Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
Division of Cancer Immunotherapy Development, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
Invest New Drugs. 2021 Aug;39(4):1036-1046. doi: 10.1007/s10637-020-01055-5. Epub 2021 Feb 9.
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/m dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m 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/m weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m 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/m 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.
这项开放标签、1 期研究调查了 TAS4464，一种有效的 NEDD8 激活酶抑制剂，用于治疗晚期/转移性实体瘤患者（ JapicCTI-173,488；于 2017 年 1 月 13 日注册）。主要目的是确定剂量限制性毒性（DLT）。最大耐受剂量（MTD）采用加速滴定设计进行研究。
起始剂量为 10mg/m，随后进行初始加速阶段（每周给药；n=11）。根据肝功能检查（LFT）结果，实施了为期 14 天的 20mg/m 导入期（每周给药导入；n=6）。
异常的 LFT 变化和胃肠道效应是最常见的与治疗相关的不良事件（AE）。56mg/m 每周剂量时，1/5 患者出现 DLT；5 例患者在 40mg/m 和 56mg/m 每周剂量时出现 2 级及以上异常 LFT 变化。由于可能发生严重的异常 LFT 变化，进一步的剂量递增停止。每周给药导入时，1/5 患者在 56mg/m 剂量时发生 DLT；由于达到该特定剂量水平的进一步入组的停药标准，MTD 无法确定。由于没有在较低剂量下进一步入组，剂量递增评估停止。严重的治疗相关 AE、导致治疗停止的 AE 和 DLT 均与异常 LFT 变化有关，提示 TAS4464 给药可能会影响肝功能。这种作用是剂量依赖性的，但被认为是可逆的。未观察到 TAS4464 的完全或部分缓解；1 例患者获得了延长的稳定疾病。
由于 TAS4464 对肝功能的影响，无法确定 MTD。需要进一步评估 NEDD8 激活酶抑制剂诱导的异常肝功能的作用机制。
JapicCTI-173,488（在日本药品信息中心注册）。注册日期：2017 年 1 月 13 日。
