title: An open-label phase I/II study of tamibarotene in patients with advanced hepatocellular carcinoma.
abstract: OBJECTIVE
  Tamibarotene is a synthetic retinoid expected to inhibit tumor-cell proliferation and to induce apoptosis by selective interaction with retinoic acid receptor α/β. We conducted an open-label phase I/II study to determine the maximum tolerated dose (MTD) and recommended dose (RD), and to evaluate the pharmacokinetics, efficacy, and safety profiles for advanced hepatocellular carcinoma (HCC).
  
  
  METHODS
  Patients with histologically confirmed, measurable, unresectable HCC of Child-Pugh classification A or B and with no effective systemic or local therapies were eligible. In phase I, patients were assigned based on the 3 + 3 dose escalation criteria to receive tamibarotene at 8, 12, and 16 mg/day. The RD determined in phase I was employed for phase II. The planned sample size in phase II was 25, including the RD-treated patients in phase I.
  
  
  RESULTS
  Thirty-six patients were enrolled. No patients experienced dose-limiting toxicity (DLT) at 8 mg/day. However, two out of six patients experienced the DLTs at 12 mg/day: one experienced thrombosis in a limb vein and pulmonary artery, and the other experienced an increase of γ-GTP. The MTD and RD were determined as 12 and 8 mg/day, respectively. In phase II, one patient achieved partial response, and seven achieved stable disease. The disease control rate was 32 % (95 % CI: 15.0-53.5). The following drug-related serious adverse events were reported: thrombosis in a limb vein, pulmonary artery, and portal vein; interstitial lung disease; and vomiting.
  
  
  CONCLUSIONS
  Tamibarotene demonstrated the inhibition of tumor cell growth in advanced HCC with acceptable tolerance.
authors.affiliation: Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan. kanaif@faculty.chiba-u.jp.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kanai
authors.affiliation: Department of Hepatology, Kyoundo Hospital, 1-8 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan. obi@po.kyoundo.jp.
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Obi
authors.affiliation: Department of Gastroenterology and Hepatology, Kumamoto Shinto General Hospital, 1-17-27 Shinyashiki, Kumamoto City, Kumamoto, 862-8655, Japan. fujiyama@k-shinto.or.jp.
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Fujiyama
authors.affiliation: Department of Gastroenterology, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. sshiina@juntendo.ac.jp.
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Shiina
authors.affiliation: Second Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama, 641-0012, Japan. tamahide@wakayama-med.ac.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tamai
authors.affiliation: Department of Gastroenterology, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu City, Yamanashi, 400-8506, Japan. h-mochiduki2a@ych.pref.yamanashi.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Department of Gastroenterology, Kanto Central Hospital, 6-25-1 Kamiyouga, Setagaya-ku, Tokyo, 158-8531, Japan. ykoike-tky@umin.ac.jp.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Koike
authors.affiliation: Division of Hepatology, Department of Internal Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan. jun.imamu@gmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Imamura
authors.affiliation: Clinical Research 1, Zeria Pharmaceutical Co., Ltd, 10-11 Nihonbashi Kobuna-cho, Chuo-ku, Tokyo, 103-8351, Japan. takayoshi-yamaguchi@zeria.co.jp.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Clinical Research 1, Zeria Pharmaceutical Co., Ltd, 10-11 Nihonbashi Kobuna-cho, Chuo-ku, Tokyo, 103-8351, Japan. isamu-saida@zeria.co.jp.
authors.forename: Isamu
authors.initials: I
authors.lastname: Saida
authors.affiliation: Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan. yokosukao@faculty.chiba-u.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
authors.affiliation: Yamanashi Prefectural Hospital Organization, 1-1-1 Fujimi, Kofu City, Yamanashi, 400-8506, Japan. momata-tky@umin.ac.jp.
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
keywords: Chemotherapy; Hepatocellular carcinoma; Retinoic acid receptor; Retinoids; Tamibarotene