Devimistat, a small molecule that targets enzymes involved in cancer cell metabolism, holds promise for older patients with relapsed or refractory acute myeloid leukemia who typically have a poor prognosis with standard-of-care chemotherapy
Devimistat (CPI-613), a small molecule that targets enzymes involved in cancer cell metabolism, holds promise for older patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who typically have a poor prognosis with standard-of-care chemotherapy, investigators said. The drug is combined with chemotherapy in the phase 3 ARMADA 2000 trial (AML003; NCT03504410).1
Devimistat is directed at the mitochondrial tricarboxylic acid (TCA) cycle, inhibiting activity of pyruvate dehydrogenase and αketoglutarate dehydrogenase, enzymes that regulate glucose-derived and glutamine-derived carbons in the TCA cycle. Devimistat therapy results in decreased oxygen consumption in AML cells, sensitizing them to chemotherapy.2
In December 2020, the FDA granted devimistat a fast track designation for the treatment of AML, a decision that “underscores the pressing need to find new ways to combat this aggressive disease,” according to Jorge Cortes, MD, principal investigator for the ARMADA 2000 trial.3
“There has been some work already in the clinic prior to this study that made us excited about this agent; it has shown increased activity from what you would expect from just chemotherapy,” Cortes said in an interview with OncologyLive®.
Cortes, who is director of the Georgia Cancer Center at Augusta University, said research still has a way to go to improve outcomes for patients with AML. “This is a hard population to treat but we are confident we have a good chance of showing some benefit for the patient. These patients need something because the response rates with standard chemotherapy are very poor and, even for the patients who respond, they tend to lose their response very quickly and survival is very poor.”
Overall, the 5-year relative survival rate for patients with AML is 28.7%, according to statistics from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program.4 The median age at diagnosis is 68 years. (Figure 14). Outcomes deteriorate for patients with AML as they age.5 Although patients may initially respond to therapy, more than 50% experience a relapse and are then likely to die within a year.2
The rationale for the ARMADA 2000 trial is based on findings from a phase 1 study (NCT01768897) that tested the addition of devimistat to cytarabine plus mitoxantrone in older patients with R/R AML. The study enrolled 67 patients with a median age of 60 years (range, 21-79); 54% were 60 years or older. The median level of blasts in the marrow was 43% (range, 4%-97%), and 72% of participants had not undergone prior salvage therapy.2
Among 62 evaluable patients, the overall response rate (ORR) was 50%, comprised of 26 participants with a complete remission (CR) and 5 with a CR with incomplete hematologic recovery (CRi). Median survival was 6.7 months. Patients achieving a CR or CRi had a median survival of 13.2 months. In participants over 60 years old, the CR/CRi rate was 47% (15 of 32 patients), with a median survival of 6.9 months. Historically, investigators said, only 33% of older patients reach a CR/CRi. They found the study regimen was well tolerated.2
The ARMADA 2000 trial is enrolling patients 50 years and older with R/R AML after prior standard therapies (FIGURE 21,6). Refractory disease is defined as failing to achieve CR/CRi after at least 1 cycle of an induction regimen containing an anthracycline, cytarabine, or fludarabine; or at least 2 cycles of a hypomethylating agent (azacytidine or decitabine) with or without venetoclax (Venclexta). Relapse is considered recurrent AML after CR/CRi has been reached on prior therapy.1
Devimistat will be assessed in combination with high-dose cytarabine plus mitoxantrone (CHAM) compared with control therapy with 1 of 3 chemotherapy regimens. In the comparator arm, physicians can choose from: high-dose cytarabine plus mitoxantrone (HAM); mitoxantrone, etoposide, plus cytarabine (MEC); or fludarabine, cytarabine, plus filgrastim (FLAG).1
In the CHAM arm, devimistat is administered intravenously at 2000 mg/m2 per day on days 1 to 5, along with cytarabine at 1 gm/m2 on days 3 through 5, and mitoxantrone at 6 gm/m2 every day following the first, second, and fifth doses of cytarabine.
In the comparator arm, the HAM regimen follows the same dosing for cytarabine and mitoxantrone. In the MEC regimen, etoposide is being given at 80 mg/m2; cytarabine at 1000 mg/m2; and mitoxantrone at 6 mg/m2, all administered on days 1 through 6. The FLAG regimen is comprised of fludarabine at 30 mg/m2 on day; cytarabine at 2 g/m2; and filgrastim at 5 µg/kg per day, all administered on days 1 through day 5.1
The primary end point is CR. Secondary end points include overall survival (OS) and CRi. The trial aims to enroll 500 patients at about 50 sites in the United States, Canada, Europe, South Korea, and Australia.6 The trial is about 85% enrolled, and an interim analyis is expected in the second quarter of this year, according the developer, Rafael Pharmaceuticals, Inc.
Because of its mechanism of action, investigators believe devimistat may be effective in other cancer types. Devimistat is being studied as a single agent and in combination regimens in multiple trials.
In solid tumors, studies are ongoing in metastatic colorectal and pancreatic cancers. A phase 1/2 study (NCT04593758) in R/R clear cell soft tissue sarcoma is planned but is not yet recruiting patients. In hematologic malignancies, the agent is being tested in R/R settings in myelodysplastic syndromes, T-cell lymphoma, and Burkitt lymphoma or high-grade B-cell lymphoma.7
The most advanced of these studies is the phase 3 AVENGER 500 (NCT03504423) trial in which devimistat is being tested in combination with modified FOLFIRINOX (folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin) compared with FOLFIRINOX alone in metastatic pancreatic cancer. This trial, which has already recruited 500 patients, will assess progression-free survival as the primary end point. Secondary end points include OS, duration of response, and ORR.8
In November 2020, the FDA granted a fast track designation to devimistat for the treatment of pancreatic cancer. Devimistat also has orphan drug designations for clear cell sarcoma, AML, pancreatic cancer, myelodysplastic syndrome, peripheral T-cell lymphoma, and Burkitt lymphoma. The compound has also received orphan drug designation for AML and pancreatic cancer from the European Medicines Agency.9