Novel IDH1 Inhibitor Demonstrates Safety and Preliminary Efficacy in R/R AML


The IDH1 inhibitor olutasidenib showed a favorable safety profile in patients with relapsed/refractory acute myeloid leukemia treated in a phase 1/2 clinical trial, according to topline results.

The IDH1 inhibitor olutasidenib showed a favorable safety profile in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) treated in a phase 1/2 clinical trial, according to topline results announced in a press release from Forma Therapeutics Holdings, Inc.1

The ongoing study (NCT02719574) is evaluating the use of olutasidenib with or without azacitidine (Vidaza) in patients with both AML and myelodysplastic syndrome (MDS) who harbor an IDH1 mutation. The coprimary end points of the study include finding the maximum tolerated dose of olutasidenib, the number of patients with dose-limiting toxicity (DLT), doses recommended for future studies, and complete response (CR) rate.

“We are pleased to announce these compelling top-line data,” said Patrick Kelly, MD, chief medical officer of Forma Therapeutics, in a statement. “The safety profile and the duration of the response we’re seeing supports the potential for olutasidenib to become a leading therapy for R/R IDH1-mutant AML patients. While the multi-cohort phase 2 trial is ongoing, this specific cohort was designed to serve as a pivotal study; these efficacy data support an early stop in enrollment in favor of moving the program forward.”

Further on the safety profile of olutasidenib, the most common adverse events (AEs) that were nausea, constipation, increased white blood cell count, decreased red blood cell count, fever, febrile neutropenia and fatigue.1 The results were similar to the safety profile observed with olutasidenib was similar to what was observed in the phase 1 dose-escalation and expansion study, which determined that is well tolerated as a monotherapy and in combination with azacitidine as treatment of patients with AML and MDS.

No DLTs were observed in the study at the dose level of 150 mg daily.2 In the dose-finding study, the most common hematologic AEs of any grade associated with olutasidenib monotherapy were thrombocytopenia (28%), anemia (22%), febrile neutropenia (22%), and leukocytosis (22%). Among the patients who received olutasidenib plus azacitidine, the most common AEs were thrombocytopenia (46%), febrile neutropenia (33%), neutropenia (30%), and leukocytosis (26%).

Notably, in the dose-finding study, IDH differentiation syndrome was observed in 4 of the patients in the monotherapy arm and 6 in the combination arm. The cases were predominantly observed during the first cycle of treatment. These cases were resolved will multiple strategies including dose interruption, dose reduction, treatment with dexamethasone, or supportive care. There were no recurrences of this syndrome in the study.

Three of the patients who received olutasidenib plus azacitidine experienced QT prolongation but were able to later resume their treatment. Left liver abnormalities were observed in 5 patients in the monotherapy arm and 5 in the combination arm. These abnormalities led to treatment discontinuation in 2 patients.

In terms of efficacy, the topline data show a composite CR rate of 33.3% in the AML cohort based on a CR rate of 30% and a CR with partial hematologic recovery rate of 3%. The median CR/CRh was not reached, but it was shown in a sensitivity analysis that the median duration of CR/CRh was 13.8 months.

The phase 2 study is ongoing and actively recruiting patients with pathologically confirmed AML and MDS, documented IDH1-R132 gene mutation, good performance status and adequate kidney and liver function.


1. Forma Therapeutics announces positive top-line olutasidenib data from a planned interim analysis of a registrational phase 2 clinical trial in acute myeloid leukemia (AML). News release. Forma Therapeutics Holdings, Inc. October 26, 2020. Accessed October 26, 2020.

2. Watts JM, Baer MR, Yang J, et al. Olutasidenib (FT-2102), an IDH1m inhibitor as a single agent or in combination with azacitidine, induces deep clinical responses with mutation clearance in patients with acute myeloid leukemia treated in a phase 1 dose escalation and expansion study.

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