University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA.
University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA.
Lancet Haematol. 2023 Jan;10(1):e46-e58. doi: 10.1016/S2352-3026(22)00292-7. Epub 2022 Nov 10.
Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1.
In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m) 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.
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). The median 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-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination 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 combination therapy 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 relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response.
Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies.
Forma Therapeutics.
Olutasidenib（FT-2102）是一种有效的、选择性的、口服、小分子突变型异柠檬酸脱氢酶 1（IDH1）抑制剂。本研究的目的是评估单药或联合阿扎胞苷治疗携带突变型 IDH1 的急性髓系白血病或骨髓增生异常综合征患者的安全性、药代动力学、药效学和临床活性。
在这项 1/2 期多中心、开放性临床试验中，我们在 18 个研究地点招募了年龄在 18 岁或以上的携带突变型 IDH1 的急性髓系白血病或中危、高危或极高危骨髓增生异常综合征患者，这些患者来自美国、澳大利亚、法国和西班牙。其他关键入选标准包括东部肿瘤协作组体能状态 0-2 分，肝肾功能良好。主要终点是剂量限制性毒性和最大耐受剂量、最大评估剂量以及推荐的 olutasidenib 2 期剂量。olutasidenib 以 150mg 每日一次、150mg 每日两次和 300mg 每日一次的剂量口服给药。阿扎胞苷（75mg/m）每日皮下或静脉注射，连用 7 天，停药 21 天。研究正在进行中，数据截止日期为 2019 年 10 月 2 日，并在 ClinicalTrials.gov 上注册，NCT02719574。
患者于 2016 年 8 月 8 日至 2018 年 11 月 14 日入组。78 例患者接受 olutasidenib 单药治疗（n=32）或联合阿扎胞苷治疗（n=46）。中位随访时间为单药治疗组 8.3 个月（IQR 3.1-13.3），联合治疗组 10.1 个月（4.2-15.3）。单药治疗组 16 例（50%）和联合治疗组 24 例（52%）患者为女性。大多数患者为白人（单药治疗组 26 例[81%]，联合治疗组 31 例[67%]）。在剂量递增队列中未报告剂量限制毒性，基于安全性、药代动力学和药效学以及临床活性，150mg 每日两次被宣布为推荐的 2 期剂量。单药治疗最常见（≥20%）的 3-4 级治疗相关不良事件为血小板减少症（32 例患者中有 9 例[28%]）、发热性中性粒细胞减少症（32 例患者中有 7 例[22%]）和贫血（32 例患者中有 7 例[22%]）；联合治疗中最常见（≥20%）的是血小板减少症（46 例患者中有 19 例[41%]）、发热性中性粒细胞减少症（46 例患者中有 13 例[28%]）、中性粒细胞减少症（46 例患者中有 13 例[28%]）和贫血（46 例患者中有 9 例[20%]）。单药治疗组有 11 例（34%）和联合治疗组有 9 例（20%）患者死亡（最常见的死因是疾病进展[32 例患者中有 3 例[9%]，46 例患者中有 4 例[9%]）。没有死亡被认为与研究药物有关。对于复发或难治性急性髓系白血病患者，接受单药治疗的患者中有 41%（95%CI 21-64；22 例患者中有 9 例）和接受联合治疗的患者中有 46%（27-67；26 例患者中有 12 例）有总体反应。对于初治的急性髓系白血病患者，接受单药治疗的患者中有 25%（1-81；4 例患者中有 1 例）和接受联合治疗的患者中有 77%（46-95；13 例患者中有 10 例）有总体反应。
Olutasidenib 单药或联合阿扎胞苷治疗携带 IDH1 突变的急性髓系白血病患者耐受性良好，具有显著的临床活性。这项 1 期研究的结果为在多个髓系恶性肿瘤患者群体中继续评估 olutasidenib 提供了依据。
Forma Therapeutics。
