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

Won Young Tak, Baek Yeol Ryoo, Ho Yeong Lim, Do Young Kim, Takuji Okusaka, Masafumi Ikeda, Hisashi Hidaka, Jong Eun Yeon, Eishiro Mizukoshi, Manabu Morimoto, Myung Ah Lee, Kohichiroh Yasui, Yasunori Kawaguchi, Jeong Heo, Sojiro Morita, Tae You Kim, Junji Furuse, Kazuhiro Katayama, Takeshi Aramaki, Rina HaraTakuya Kimura, Osamu Nakamura, Masatoshi Kudo

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1072-1084
Number of pages13
JournalInvestigational New Drugs
Volume36
Issue number6
DOIs
Publication statusPublished - 2018 Dec 1

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Funding Information:
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.

Funding Information:
This study was supported by Yakult Honsha Co., Ltd.

Funding Information:
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.

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this