National Cancer Center Hospital East, Kashiwa, Japan.
Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
Cancer Chemother Pharmacol. 2024 Jun;93(6):605-616. doi: 10.1007/s00280-023-04631-7. Epub 2024 Feb 27.
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.
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.
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.
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.
jRCT2080222728 (January 29, 2015).
TAS-117 是一种高活性和选择性的口服变构泛 AKT 抑制剂，目前正在开发用于治疗晚期/转移性实体瘤。本研究旨在评估其安全性、临床药理学、药物基因组学和疗效。
这是一项 I 期、开放标签、非随机、剂量递增、首次人体研究，纳入了晚期/转移性实体瘤患者，包括三个阶段（剂量递增阶段 [DEP]、方案调整阶段 [RMP] 和安全性评估阶段 [SAP]）。SAP 的剂量和方案在 DEP 和 RMP 中确定。研究了每日一次和间歇性给药（连续 4 天给药/停药 3 天，21 天周期）。主要终点为 DEP 和 RMP 中第 1 周期的剂量限制性毒性（DLT）和 SAP 中不良反应（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。
在 66 名入组患者中，65 名接受了 TAS-117 治疗（DEP，n=12；RMP，n=10；SAP，n=43）。24 毫克/天的间歇性剂量未报告 DLT，因此被选为 SAP 的推荐剂量。在 SAP 中，98.5%的患者发生了 AE 和 ADR（≥3 级，分别为 67.7%和 60.0%）。在测试的剂量范围内（8 至 32 毫克/天），TAS-117 的药代动力学呈剂量相关性，药效学分析显示 AKT 的直接底物磷酸化 PRAS40 减少。SAP 中有 4 名患者有确认的部分缓解。
口服 TAS-117 每日一次最高至 16 毫克/天，间歇性 24 毫克/天的剂量耐受性良好。在评估的剂量下，TAS-117 的药代动力学呈剂量相关性。抗肿瘤活性可能通过 AKT 抑制发生。
jRCT2080222728（2015 年 1 月 29 日）。
