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

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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

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Tak, W. Y., Ryoo, B. Y., Lim, H. Y., Kim, D. Y., Okusaka, T., Ikeda, M., Hidaka, H., Yeon, J. E., Mizukoshi, E., Morimoto, M., Lee, M. A., Yasui, K., Kawaguchi, Y., Heo, J., Morita, S., Kim, T. Y., Furuse, J., Katayama, K., Aramaki, T., ... Kudo, M. (2018). 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. Investigational New Drugs, 36(6), 1072-1084. https://doi.org/10.1007/s10637-018-0658-x