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
- Tak, Won Young; Ryoo, Baek-Yeol; Lim, Ho Yeong; Kim, Do-Young; Okusaka, Takuji; Ikeda, Masafumi; Hidaka, Hisashi; Yeon, Jong-Eun; Mizukoshi, Eishiro; Morimoto, Manabu; Lee, Myung-Ah; Yasui, Kohichiroh; Kawaguchi, Yasunori; Heo, Jeong; Morita, Sojiro; Kim, Tae-You; Furuse, Junji; Katayama, Kazuhiro; Aramaki, Takeshi; Hara, Rina; Kimura, Takuya; Nakamura, Osamu; Kudo, Masatoshi
- Issue Date
- Kluwer Academic Publishers
- Hepatocellular carcinoma; HDAC; Resminostat; Sorafenib; Systemic chemotherapy
- Investigational New Drugs, v.36, no.6, pp.1072 - 1084
- Journal Title
- Investigational New Drugs
- Start Page
- End Page
- 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 (400mg or 600mg/day on days 1 to 5 every 14days) was administered with sorafenib (800mg/day for 14days) 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: 400mg, 6: 600mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1months with monotherapy versus 2.8/11.8months 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 1.5/6.9months for monotherapy versus 2.8/13.1months 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 ( 150x10(3)/mm(3)).
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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- 2. Clinical Science > Department of Gastroenterology and Hepatology > 1. Journal Articles
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