BEZ235 是一种双重 PI3-激酶/mTOR 抑制剂，在复发性或难治性急性白血病的成年患者中开展的 I 期研究。
A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia.
机构信息
Department of Medicine, Hematology and Oncology, Goethe University Hospital, Frankfurt, Germany.
Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Leipzig, Germany.
出版信息
BMC Pharmacol Toxicol. 2020 Sep 29;21(1):70. doi: 10.1186/s40360-020-00446-x.
BACKGROUND
Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia.
METHODS
Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300-400 mg BID (cohort - 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule ("Rolling Six"), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase.
RESULTS
Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability.
CONCLUSIONS
Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML.
TRIAL REGISTRATION
ClinicalTrials.gov , identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118 .
背景
磷脂酰肌醇 3-激酶（PI3K）和雷帕霉素哺乳动物靶标（mTOR）复合物的联合抑制可能是治疗急性白血病的有效方法。本单中心、开放标签、I 期研究的主要目的是确定晚期白血病患者中双重泛 I 类 PI3K 和 mTOR 抑制剂 BEZ235 的最大耐受剂量（MTD）和推荐的 II 期剂量（RP2D）。
方法
在此，年龄大于 18 岁的复发或难治性白血病患者接受 BEZ235（口服，每日 2 次，每次 300-400mg（队列 1/1））治疗，以评估安全性、耐受性、初步疗效和药代动力学（PK）。分析不良事件数据和严重不良事件，并从实验室检测参数评估血液学和临床生化毒性。在第 1 周期结束时（第 29 天）首次评估反应，并在随后的每个周期后评估。还包括 BEZ235 的药代动力学和药效学分析（BEZ235 血浆水平、AKT、S6 和 4EBP1 的磷酸化）。在统计学上，该试验是一项递增剂量研究，采用了“Rolling Six”的后续变体，在剂量递增阶段招募了至少 6 名和最多 12 名患者，在扩展阶段计划招募另外 5 名患者。
结果
共纳入 24 例 ALL（n=11）或 AML（n=12）或 CML-BP（n=1）患者。所有患者均已接受过一种（n=5）或多种治疗（n=5），14 例患者处于难治/难治复发状态。未确定正式的 MTD，400mg BID 剂量的口腔炎和胃肠道毒性被认为与延长治疗不兼容。BEZ235 的 RP2D 定义为 300mg BID。24 例患者中有 4 例显示临床获益。24 例患者中有 22 例因进展而停药，（中位无进展生存期 27 天（4d-112d）。PK 参数与疗效或耐受性之间没有关联。
结论
PI3K 和 mTOR 的联合抑制抑制了一小部分 ALL 患者中具有临床意义的驱动途径，但对 AML 患者没有益处。
试验注册
ClinicalTrials.gov，标识符 NCT01756118。于 2012 年 12 月 19 日回顾性注册，https://clinicaltrials.gov/ct2/show/NCT01756118。
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