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A phase 1 study of oral ASP5878, a selective small-molecule inhibitor of fibroblast growth factor receptors 1–4, as a single dose and multiple doses in patients with solid malignancies

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Summary

ASP5878 is a selective small-molecule inhibitor of fibroblast growth factor receptors (FGFRs). This study investigated safety, tolerability, and antitumor effect of single and multiple oral doses of ASP5878 in patients with solid tumors. This phase 1, open label, first-in-human study comprised dose-escalation and dose-expansion parts. Primary objectives of the dose-escalation part were to identify the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended dose of ASP5878 for the dose-expansion part. Nine dose cohorts of ASP5878 were evaluated (0.5─2 mg once daily; 2─40 mg twice daily [BID]). A single dose of ASP5878 was followed by a 2-day pharmacokinetic collection, and then either 28-day cycles of daily dosing (ASP5878 ≤ 10 mg BID) or 5-day dosing/2-day interruption (ASP5878 ≥ 20 mg BID). The primary objective of the dose-expansion part was to determine the safety of ASP5878 (16 mg BID) administered in 28-day cycles of 5-day dosing/2-day interruption in patients with urothelial carcinoma, hepatocellular carcinoma, or squamous cell lung carcinoma with FGFR genetic alterations. Safety was assessed by monitoring adverse events (AEs). Thirty-five patients were enrolled and 31 discontinued in the dose-escalation part; 51 patients were enrolled and 51 discontinued in the dose-expansion part. In the dose-escalation part, 66.7% of patients in the 20 mg BID 5-day dosing/2-day interruption group reported DLTs of hyperphosphatemia. The recommended dose for the dose-expansion part was 16 mg BID. Common AEs included retinal detachment, diarrhea, and increased alanine aminotransferase. One death occurred that was not related to ASP5878. ASP5878 was well tolerated with manageable toxicities including hyperphosphatemia.

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Data availability

Access to anonymized individual participant level data collected during the trial, in addition to supporting clinical documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com. Study-related supporting documentation is redacted and provided if available, such as the protocol and amendments, statistical analysis plan and clinical study report. Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data. Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.

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Acknowledgements

Medical writing and editorial assistance were provided by OPEN Health Medical Communications (Chicago, IL) and funded by Astellas Pharma, Inc.

Funding

This work was supported by Astellas Pharma, Inc.

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Authors and Affiliations

  1. Department of Experimental Therapeutics, Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan

    Noboru Yamamoto

  2. Department of Oncology, Asan Medical Center, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea

    Baek-Yeol Ryoo

  3. Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro Jongno-gu, Seoul, 03080, Republic of Korea

    Bhumsuk Keam

  4. Department of Gastroenterology and Hepatology, School of Medicine, Kindai University, 3-4-1 Kowakae, Higashiosaka City, Osaka, 577-8502, Japan

    Masatoshi Kudo

  5. Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S Rd, Taipei, 10002, Taiwan

    Chia-Chi Lin

  6. Medical Science Oncology, Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA

    Futoshi Kunieda

  7. Clinical Pharmacology & Exploratory Development – Oncology, Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA

    Howard A. Ball & Diarmuid Moran

  8. Clinical Pharmacology, Astellas Pharma, Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan

    Kanji Komatsu

  9. Data Science, Astellas Pharma Global Development, Inc., 1 Astellas Way, Northbrook, IL, 60062, USA

    Kentaro Takeda

  10. Japan-Asia Data Science, Astellas Pharma, Inc., 2-5-1 Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan

    Musashi Fukuda

  11. Department of Medical Oncology, Kyorin University School of Medicine, Faculty of Medicine, 6-20-2, Shinkawa, Mitaka, Tokyo, 181-8611, Japan

    Junji Furuse

  12. Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, sakyo-ku, Kyoto, 606-8501, Japan

    Satoshi Morita

  13. Experimental Therapeutics of Digestive Endoscopy/Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan

    Toshihiko Doi

Authors
  1. Noboru Yamamoto
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  2. Baek-Yeol Ryoo
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  5. Chia-Chi Lin
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  6. Futoshi Kunieda
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  7. Howard A. Ball
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  8. Diarmuid Moran
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  9. Kanji Komatsu
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  11. Musashi Fukuda
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  12. Junji Furuse
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  13. Satoshi Morita
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  14. Toshihiko Doi
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Corresponding author

Correspondence to Noboru Yamamoto.

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Conflict of interest

N. Yamamoto reports research grants from Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, ONO PHARMACEUTICAL CO., LTD, and Takeda; honoraria from ONO PHARMACEUTICAL CO., LTD, Chugai, AstraZeneca, Pfizer, Lilly, and Bristol-Myers Squibb; and consulting fees from Eisai, Otsuka, Takeda, and Boehringer Ingelheim. M. Kudo reports grants from Bristol-Myers Squibb, Bayer, Eisai, Merck Sharp & Dohme, Chugal, Otsuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi Sankyo, Abbvie, Medico’s Hirata, and Astellas Pharma; personal fees from ONO PHARMACEUTICAL CO., LTD, Bayer, Eisai, Merck Sharp & Dohme, and Ajinomoto; and advisory consulting fees from Bayer, Eisai, Merck Sharp & Dohme, Chugal, Taiho, Kowa, and Bristol-Myers Squibb. J. Furuse reports grants from Astellas Pharma, Taiho Pharmaceutical, ONO PHARMACEUTICAL CO., LTD, Onco Therapy Science, Merck Serono, Zeria Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Pharmaceutical, Yakult, Sumitomo Dainippom Pharma, Daiichi Sankyo, SHIONOGI, Novartis Pharma, J-Pharma, Bristol-Myers Squibb, Sanofi, Kyowa Hakko Kirin, Mochida Pharma, Hisamitsu Pharmaceutical, Pfizer, Merck Sharp & Dohme, AstraZeneca, Eisai, NanoCarrier, and Shire; and personal fees from Astellas Pharma, Taiho Pharmaceutical, ONO PHARMACEUTICAL CO., LTD, Merck Serono, Zeria Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Pharmaceutical, Yakult, Sumitomo Dainippom Pharma, Daiichi Sankyo, SHIONOGI, Novartis Pharma, J-Pharma, Bristol-Myers Squibb, Sanofi, Kyowa Hakko Kirin, Mochida Pharma, Pfizer, Mitsubishi Tanabe, Merck Sharp & Dohme, AstraZeneca, Sawai, Fujifilm, EA Pharma, Otsuka, Boehringer Ingelheim, Sandoz, Eisai, and Shire. S. Morita reports personal fees from Astellas. T. Doi reports grants from Lilly, Chugai Pharma, Kyowa Hakko Kirin, Merck Sharp & Dohme, Daiichi Sankyo, Taiho, Novartis, Merck Serono, Astellas Pharma, Janssen, Boehringer Ingellheim, Takeda, Pfizer, Dainippon Sumitomo, Celegene, Bristol Myers Squibb, Abbvie, and Quintiles; and personal fees from Lilly, Chugai Pharma, Kyowa Hakko Kirin, Merck Sharp & Dohme, Daiichi Sankyo, Amgen, Taiho, and Dainippon Sumitomo. F. Kunieda, D. Moran, K. Komatsu, K. Takeda, and M. Fukuda are Employees of Astellas. H.A. Ball was an employee of Astellas during the time the study was conducted. B-Y. Ryoo, B. Keam, and C-C. Lin declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Yamamoto, N., Ryoo, BY., Keam, B. et al. A phase 1 study of oral ASP5878, a selective small-molecule inhibitor of fibroblast growth factor receptors 1–4, as a single dose and multiple doses in patients with solid malignancies. Invest New Drugs 38, 445–456 (2020). https://doi.org/10.1007/s10637-019-00780-w

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