Enrollment Milestone Reached for Phase 3 Study of Devimistat in AML

The phase 3 ARMADA 2000 (NCT03504410) trial, which aims to determine the efficacy and safety of devimistat (CPI-613) in combination with high-dose cytarabine and mitoxantrone (CHAM) compared to controls for older patients with relapsed or refractory (R/R) acute myeloid leukemia (AML), has crossed the enrollment of 150 participants, according to a press release by Rafael Pharmaceuticals, Inc.¹ 

Devimistat targets enzymes located in the mitochondria that are involved in cancer cell energy metabolism. It is designed to target the mitochondrial tricarboxylic acid cycle, which is essential to cancer cell survival and multiplication. It increases tumor cell’s sensitivity to chemotherapy while also potentially allowing for lower doses of the agents. This allows for the therapy to be more effective while also being less toxic. It has also been approved by the FDA for study in pancreatic cancer. The FDA has granted orphan drug status to devimistat for pancreatic cancer, AML, myelodysplastic syndrome, peripheral T-cell lymphoma, and Burkitt’s lymphoma. The agent has also received fast-track designation for the treatment of AML at the end of 2020.

The ARMADA-2000 study has an estimated enrollment of 500 patients and has an estimated completion date of March 2023. The primary end point of the study is complete remission (CR) with a time frame of 8 months. Secondary outcomes include overall survival and CR or CR with partial hematological recovery.

The study is split into 2 arms. In the first arm, patients receive 2000/mg/m2/day of devimistat from days 1 to 5 and 5 doses of cytarabine at 1gm/m2 every 12 hours starting on day 3. The patients also receive 3 doses of mitoxantrone at 6gm/m2 every day following the 1,2, and 5 doses of cytarabine. Patients in arm 2 are split into 3 separate subgroups. In one subgroup, patients receive the same dose of cytarabine and mitoxantrone as the patients in arm 1. In another subgroup, participants receive 6 doses of etoposide at 800 mg/m2 over 60 minutes, 1000/mg/m2 of cytarabine on days 1 through 6, and 6 mg/m2 of mitoxantrone on days 1 through 6. In the third subgroup, patients receive fludarabine at 300mg/m2/day on days 1 through 5. Additionally, the receive 2g/m2 of cytarabine 4 hours after the fludarabine and Filgrastim 5µg/kg/day on days 1-5.

Currently, there is no standard AML therapy. Additionally, older patients face a grimmer prognosis than other patients.

“The need for new and novel treatments in AML continues to grow alongside the estimated incidence rate,” said Richard Larson, MD, Director of the Hematologic Malignancies Program at the University of Chicago Medical Center and a principal investigator on the phase 3 clinical trial in a press release. “As patients face a diagnosis with relapsed or refractory AML, the potential of these treatments is incredibly important.”

Deviminstat first demonstrated promise in a phase 1 study with CR rate of 50% in patients with R/R AML. Additionally, a phase 1/2 of older patients with AML, the agent achieved a CR rate of 52%. These studies provided ationale to explore the use of deviminstat in a larger pool of older patients with R/R AML.²

 In order to participate, patients must be 50 years of age or older, a diagnosis of R/R AML, and an expected survival greater than 3 months. Patients who received cytotoxic chemotherapy treatment for R/R AML are not eligible to participate.

Every enrollment is an opportunity for us to hope for the future of this therapy for very hard-to-treat cancers,” said Sanjeev Luther, president and chief executive officer of Rafael Pharmaceuticals in a press release. “The pace at which we are enrolling patients demonstrates the need for more effective AML treatments.

_REFERENCE:

_{1. Rafael Pharmaceuticals crosses enrollment of 150 patients in pivotal phase 3 trial (ARMADA 2000) of CPI-613® (Devimistat) for relapsed or refractory acute myeloid leukemia (AML). News Release. April 1, 2021. Accessed March 31, 2021. https://bit.ly/3fx8qNM.}

_{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). doi: 10.2217/fon-2019-0201}