Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial
Mené sur 78 patients atteints d'une leucémie myéloïde aiguë ou d'un syndrome myélodysplasique présentant une mutation IDH1 (durées médianes de suivi : 8,3 et 10,1 mois), cet essai évalue la dose maximale tolérée de l'olutasidénib (un inhibiteur d'IDH1), en monothérapie ou en combinaison avec l'azacitidine, puis analyse ses caractéristiques pharmacocinétiques et pharmacodynamiques
Background : Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutantisocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study wereto assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity ofolutasidenib, as monotherapy or in combination with azacitidine, in patients withacute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1. Methods : In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged18 years or older with acute myeloid leukaemia or intermediate, high, or very highrisk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibilitycriteria included Eastern Cooperative Oncology Group performance status 0–2 with adequateliver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose ofolutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily,150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously daily for 7 days on, 21 days off.The study was ongoing at the data cutoff (Oct 2, 2019) and is registered with ClinicalTrials.gov, NCT02719574. Findings : Patients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). Themedian follow-up was 8·3 months (IQR 3·1–13·3) for monotherapy and 10·1 months (4·2–15·3)for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%)of 46 patients in the combination therapy group were women. Most patients were White(26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limitingtoxicities were reported in the dose-escalation cohorts and 150 mg twice per day wasdeclared the recommended phase 2 dose on the basis of safety, pharmacokinetics andpharmacodynamics, and clinical activity. The most common (≥20%) grade 3–4 treatment-emergentadverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients),febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and withcombination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13[28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%)of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combinationtherapy group died (most commonly from disease progression [three (9%) of 32 and four(9%) of 46]). No deaths were considered study-drug related. For patients with relapsedor refractory acute myeloid leukaemia, 41% (95% CI 21–64; nine of 22) receiving monotherapyand 46% (27–67; 12 of 26) receiving combination therapy had an overall response. Fortreatment-naive patients with acute myeloid leukaemia, 25% (1–81; one of four) receivingmonotherapy and 77% (46–95; ten of 13) receiving combination therapy had an overallresponse. Interpretation : Olutasidenib, with or without azacitidine, was well tolerated and showed meaningfulclinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationalefor the continued evaluation of olutasidenib in multiple patient populations withmyeloid malignancies.