First-in-human phase 1 study of novel dUTPase inhibitor TAS-114 in combination with S-1 in Japanese patients with advanced solid tumors

Toshihiko Doi, Kiyotaka Yoh, Kohei Shitara, Hideaki Takahashi, Makoto Ueno, Satoshi Kobayashi, Manabu Morimoto, Takuji Okusaka, Hideki Ueno, Chigusa Morizane, Naohiro Okano, Fumio Nagashima, Junji Furuse, Toshihiko Doi, Kiyotaka Yoh, Kohei Shitara, Hideaki Takahashi, Makoto Ueno, Satoshi Kobayashi, Manabu Morimoto, Takuji Okusaka, Hideki Ueno, Chigusa Morizane, Naohiro Okano, Fumio Nagashima, Junji Furuse

Abstract

Background This first-in-human phase 1 study assessed the safety of TAS-114, a novel deoxyuridine triphosphatase inhibitor, combined with S-1 to determine its maximum tolerated dose (MTD) and recommended dose (RD). Methods In this dose-escalation study with a 3 + 3 design, TAS-114 and S-1 were concurrently administered orally under fasting conditions at 5-240 mg/m2 and 30-36 mg/m2, respectively, in patients with advanced solid tumors. Safety, efficacy, and pharmacokinetics (PK) were evaluated. Results Seventy-six patients were enrolled. The MTD and RD were TAS-114 200 mg/m2 plus S-1 36 mg/m2 and TAS-114 240 mg/m2 plus S-1 30 mg/m2, respectively. Common treatment-related adverse events were anemia, lymphocytopenia, leukopenia, neutropenia, decreased appetite, rash, nausea, and pigmentation disorder. Partial response (PR) was observed in 10 patients (non-small cell lung cancer [NSCLC], n = 5; pancreatic neuroendocrine tumor, n = 2; gastric cancer, n = 2; gallbladder cancer, n = 1). Of these, four patients achieved PR despite prior treatment history with S-1. Patients administered TAS-114 exhibited linear PK and CYP3A4 induction, with no effect on the PK of S-1. Conclusion TAS-114 plus S-1 showed tolerable, safe, and potentially effective results. To confirm safety and efficacy, two phase 2 studies are ongoing in NSCLC and gastric cancer patients. Clinical trial registration ClinicalTrials.gov ( NCT01610479 ) .

Keywords: Dose-escalation; Phase 1; S-1; Solid tumor; TAS-114; dUTPase.

Conflict of interest statement

Toshihiko Doi has received fees for consulting or advisory role from Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Daiichi Sankyo Co., Ltd., Amgen Inc., Sumitomo Dainippon Pharma Co., and Taiho Pharmaceutical Co. Ltd., as well as research funding from Taiho Pharmaceutical Co. Ltd., Novartis Pharma K.K., Merck Serono Co., Ltd., Astellas Pharma Inc., MSD K.K., Janssen Pharmaceutical K.K., Nippon Boehringer Ingelheim Co., Takeda Pharmaceuticals, Pfizer Inc., Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co., Chugai Pharmaceutical Co., Kyowa Hakko Kirin Co., Ltd., Daiichi Sankyo Co., Ltd., Celgene Corporation, Bristol-Myers Squibb, AbbVie Inc., and Quintiles IMS Holdings, Inc. Kiyotaka Yoh has received grants and personal fees from Taiho Pharmaceutical, during the conduct of the study; grants and/or personal fees from Chugai Pharmaceutical Co., AstraZeneca K.K., Eli Lilly Japan, K.K., Boehringer Ingelheim Co., Ono Pharmaceutical Co., Novartis Pharma K.K., Bayer Yakuhin, Ltd., Pfizer Inc., MSD K.K., Bristol-Myers Squibb, in relation to work other than that submitted here. Kohei Shitara has received grants and/or personal fees from Astellas Pharma Inc., Eli Lilly Japan K.K., Bristol-Myers Squibb, Takeda Pharmaceuticals, Pfizer Inc., Ono Pharmaceutical Co., Novartis Pharma K.K., AbbVie Inc., Yakult Honsha Co., Ltd., Sumitomo Dainippon Pharma Co., Daiichi Sankyo Co., Taiho Pharmaceutical Co., Chugai Pharmaceutical Co., MSD K.K in relation to work other than that submitted here. Hideaki Takahashi has received honoraria from Taiho Pharmaceutical Co., Bayer Yakuhin, Ltd., and Torii Pharmaceutical Co. Ltd., as well as research funding from Bristol-Myers Squibb and Bayer Yakuhin, Ltd. Makoto Ueno has received honoraria from Taiho Pharmaceutical Co., Yakult Honsha Co., Ltd., AstraZeneca K.K., Novartis Pharma K.K., Eli Lilly Japan K.K., Teijin Pharma, Ltd., Shire Plc, Ono Pharmaceutical Co., received fees consulting or advisory role from Eisai Co., and research funding from Taiho Pharmaceutical Co., Shire Plc, Daiichi Sankyo Co., Eisai Co., AstraZeneca K.K., Ono Pharmaceutical Co., MSD K.K., Merck Serono Co., Ltd., NanoCarrier, Co., Ltd., Sumitomo Dainippon Pharma Co., and Incyte Corp. Satoshi Kobayashi received honoraria from Taiho Pharmaceutical Co., Yakult Honsha Co., Ltd., AstraZeneca K.K., Boston Scientific Corp., Merck Serono Co., Nippon Kayaku Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Daiichi Sankyo Co., Bayer Yakuhin, Ltd., a speaker’s bureau from Kyowa Hakko Kirin Co., research funding from Taiho Pharmaceutical Co., Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co., Chugai Pharmaceutical Co., and Yakult Honsha Co., Ltd., and travel, accommodation, and expenses reimbursement from Novartis Pharma K.K. Manabu Morimoto has received honoraria from Bayer Yakuhin, Ltd., Eisai Co., Ltd., and Nippon Kayaku Co., Ltd., as well as research funding from Bayer Yakuhin, Ltd., Yakult Honsha Co., Ltd., Shionogi & Co., Ltd., and Eli Lilly Japan K.K. Takuji Okusaka has received honoraria, fees for consulting or advisory role, or research funding from Novartis Pharma K.K., Taiho Pharmaceutical Co. Ltd., Merck Serono Co., Ltd., Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co., Ltd., Bayer Yakuhin, Ltd., Yakult Honsha Co., Ltd., Nobelpharma Co., Ltd., Nippon Kayaku Co., Ltd., Baxter Limited, FUJIFILM RI Pharma Co., Ltd., AstraZeneca K.K., Ono Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Nippon Chemiphar Co., Ltd., Celgene, K.K., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Zeria Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Kowa company, Ltd., Kyowa Hakko Kirin Co., Ltd., Glaxo Smith Kline K.K., Shizuoka Industry Nano Carrier Co., Ltd., and Pfizer Japan Inc. Hideki Ueno has received honoraria and research funding from Taiho Pharmaceutical Co., Ltd. Chigusa Morizane has received honoraria from Pfizer Inc., Novartis Pharma K.K., Yakult Honsha Co., Ltd., Nobelpharma Co., Ltd., Eli Lilly Japan K.K., and FUJIFILM RI Pharma Co., Ltd., fees for consulting or advisory role from Eisai Co., Ltd., Daiichi Sankyo Co., Ltd., and Novartis Pharma K.K., and research funding from Yakult Honsha Co., Ltd., Ono Pharmaceutical Co., Ltd., Eisai Co., Ltd., Taiho Pharmaceutical Co. Ltd., and Pfizer Inc. Naohiro Okano has received honoraria from Taiho Pharmaceutical Co. Ltd. and Merck Serono Co., Ltd. Fumio Nagashima has received research funding from Taiho Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Daiichi Sankyo Co., Ltd., Sanofi K.K., MSD K.K., Eisai Co., Ltd., and Sumitomo Dainippon Pharma Co., Ltd. Junji Furuse has received honoraria from Taiho Pharmaceutical Co. Ltd., Yakult Honsha Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly Japan K.K., Astellas Pharma Inc., Mochida Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Inc., Bayer Yakuhin, Ltd., Novartis Pharma K.K., Merck Serono Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceuticals, Nippon Kayaku Co., Ltd., Daiichi Sankyo Co., Ltd., EA Pharma Co., Ltd., Sawai Pharmaceutical Co., Ltd., and MSD K.K.

Figures

Fig. 1
Fig. 1
Patient analysis sets. Abbreviations: DLT, dose-limiting toxicity; PGx, pharmacogenomics; PK, pharmacokinetic. a All patients enrolled in Part 1 or Part 2. b Of patients enrolled in Part 1 or Part 2, all treated patients including those who received at least 1 dose of TAS-114 and S-1. c DLTs were evaluated based on the patients in Part 1 who experienced DLTs and those who did not experience DLTs but received ≥80% of the planned total dose of the study drug in Cycle 1. d Of patients who received study treatment in Part 1 or Part 2, the full analysis set included those who met all inclusion criteria, did not meet any of the exclusion criteria, and provided at least one measured value for efficacy endpoints after the start of study drug administration. e PK evaluable patients included those who received TAS-114 and S-1 at the assigned doses and provided blood and urine samples needed for calculation of PK parameters. f Of patients who received study treatment, PGx evaluable patients included those who provided measured values for PGx analyses
Fig. 2
Fig. 2
Waterfall plots showing the best percent change from baseline in the longest diameter of the target lesions for S-1 30 mg/m2 and S-1 36 mg/m2. Abbreviations: NSCLC, non-small cell lung cancer; p-NET, pancreatic neuroendocrine tumor. Analysis Set: Full Analysis Set. Dose of S-1: Level 3 = 30 mg/m2 and 36 mg/m2. Change from baseline (%) = min ([value at each date - baseline value] / baseline value × 100) † S-1 36 mg/m2
Fig. 3
Fig. 3
Pharmacokinetics. a. Correlation between TAS-114 AUC0-last on C1D1 and BSA dose of TAS-114. b. Correlation between TAS-114 AUC0–12 on C1D7 and BSA dose of TAS-114. c. Correlation between TAS-114 AUC0–12 on C1D14 and BSA dose of TAS-114. Abbreviations: AUC0-last, area under plasma concentration-time curve from time 0 to last quantifiable concentration; AUC0–12, area under the plasma concentration-time curve from time 0 to 12 h; BSA, body surface area; C1D1, Day 1 of Cycle 1; C1D7, Day 7 of Cycle 1; C1D14, Day 14 of Cycle 1

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