Toshihiko Doi, Shunji Takahashi, Daisuke Aoki, Kan Yonemori, Hiroki Hara, Kosei Hasegawa, Kazuhiro Takehara, Kenichi Harano, Mayu Yunokawa, Hiroyuki Nomura, Tatsunori Shimoi, Koji Horie, Aiko Ogasawara, Shinichi Okame
{"title":"TAS-117 是一种异位 AKT 抑制剂，对晚期实体瘤患者进行了首次人体 I 期研究。","authors":"Toshihiko Doi, Shunji Takahashi, Daisuke Aoki, Kan Yonemori, Hiroki Hara, Kosei Hasegawa, Kazuhiro Takehara, Kenichi Harano, Mayu Yunokawa, Hiroyuki Nomura, Tatsunori Shimoi, Koji Horie, Aiko Ogasawara, Shinichi Okame","doi":"10.1007/s00280-023-04631-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial registration: </strong>jRCT2080222728 (January 29, 2015).</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":null,"pages":null},"PeriodicalIF":2.7000,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11129975/pdf/","citationCount":"0","resultStr":"{\"title\":\"A first-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors.\",\"authors\":\"Toshihiko Doi, Shunji Takahashi, Daisuke Aoki, Kan Yonemori, Hiroki Hara, Kosei Hasegawa, Kazuhiro Takehara, Kenichi Harano, Mayu Yunokawa, Hiroyuki Nomura, Tatsunori Shimoi, Koji Horie, Aiko Ogasawara, Shinichi Okame\",\"doi\":\"10.1007/s00280-023-04631-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial registration: </strong>jRCT2080222728 (January 29, 2015).</p>\",\"PeriodicalId\":9556,\"journal\":{\"name\":\"Cancer Chemotherapy and Pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2024-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11129975/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancer Chemotherapy and Pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00280-023-04631-7\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/2/27 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Chemotherapy and Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00280-023-04631-7","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/2/27 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的：TAS-117 是一种高效、选择性口服异构泛 AKT 抑制剂，正在开发用于晚期/转移性实体瘤的治疗。该研究对其安全性、临床药理学、药物基因组学和疗效进行了调查：这项I期、开放标签、非随机、剂量递增、首次人体试验研究招募了晚期/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 的剂量和治疗方案在 DEP 和 RMP 中确定。研究了每日一次给药和间歇给药（服药 4 天/停药 3 天，21 天为一个周期）。主要终点是 DEP 和 RMP 第一周期的剂量限制性毒性（DLT）以及 SAP 的不良事件（AE）和药物不良反应（ADR）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人接受了TAS-117治疗（DEP，12人；RMP，10人；SAP，43人）。24毫克/天的间歇给药剂量未出现DLT，该剂量被选为SAP的推荐剂量。在 SAP 中，98.5% 的患者同时出现 AE 和 ADR（等级≥3，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 的药代动力学与剂量成正比，药效学分析表明磷酸化 PRAS40（AKT 的直接底物）减少。SAP中的4名患者已证实有部分反应：结论：TAS-117的口服剂量为每天一次至16毫克，间歇剂量为每天24毫克，耐受性良好。在所评估的剂量下，TAS-117的药代动力学与剂量成正比。抗肿瘤活性可能是通过抑制AKT产生的。试验注册：jRCT2080222728（2015年1月29日）。
A first-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors.
Purpose: 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.
Conclusion: 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.
期刊介绍：
Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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