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Supplementary Methods SM1 from Safety, Tolerability, and Pharmacokinetics of TAK-931, a Cell Division Cycle 7 Inhibitor, in Patients with Advanced Solid Tumors: A Phase I First-in-Human Study

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posted on 2023-04-04, 01:41 authored by Yasutoshi Kuboki, Toshio Shimizu, Kan Yonemori, Takashi Kojima, Shunsuke Kondo, Shigehiro Koganemaru, Satoru Iwasa, Kenichi Harano, Takafumi Koyama, Vickie Lu, Xiaofei Zhou, Huifeng Niu, Tomoko Yanai, Ignacio Garcia-Ribas, Toshihiko Doi, Noboru Yamamoto

Supplementary methods including inclusion and exclusion criteria

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ARTICLE ABSTRACT

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 (n = 3) or grade 4 neutropenia (n = 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.