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Abstract：
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).
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).
摘要：
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）。
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）。
