Article
FDA Grants Fast Track Designation to Devimistat for AML
Author(s):
December 15, 2020 - The FDA has granted a fast track designation to devimistat for the treatment of patients with acute myeloid leukemia.
The FDA has granted a fast track designation to devimistat (CPI-613) for the treatment of patients with acute myeloid leukemia (AML).1
“Receiving fast track designation, especially during a pandemic that has created significant challenges for many trials across the globe, is a testament to the dedicated work of the Rafael team,” Sanjeev Luther, president and CEO of Rafael Pharmaceuticals, Inc, stated in a press release. “We would not be here without the support of the FDA, our doctors, our patients, and all who are invested in the hope of finding a successful treatment for this hard-to-treat cancer.”
Devimistat was developed to selectively target the mitochondrial tricarboxylic acid (TCA) cycle in cancer cells, which is a process that is heavily involved with tumor cell proliferation and survival.2 The impact of the agent on the TCA cycle works to significantly increase the sensitivity of cancer cells to a wide range of chemotherapy agents; this also allows for the agent to be combined with lower doses of these agents to offer strong efficacy with fewer toxicities.
In the multicenter, open-label, randomized phase 3 ARMADA trial (NCT03504410), investigators have set out to examine the efficacy and safety of devimistat in combination with high-dose cytarabine and mitoxantrone vs high-dose cytarabine and mitoxantrone and control subgroups comprised of mitoxantrone, etoposide, and cytarabine (MEC), as well as fludarabine, cytarabine, and filgrastim (FLAG) in older patients with relapsed/refractory AML.3,4
To be eligible for participation, patients had to be at least 50 years of age with histologically documented AML that is relapsed from, or refractory to, previous standard therapy. They had to have an ECOG performance status ranging from 0-2, an anticipated survival of longer than 3 months, no history of additional risk factors for torsade de pointes, and no marked baseline prolongation of QT/QTc interval. Patients also needed to have acceptable hepatic and renal function and adequate coagulation.
Participants in the experimental arm received devimistat at a daily dose of 2,000 mg/m2 from day 1-5, cytarabine at a dose of 1 gm/m2 for 5 doses every 12 hours starting on day 3, and mitoxantrone at a dose of 6 gm/m2 for 3 doses daily following the first, second, and fifth doses of cytarabine.
In the control arm of cytarabine and mitoxantrone, the drugs were administered at the same dose and schedule as the experimental cohort. In the MEC subgroup, etoposide was given at a dose of 80 mg/m over the course of 60 minutes via intravenous (IV) infusion; doses were administered on days 1-6 and cytarabine was given at a dose of 1000 mg/m2 over a 3-hour IV infusion for 6 doses on days 1-6. Lastly, IV mitoxantrone was given at a dose of 6 mg/m2 over the course of 30 minutes for 6 doses on days 1-6. In the FLAG subgroup, patients were given IV fludarabine at a daily dose of 30 mg/m2 over 30 minutes for 5 doses on days 1-5, IV cytarabine at a dose of 2 g/m2 over the course of 4 hours, 4 hours following fludarabine, which was given for 5 doses on days 1-5. Filgrastim was given at a daily subcutaneous dose of 5 µg/kg in accordance with institutional guidelines on days 1-5.
The primary end point of the trial is complete remission (CR) in a time frame of 8 months, while key secondary end points comprise overall survival and CR plus CR with partial hematological recovery.
The trial was initiated in November 2018,5 and it crossed the enrollment of 100 patients in October 2020.6 An earlier dose-escalation phase 1 trial (NCT01768897) examined the safety of devimistat plus high-dose cytarabine and mitoxantrone in patients with relapsed or refractory AML and found that the combination elicited an overall response rate (ORR) of 50% and a median survival of 6.7 months in a total of 62 response-evaluable patients.5 In the phase 2 trial (NCT02484391) examining the regimen, the ORR was 45% in 48 response-evaluable patients, with a median survival of 10.4 months.5
Previously, in November 2020, the agent was granted a fast track designation for use in the treatment of patients with metastatic pancreatic cancer6, and the phase 3 AVENGER 500 trial (NCT03504423) was launched to examine the safety and efficacy of devimistat in patients with pancreatic cancer; the trial met its target enrollment of 500 patients in August 2020.7
Most recently, in November 2020, devimistat was granted an orphan drug designation for the treatment of patients with soft tissue sarcoma, and a clinical trial is planned to examine its use in patients with relapsed/refractory clear cell disease.8
References
1. UPDATE – 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 December 15, 2020. http://bit.ly/3r07BQV.
2. CPI-613 (devimistat). Rafael Pharmaceuticals, Inc, website. Accessed December 15, 2020. http://bit.ly/2WpnP7T.
3. Clinical trial AML003: older patients with acute myeloid leukemia (AML) – relapsed or refractory. Rafael Pharmaceuticals, Inc, website. Accessed December 15, 2020. http://bit.ly/3r36FLq.
4. Study evaluating efficacy and safety of CPI-613 in combination with HD cytarabine and mitoxantrone compared to HD cytarabine and mitoxantrone and control sub-groups: MEC and FLAG in older patients with R/R AML. ClinicalTrials.gov. Updated July 20, 2020. Accessed December 15, 2020. https://clinicaltrials.gov/ct2/show/NCT03504410.
5. Rafael Pharmaceuticals announces initiation of pivotal phase 3 trial (ARMADA 2000) of CPI-613 (devimistat) in patients with relapsed or refractory acute myeloid leukemia (AML). News release. Rafael Pharmaceuticals, Inc. November 29, 2018. Accessed December 15, 2020. http://bit.ly/3r1abGs.
6. Rafael Pharmaceuticals crosses enrollment of 100th patient in pivotal phase 3 trial (ARMADA 2000) of CPI-613 (devimistat) for relapsed or refractory acute myeloid leukemia (AML). News release. Rafael Pharmaceuticals, Inc. October 27, 2020. Accessed December 15, 2020. http://bit.ly/3r3mbHd.
7. FDA grants Rafael Pharmaceuticals orphan drug designation for CPI-613 (devimistat) for treatment of soft tissue sarcoma. News release. Rafael Pharmaceuticals, Inc. October 29, 2020. Accessed December 15, 2020. https://bit.ly/35WsDqY.
