DiNardo Courtney D, Hochhaus Andreas, Frattini Mark G, Yee Karen, Zander Thomas, Krämer Alwin, Chen Xueying, Ji Yan, Parikh Nehal S, Choi Joanne, Wei Andrew H
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Klinik für Innere Medizin II, Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany.
J Cancer Res Clin Oncol. 2023 Mar;149(3):1145-1158. doi: 10.1007/s00432-022-03983-6. Epub 2022 Mar 30.
Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
IDH305 was given at doses 75-750 mg twice daily in 41 patients with IDH1-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting toxicity.
IDH305 exhibited rapid absorption with mean T approximately 4-10 h across doses. Interpatient variability was moderate and exposure increased with dose in a less than dose proportional manner. Most patients (35/41) demonstrated target engagement with reduction in 2-HG concentration at all doses. Complete remission (CR) or CR with incomplete count recovery occurred in 10/37 (27%) patients with AML and 1/ 4 patients with MDS. Adverse events (AEs) suspected to be related to study drug were reported in 53.7% of patients: increased blood bilirubin (14.6%), nausea (14.6%), increased alanine aminotransferase and aspartate aminotransferase (12.2%, each); most frequent grade 3 or 4 AEs were differentiation syndrome and tumor lysis syndrome (n = 3; 7.3%, each). Hepatotoxicity was manageable with dose modification.
Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared.
Clinicaltrials.gov identifier: NCT02381886.
异柠檬酸脱氢酶1（IDH1）第132位氨基酸残基（R132*）处的突变会导致致癌代谢物2-羟基戊二酸（2-HG）在细胞内蓄积。IDH305是一种口服生物利用度高、可穿透血脑屏障、对突变体具有选择性的变构IDH1抑制剂，在临床前模型中显示出靶点结合活性。这项首次人体研究旨在确定IDH305在IDH1突变的急性髓系白血病（AML）和骨髓增生异常综合征（MDS）患者中的推荐扩展剂量/最大耐受剂量。
41例IDH1突变的AML/MDS患者接受IDH305治疗，剂量为75 - 750mg，每日两次。剂量递增采用贝叶斯分层模型设计，遵循过量控制原则并考虑与剂量限制性毒性的关系。
IDH305吸收迅速，各剂量下平均达峰时间约为4 - 10小时。患者间变异性中等，暴露量随剂量增加，但增加幅度小于剂量比例。大多数患者（35/41）在所有剂量下均表现出靶点结合活性，2-HG浓度降低。10/37（27%）的AML患者和1/4的MDS患者出现完全缓解（CR）或血细胞计数未完全恢复的CR。53.7%的患者报告了疑似与研究药物相关的不良事件：血胆红素升高（14.6%）、恶心（14.6%）、丙氨酸转氨酶和天冬氨酸转氨酶升高（各12.2%）；最常见的3级或4级不良事件是分化综合征和肿瘤溶解综合征（各n = 3；7.3%）。肝毒性可通过调整剂量控制。
由于潜在的治疗窗较窄，该研究提前终止，无法确定推荐的2期剂量。
Clinicaltrials.gov标识符：NCT02381886。
