate of 50% in patients with relapsed or refractory AML.

In the combined phase 1/2 trial, devimistat was given at a dose of 2000 mg/m2 to older patients with relapsed/refractory disease; these patients experienced a CR/CR with incomplete hematologic (CRh) recovery rate of 32%. The median overall survival achieved with the agent in these patients was 12.4 months.

In the open-label, multicenter, phase 3 trial, the safety and efficacy of devimistat plus high-dose cytarabine and mitoxantrone is under examination in older patients with relapsed/refractory AML.

In the futility analysis, 2 cohorts were compared: those who received the agent with high-dose cytarabine and mitoxantrone and those who were only given high-dose cytarabine and mitoxantrone. Control subgroups will include mitoxantrone, etoposide, and cytarabine, as well as a regimen comprised of fludarabine, cytarabine, and filgrastim.

The primary end point of the trial is CR, and secondary end points include overall survival and CR+CRh.

Devimistat was granted an orphan drug designation for the treatment of patients with pancreatic cancer, AML, myelodysplastic syndrome, peripheral T-cell lymphoma, soft tissue sarcoma, Burkitt lymphoma, and biliary cancer. The European Medicines Agency has granted an orphan drug designation to the agent as a potential option for pancreatic cancer and AML.

References

1. Rafael Pharmaceuticals announces positive preplanned interim futility analysis of pivotal phase 3 trial (ARMADA 2000) of CPI-613 (devimistat) for relapsed or refractory acute myeloid leukemia (AML). News release. Rafael Pharmaceuticals, Inc. July 1, 2021. Accessed July 1, 2021. https://bit.ly/3xe1YBd
2. Pardee TS, Luther S, Buyse M, et al. Devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone in older patients with relapsed/refractory acute myeloid leukemia: ARMADA 2000 phase III study. Future Oncol. 2019;15(28):3197-3208. doi:10.2217/fon-2019-0201