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.

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 ( 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.

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© 2022 The Authors; Published by the American Association for Cancer Research.

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Y. Kuboki reports grants and personal fees from Takeda during the conduct of the study; grants and personal fees from Taiho, Lilly, Boehringer Ingelheim, Bristol-Myers-Squibb; grants from Astelas, Daiichi-Sankyo, AstraZeneca, Chugai, Genmab, GlaxoSmithkline, Incyte, Abbie; grants, personal fees, and non-financial support from Amgen outside the submitted work. T. Shimizu reports grants and personal fees from Takeda during the conduct of the study; grants from AbbVie, Eli Lilly, LOXO Oncology, Novartis, Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Eisai, AstraZeneca, Astellas, Incyte, Chordia Therapeutics, 3D-Medicine, Symbio Pharmaceuticals, PharmaMar; personal fees from Chugai, MSD, Eli Lilly, and Chordia Therapeutics outside the submitted work. K. Yonemori reports personal fees from Pfizer, Eisai, Takeda, AstraZeneca, Eli Lilly, Daiichi Sankyo, Chugai, Fuji Film, MSD, Ono, Bayel, Boeringer Ingelheim, OncoXerna, Genmab; grants from MSD, Takeda, Sanofi, Chugai, Daiichi Sankyo, AstraZeneca, Taiho, Pfizer, Novartis, Ono, Seagen, genmab, Eli Lilly, Haihe, Boeringer Ingelheim, Nihon Kayaku, and Bayel outside the submitted work. T. Kojima reports personal fees from Merck Biopharma Co., Ltd, Oncolys BioPharma Inc, Astellas Pharma Inc, Bristol Myers Squibb, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd, Covidien Japan, Inc, MSD K.K, Taiho Pharmaceutical Co., Ltd., Oncolys BioPharma Inc; grants from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, BeiGene Ltd., EPS Corporation, MSD K.K, Amgen Inc, Shionogi & Co., Ltd, Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd., Parexel International, and Merck Biopharma Co., Ltd. outside the submitted work. S. Koganemaru reports other from Eisai Inc. outside the submitted work. S. Iwasa reports grants from Takeda during the conduct of the study; grants and personal fees from Daiichi Sankyo, Taiho, BMS, Ono; personal fees from Lilly, Chugai, Agilent; grants from Pfizer, Zymeworks, Segen, Bayer, and Amgen outside the submitted work. K. Harano reports personal fees from AstraZeneca, Takeda, Chugai, and Nihon Kayaku; grants and personal fees from MSD; grants from Diichi-Sankyo during the conduct of the study; personal fees from AstraZeneca, Takeda, Chugai, and Nihon Kayaku; grants and personal fees from MSD; grants from Daiichi-Sankyo outside the submitted work. T. Koyama reports personal fees from Sysmex; grants from Chugai, Lilly, Takeda, Daiichi Sankyo, and Novartis outside the submitted work. X. Zhou reports other from Takeda Development Center Americas outside the submitted work. T. Yanai reports personal fees from Takeda Pharmaceutical company outside the submitted work; and is an employee of Takeda Pharmaceutical Company. I. Garcia-Ribas reports personal fees from Takeda during the conduct of the study. T. Doi reports grants from Lilly, MSD, Novartis, Merck Biopharma, Janssen Pharma, Boehringer Ingelheim, Pfizer, Eisai, IQVIA; grants and personal fees from Daiichi Sankyo, Sumitomo Dainippon, Taiho, BMS, Abbvie, Chugai Pharma; personal fees from Takeda, Bayer, Rakuten Medical, Otsuka Pharma, Kaken Pharma, Kyowa Kirin, Shionogi, PRA Health Science, Ono Pharma, and AstraZeneca outside the submitted work. N. Yamamoto reports grants from Chugai, Taiho, Eisai, Eli Lilly, Astellas, BMS, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical Co., Ltd, Takeda, Janssen Pharma, MSD, Merck, GSK, Sumitomo Dainippon, Chiome Bioscience Inc., Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY; personal fees from Ono Pharmaceutical Co., Ltd, Chugai, BMS, Sysmex, Eisai, Eisai, Otsuka, Takeda, Boehringer Ingelheim, and Cimic outside the submitted work. No disclosures were reported by the other authors.