A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

被引：0
作者：
Noboru Yamamoto
Toshio Shimizu
Kan Yonemori
Shigehisa Kitano
Shunsuke Kondo
Satoru Iwasa
Takafumi Koyama
Kazuki Sudo
Jun Sato
Kenji Tamura
Junichi Tomomatsu
Makiko Ono
Naoki Fukuda
Shunji Takahashi
机构：
[1] National Cancer Center Hospital,Department of Experimental Therapeutics
[2] Cancer Institute Hospital of the Japanese Foundation for Cancer Research,Division of Cancer Immunotherapy Development
[3] National Cancer Center Hospital,Department of Breast and Medical Oncology
[4] Shimane University Hospital,Innovative Cancer Center
[5] Cancer Institute Hospital of the Japanese Foundation for Cancer Research,Department of Medical Oncology
来源：
Investigational New Drugs | 2021年 / 39卷
关键词：
Phase 1; Solid tumors; TAS4464; NEDD8 activating enzyme E1 inhibitor; Pharmacokinetics; Safety;
D O I：
暂无
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学科分类号：
摘要：
Background This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017
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页码：1036 / 1046
页数：10
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