Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan.
Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
Cancer Res Commun. 2022 Nov 14;2(11):1426-1435. doi: 10.1158/2767-9764.CRC-22-0277. eCollection 2022 Nov.
We conducted a first-in-human, dose-escalation study, to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and activity of TAK-931, a cell division cycle 7 inhibitor, in Japanese patients with advanced solid tumors.
Patients ages ≥20 years received oral TAK-931: once daily for 14 days in 21-day cycles (schedule A; from 30 mg); once daily or twice daily for 7 days on, 7 days off in 28-day cycles (schedule B; from 60 mg); continuous once daily (schedule D; from 20 mg); or once daily for 2 days on, 5 days off (schedule E; from 100 mg) in 21-day cycles.
Of the 80 patients enrolled, all had prior systemic treatment and 86% had stage IV disease. In schedule A, 2 patients experienced dose-limiting toxicities (DLTs) of grade 4 neutropenia and the maximum tolerated dose (MTD) was 50 mg. In schedule B, 4 patients experienced DLTs of grade 3 febrile neutropenia ( = 3) or grade 4 neutropenia ( = 1); the MTD was 100 mg. Schedules D and E were discontinued before MTD determination. The most common adverse events were nausea (60%) and neutropenia (56%). Time to maximum plasma concentration of TAK-931 was approximately 1-4 hours postdose; systemic exposure was approximately dose proportional. Posttreatment pharmacodynamic effects correlating to drug exposure were observed. Overall, 5 patients achieved a partial response.
TAK-931 was tolerable with a manageable safety profile. TAK-931 50 mg once daily days 1-14 in 21-day cycles was selected as a recommended phase II dose and achieved proof of mechanism.
NCT02699749.
This was the first-in-human study of the CDC7 inhibitor, TAK-931, in patients with solid tumors. TAK-931 was generally tolerable with a manageable safety profile. The recommend phase II dose was determined to be TAK-931 50 mg administered once daily on days 1-14 of each 21-day cycle. A phase II study is ongoing to confirm the safety, tolerability, and antitumor activity of TAK-931 in patients with metastatic solid tumors.
我们进行了一项首次人体、剂量递增研究，以评估细胞分裂周期 7 抑制剂 TAK-931 在日本晚期实体瘤患者中的安全性、耐受性、药代动力学、药效学和活性。
年龄≥20 岁的患者接受口服 TAK-931：21 天周期中，每日一次，连续 14 天（方案 A；30mg）；28 天周期中，每日一次或每日两次，连续 7 天，停药 7 天（方案 B；60mg）；连续每日一次（方案 D；20mg）；或 21 天周期中，每日一次，连续 2 天，停药 5 天（方案 E；100mg）。
80 名入组患者均有既往系统治疗，86%为 IV 期疾病。在方案 A 中，2 名患者发生 4 级中性粒细胞减少症的剂量限制毒性（DLT），最大耐受剂量（MTD）为 50mg。在方案 B 中，4 名患者发生 3 级发热性中性粒细胞减少症（=3）或 4 级中性粒细胞减少症（=1）的 DLT；MTD 为 100mg。方案 D 和 E 在确定 MTD 之前停止。最常见的不良反应是恶心（60%）和中性粒细胞减少（56%）。TAK-931 的最大血浆浓度时间约为给药后 1-4 小时；全身暴露与剂量大致成正比。观察到与药物暴露相关的治疗后药效学效应。总体而言，5 名患者获得部分缓解。
TAK-931 具有可管理的安全性特征，耐受性良好。在 21 天周期中，每日一次，连续 14 天给予 50mg TAK-931 被选为推荐的 II 期剂量，并证实了作用机制。
试验注册 ID：NCT02699749。
这是细胞分裂周期 7 抑制剂 TAK-931 在实体瘤患者中的首次人体研究。TAK-931 总体上具有可管理的安全性特征，耐受性良好。确定的 II 期推荐剂量为 TAK-931 50mg，每日一次，在每个 21 天周期的第 1-14 天给药。一项 II 期研究正在进行中，以确认 TAK-931 在转移性实体瘤患者中的安全性、耐受性和抗肿瘤活性。
