Devimistat Demonstrates Positive Outcomes in Relapsed/Refractory Acute AML

Update from a preplanned clinical trial analysis shows promise of devimistat in relapsed/refractory acute myeloid leukemia.

Devimistat (CPI-613) has yielded positive outcomes in patients with relapsed or refractory acute myeloid leukemia (AML), according to the results of a preplanned interim futility analysis of the pivotal phase 3 ARMADA 2000 trial (NCT03504410).1

As of June 25, 2021, an independent data monitoring committee determined that the study was non-futile based on the responses of 142 patients comprising the intent-to-treat population and recommended that the trial continue.

“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, said in a press release. “As we continue to advance devimistat through clinical trials, we remain hopeful for the cancer community.”

The multicenter, open label, randomized trial is assessing the safety and efficacy of devimistat in combination with high-dose cytarabine and mitoxantrone (Novantrone) in older patients with relapsed/refractory disease. In particular, the futility analysis examined 2 cohorts of patients, one of which received the combination regimen with devimistat, high-dose cytarabine, and mitoxantrone compared with the high-dose cytarabine and mitoxantrone regimen alone. The control subgroups utilized a combination of mitoxantrone, etoposide, and cytarabine, as well as a combination of fludarabine, cytarabine, filgrastim (Neupogen).

The study has a target enrollment of 500 patients who will be randomized to receive either a 2000 mg/m2 dose of devimistat from day 1 to 5 and 1 gm/m2 of cytarabine every 12 hours on day 3, and 3 doses of mitoxantrone at 6 gm/m2 every day following the first, second, and fifth doses of cytarabine; 1 gm/m2 of cytarabine every 12 hours starting at day 3 and mitoxantrone at 6 gm/m2 every day following treatment with cytarabine; intravenous etoposide (80 mg/m), cytarabine (1000 mg/m2), and mitoxantrone (6 mg/m2); or fludarabine (30 mg/m2), cytarabine (2 g/m2), and filgrastim (5µg/kg per day) on days 1 through 5.

In order to enroll, patients needed to be 50 years of age or older with an ECOG performance status of 0 to 2 and an expected survival of more than 3 months. Additionally, radiotherapy and treatment with cytotoxic chemotherapy, biologic agents, or any anti-cancer therapy for relapsed/refractory AML within 1 week of beginning treatment with devimistat was not allowed. Other exclusion criteria are a history or evidence of a significant disorder, condition, or disease; active central nervous system involvement; and any active, uncontrolled bleeding.

The primary end point of the study is complete remission (CR), with key secondary end points including overall survival (OS) and CR/CR with partial hematologic recovery (CRh).

Devimistat is a first-in-class compound that targets enzymes that are involved in cancer cell energy metabolism. The agent is able to target the mitochondrial tricarboxylic acid cycle, which is an important part of cancer cell multiplication and survival. Moreover, devimistat is able to notably increase cancer cell sensitivity with regard to chemotherapy agents, meaning there is potential synergy for combination regimens.

The FDA had previously granted devimistat a fast track designation in December 2020 for the treatment of AML.2 The FDA has also approved the initiation of a clinical trial to examine devimistat in pancreatic cancer through the phase 3 AVENGER 500 study (NCT03504423). Additionally, the drug has been granted orphan drug designation in a number of cancer types, including pancreatic cancer, AML, myelodysplastic syndrome, peripheral T-cell lymphoma, soft tissue sarcoma, Burkitt's lymphoma, and biliary cancer. The EMA has also given devimistat an orphan drug designation for both pancreatic cancer and AML.

In a previous phase 1 study, devimistat in combination with cytarabine and mitoxantrone yielded a CR rate of 50% in patients with relapsed/refractory disease.3 Moreover, a combined phase 1/2 trial indicated that older patients who received a 2000 mg/m2 dose of devimistat experienced a 52% CR/CRh, as well as a median OS of 12.4 months.


  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.
  2. Rafael Pharmaceuticals receives FDA fast track designation for CPI-613® (devimistat) for the treatment of acute myeloid leukemia (AML). News release. Rafael Pharmaceuticals, Inc. December 15, 2020. Accessed July 1, 2021.
  3. 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
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