The following is a summary of “Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial” published in the January 2023 issue of Haematology by Watts, et al.

The small-molecule inhibitor olutasidenib (FT-2102) is an extremely effective and specific inhibitor of mutant isocitrate dehydrogenase 1. (IDH1). Patients with acute myeloid leukemia or myelodysplastic syndrome who carry a mutation in the IDH1 gene were included in this phase 1/2 study to evaluate the safety, pharmacokinetics, pharmacodynamics, and clinical efficacy of olutasidenib as monotherapy or in combination with azacitidine. Patients with intermediate, high, or very high-risk myelodysplastic syndrome or acute myeloid leukemia harboring mutant IDH1 were enrolled from 18 sites in the United States, Australia, France, and Spain in this phase 1/2, multicentre, open-label clinical research. Eastern Cooperative Oncology Group performance status 0-2 with good hepatic and renal function were other important criteria for inclusion. The key endpoints included the occurrence of dose-limiting toxicities and the determination of the maximum tolerated dose, the maximum evaluated dose and the recommended dose of olutasidenib for use in phase 2. There were three different oral dosing schedules for olumasidenib: 150 mg once a day, 150 mg twice daily, and 300 mg once daily. 

Subcutaneously or intravenously given azacitidine (75 mg/m2) was used for 7 days on, 21 days off. Patients were enrolled between August 8, 2016, and November 14, 2018. A total of 78 patients were given olutasidenib, either as a single agent (n=32) or in combination with azacitidine (n=46). The median follow-up time for monotherapy was 8.3 months (IQR 3.1-13.3), while for combination therapy, it was 10.1 months (4.2-15.3). 16 (50%) of 32 patients in the monotherapy group; 24 (52%) of 46 patients in the combination therapy group were women. Most of the patients were Caucasian (26 (81%) for monotherapy and 31 (67%) for combo therapy). Considering safety, pharmacokinetics, pharmacodynamics, and clinical activity, a dose of 150 mg twice daily was suggested for phase 2. No dose-limiting toxicities were reported in the dose-escalation groups. The most common treatment-emergent adverse events (20%) were thrombocytopenia (28% of 32 patients), febrile neutropenia (22% of 32 patients), and anemia (22% of 32 patients) with monotherapy, and thrombocytopenia (41% of 46 patients), febrile neutropenia (28% of 46 patients), neutropenia (28% of 46 patients), and anemia (9% of 46 patients) with combination therapy. 

Death occurred in 11 (34%) of the 32 patients receiving monotherapy and 9 (20%) of the 46 patients receiving combination therapy, with disease progression being the leading cause of death in both groups. The research drugs were not linked to any fatalities. Overall response rates were 41% (95% CI 21-64) for patients on monotherapy for relapsed or refractory acute myeloid leukemia (9/22) and 46% (27-67) for those on combination therapy (12/26). Patients previously untreated for acute myeloid leukemia showed a 25% overall response rate (1 in 81 on monotherapy and 10 in 13 on combination therapy). Patients with IDH1-mutated acute myeloid leukemia who received olumasidenib, either with or without azacitidine, reported good safety and clinical outcomes. This phase 1 study’s findings support further investigation of olutasidenib for treating various myeloid malignancies in various patient populations.