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Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients

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Summary

Purpose: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). Experimental design: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Results: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). Conclusions: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.

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Acknowledgments

We would like to thank all of the patients, clinicians, and support staff who participated in this study. We thank Ichinosuke Hyodo for providing advice as a medical expert. We would also like to thank Professor Jeremy Williams (Tokyo Medical University) for his assistance with preparation of this manuscript.

Funding support

This study was supported by Yakult Honsha Co., Ltd.

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Internal medicine, School of Medicine, Kyungpook National University, 130 Dongdeok-Ro, Jung-Gu, Daegu, 41944, South Korea

    Won Young Tak

  2. Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Baek-Yeol Ryoo

  3. Hematology and Oncology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea

    Ho Yeong Lim

  4. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea

    Do-Young Kim

  5. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan

    Takuji Okusaka

  6. Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan

    Masafumi Ikeda

  7. Department of Gastroenterology, Kitasato University Hospital, Kanagawa, Japan

    Hisashi Hidaka

  8. Liver Center, Korea University Guro Hospital, Seoul, South Korea

    Jong-Eun Yeon

  9. Department of Gastroenterology, Kanazawa University Hospital, Ishikawa, Japan

    Eishiro Mizukoshi

  10. Department of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Kanagawa, Japan

    Manabu Morimoto

  11. Oncology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea

    Myung-Ah Lee

  12. Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Kohichiroh Yasui

  13. Department of Hepato-Biliary-Pancreatology, Saga-ken Medical Centre Koseikan, Saga, Japan

    Yasunori Kawaguchi

  14. Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, South Korea

    Jeong Heo

  15. Department of Radiology, Kochi Health Sciences Center, Kochi, Japan

    Sojiro Morita

  16. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea

    Tae-You Kim

  17. Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan

    Junji Furuse

  18. Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan

    Kazuhiro Katayama

  19. Division of Interventional Radiology, Shizuoka Cancer Center, Shizuoka, Japan

    Takeshi Aramaki

  20. Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd., Tokyo, Japan

    Rina Hara, Takuya Kimura & Osamu Nakamura

  21. Department of Gastroenterology and Hepatology, Kindai University Hospital, Osaka, Japan

    Masatoshi Kudo

Authors
  1. Won Young Tak
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  2. Baek-Yeol Ryoo
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  3. Ho Yeong Lim
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  6. Masafumi Ikeda
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  10. Manabu Morimoto
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  13. Yasunori Kawaguchi
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  14. Jeong Heo
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  15. Sojiro Morita
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  16. Tae-You Kim
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  17. Junji Furuse
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  18. Kazuhiro Katayama
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  19. Takeshi Aramaki
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  20. Rina Hara
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  21. Takuya Kimura
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  22. Osamu Nakamura
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  23. Masatoshi Kudo
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Corresponding author

Correspondence to Won Young Tak.

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Conflict of interest

Won Young Tak has served as a compensated consultant/advisor for Bayer HealthCare Pharmaceuticals Inc., Gilead Science Korea Ltd., AbbVie Ltd., Ono Pharma Korea Co., Ltd., Eisai Korea Inc., and Bukwang Pharmaceutical Co., Ltd. He has also received research grant support from Samil Pharm Co., Ltd. as well as honoraria from Bayer Korea Ltd., MSD Korea Ltd., Gilead Science Korea Ltd., AbbVie Ltd., Samil Pharm Co., Ltd., and Yuhan Co., Ltd.

Takuji Okusaka has received honoraria from Novartis Pharma K.K., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Dainippon Sumitomo Pharma Co., Ltd., Bayer Yakuhin, Ltd., Yakult Honsha Co., Ltd., Nobelpharma Co., Ltd., 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., Bristol-Myers K.K., Eisai Co., Ltd., Pfizer Japan Inc., Teijin Pharma Ltd., Daiichi Sankyo Co., Ltd., and MSD, K.K. He has also served as a compensated consultant/advisor for Dainippon Sumitomo Pharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Zeria Pharmaceutical Co., Ltd., and Daiichi Sankyo Co., Ltd. Furthermore, he has received research grant support from Eli Lilly Japan K.K., Eisai Co., Ltd., Novartis Pharma K.K., Yakult Honsha Co., Ltd., Taiho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Kowa Company, LTD, Kyowa Hakko Kirin Co., Ltd., Merck Serono Co., Ltd., Ono Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., AstraZeneca K.K., Dainippon Sumitomo Pharma Co., Ltd., Nano Carrier Co., Ltd., and Baxter.

Masafumi Ikeda has received research grants from Bayer Yakuhin, Kyowa Hakko Kirin, Yakult Honsha, Taiho Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Zeria Pharmaceutical, Baxalta Japan Limited, Chugai Pharmaceutical, Bristol-Myers Squibb, Merck Serono, Kowa, Nano Carrier, ASLAN Pharmaceuticals, Novartis Pharma, and Takara Bio. He has also received honoraria from Novartis Pharma, Bayer Yakuhin, Bristol-Myers Squibb, Abbott Japan, Eisai, Taiho Pharmaceutical, Eli Lilly Japan, Daiichi-Sankyo, Yakult Honsha, Otsuka Pharmaceutical, Nobelpharma, Sumitomo Dainippon Pharma, and Teijin Pharma. Furthermore, he has received consulting fees from Nano Carrier, Bayer Yakuhin, Eisai, Kyowa Hakko Kirin, Novartis Pharma, Shire, MSD, Bristol-Myers Squibb, Teijin Pharma, and Daiichi-Sankyo.

Manabu Morimoto has received honoraria from Bayer, Dainippon-Sumitomo, Eisai, and Nippon-Kayaku as well as research grant support from Bayer, Yakuruto, Shionogi, Eli Lilly, Kyowa-Hakko-Kirin, and Kowa.

Junji Furuse has received honoraria from Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Sumitomo Dainippon, Eli Lilly Japan, Astellas Pharma, Ono Pharmaceutical, Pfizer, Bayer Yakuhin, Novartis, Merck Serono, Takeda, Eisai, MSD, Shionogi Pharma, J-Pharma, Daiichi Sankyo, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku, EA Pharma, Sawai Pharmaceutical Co, and Teijin Pharma. He has also served as a compensated consultant/advisor for Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Sumitomo Dainippom, Eli Lilly Japan, Astellas Pharma, Ono Pharmaceutical, Pfizer Bayer Pharmaceutical, Novartis, Merck Serono, Takeda, Eisai, MSD, Shionogi Pharma, J-Pharma, Daiichi Sankyo, Kyowa Hakko Kirin, Sanofi, Sandoz, Otsuka, Zeria Pharmaceutical, Fujifilm, AstraZeneca, Asahi Kasei and Shire. Furthermore, he has received research grant support from J-Pharma, Taiho Pharmaceutical, Sumitomo Dainippom, Janssen, Daiichi Sankyo, MSD, Yakult Honsha, Takeda, Chugai Pharma, Ono Pharmaceutical, Astellas Pharma, Zeria Pharmaceutical, Novartis, NanoCarrier, Shionogi Pharma, Onco Therapy Science, Eli Lilly Japan, Bayer, Bristol-Myers Squibb, Merck Serono, Kyowa Hakko Kirin, Eisai, Mochida Pharmaceutical Co. Ltd., Baxalta and Sanofi.

Kazuhiro Katayama has received speaker’s bureau honorarium from Ajinomoto, Otsuka, Chugai, MSD, Bristol-Myers, Daiichi-Sankyo, Bayer, Nobelpharma Co., Ltd. He has also received research grant support from Bayer, Asuka, Kowa, and Bristol-Meyers.

Masatoshi Kudo has received honoraria from Bayer, Eisai, MSD, and Ajinomoto. He has served as a compensated consultant/advisor for Bayer, Eisai, Kowa, MSD, BMS, Chugai, and Taiho. Furthermore, he has received research grant support from Daiichi Sankyo, Medico’s Hirata, Otsuka, Taiho, Astellas Pharma, Chugai, Abbvie, Bristol-Myers Squibb, Takeda, MSD, Eisai, Sumitomo Dainippon, and Bayer.

Rina Hara has stock ownership of Yakult. Rina Hara, Takuya Kimura, and Osamu Nakamura are employees of Yakult.

No potential conflicts of interest were disclosed by the other authors.

Ethical approval

This article does not contain any studies with animals performed by any of the authors. 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. Informed consent was obtained from all individual participants included in the study.

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Tak, W.Y., Ryoo, BY., Lim, H.Y. et al. Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients. Invest New Drugs 36, 1072–1084 (2018). https://doi.org/10.1007/s10637-018-0658-x

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