目的:TAS-117是一种高度有效和选择性的,口服,变构pan-AKT抑制剂正在开发中用于晚期/转移性实体瘤。安全,临床药理学,研究了药物基因组学和疗效。
方法:第一阶段,开放标签,非随机化,剂量递增,首次人体研究纳入晚期/转移性实体瘤患者,包括三个阶段(剂量递增阶段[DEP],方案修改阶段[RMP],和安全评估阶段[SAP])。在DEP和RMP中确定SAP剂量和方案。每日一次和间歇给药(4天/3天休息,21天周期)进行了调查。主要终点是DEP和RMP第1周期的剂量限制性毒性(DLTs)以及SAP中不良事件(AE)和药物不良反应(ADR)的发生率。次要终点包括药代动力学,药效学,药物基因组学,和抗肿瘤活性。
结果:在66名入组患者中,65收到TAS-117(DEP,n=12;RMP,n=10;SAP,n=43)。24mg/天间歇给药未报告DLT,选择作为SAP的推荐剂量。在SAP中,98.5%的患者同时出现不良事件和不良反应(≥3级,67.7%和60.0%,分别)。在测试的剂量范围内(8至32mg/天),TAS-117药代动力学与剂量成正比,和药效学分析显示磷酸化PRAS40(AKT的直接底物)的减少。SAP中的四名患者已确认部分反应。
结论:口服剂量TAS-117每日一次至16mg/天和间歇给药24mg/天的耐受性良好。TAS-117药代动力学与所评估的剂量成剂量比例。抗肿瘤活性可通过AKT抑制而发生。
背景:jRCT2080222728(2015年1月29日)。
OBJECTIVE: TAS-117 is a highly potent and selective, oral, allosteric pan-AKT inhibitor under development for advanced/metastatic solid tumors. The safety, clinical pharmacology, pharmacogenomics and efficacy were investigated.
METHODS: This phase I, open-label, non-randomized, dose-escalating, first-in-human
study enrolled patients with advanced/metastatic solid tumors and comprised three phases (dose escalation phase [DEP], regimen modification phase [RMP], and safety assessment phase [SAP]). The SAP dose and regimen were determined in the DEP and RMP. Once-daily and intermittent dosing (4 days on/3 days off, 21-day cycles) were investigated. The primary endpoints were dose-limiting toxicities (DLTs) in Cycle 1 of the DEP and RMP and incidences of adverse events (AEs) and adverse drug reactions (ADRs) in the SAP. Secondary endpoints included pharmacokinetics, pharmacodynamics, pharmacogenomics, and antitumor activity.
RESULTS: Of 66 enrolled patients, 65 received TAS-117 (DEP, n = 12; RMP, n = 10; SAP, n = 43). No DLTs were reported with 24-mg/day intermittent dosing, which was selected as a recommended dose in SAP. In the SAP, 98.5% of patients experienced both AEs and ADRs (grade ≥ 3, 67.7% and 60.0%, respectively). In the dose range tested (8 to 32 mg/day), TAS-117 pharmacokinetics were dose proportional, and pharmacodynamic analysis showed a reduction of phosphorylated PRAS40, a direct substrate of AKT. Four patients in the SAP had confirmed partial response.
CONCLUSIONS: Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition.
BACKGROUND: jRCT2080222728 (January 29, 2015).