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Invest New Drugs. 2018 Dec;36(6):1072-1084. doi: 10.1007/s10637-018-0658-x. Epub 2018 Sep 10.

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.

Author information

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. wytak@knu.ac.kr.
2
Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
3
Hematology and Oncology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea.
4
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
5
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
6
Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, Japan.
7
Department of Gastroenterology, Kitasato University Hospital, Kanagawa, Japan.
8
Liver Center, Korea University Guro Hospital, Seoul, South Korea.
9
Department of Gastroenterology, Kanazawa University Hospital, Ishikawa, Japan.
10
Department of Hepatobiliary and Pancreatic Oncology, Kanagawa Cancer Center, Kanagawa, Japan.
11
Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea.
12
Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
13
Department of Hepato-Biliary-Pancreatology, Saga-ken Medical Centre Koseikan, Saga, Japan.
14
Department of Internal Medicine, College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, South Korea.
15
Department of Radiology, Kochi Health Sciences Center, Kochi, Japan.
16
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
17
Department of Medical Oncology, Kyorin University Faculty of Medicine, Tokyo, Japan.
18
Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka, Japan.
19
Division of Interventional Radiology, Shizuoka Cancer Center, Shizuoka, Japan.
20
Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd., Tokyo, Japan.
21
Department of Gastroenterology and Hepatology, Kindai University Hospital, Osaka, Japan.

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.

KEYWORDS:

HDAC; Hepatocellular carcinoma; Resminostat; Sorafenib; Systemic chemotherapy

PMID:
30198057
DOI:
10.1007/s10637-018-0658-x

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