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An open-label phase I/II study of tamibarotene in patients with advanced hepatocellular carcinoma

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Abstract

Aim

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.

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Acknowledgements

We are grateful to all the patients for participating in this study. We are also grateful to the members of the independent review committee and the independent safety monitoring committee. This study was supported by Zeria Pharmaceutical Co., Ltd.

Conflict of interest

Kanai F, Obi S, Shiina S, Tamai H, Mochizuki H, Koike Y, Imamura J, and Yokosuka O were provided research funding for this study from Zeria Pharmaceutical Co., Ltd. Saida I and Yamaguchi T are employees of Zeria Pharmaceutical Co., Ltd.

Compliance with ethical requirements

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Documented approval from appropriate institutional review boards was obtained for all participating sites.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba City, Chiba, 260-8670, Japan

    Fumihiko Kanai & Osamu Yokosuka

  2. Department of Hepatology, Kyoundo Hospital, 1-8 Kandasurugadai, Chiyoda-ku, Tokyo, 101-0062, Japan

    Shuntaro Obi

  3. Department of Gastroenterology and Hepatology, Kumamoto Shinto General Hospital, 1-17-27 Shinyashiki, Kumamoto City, Kumamoto, 862-8655, Japan

    Shigetoshi Fujiyama

  4. Department of Gastroenterology, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Shuichiro Shiina

  5. Second Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama City, Wakayama, 641-0012, Japan

    Hideyuki Tamai

  6. Department of Gastroenterology, Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu City, Yamanashi, 400-8506, Japan

    Hitoshi Mochizuki

  7. Department of Gastroenterology, Kanto Central Hospital, 6-25-1 Kamiyouga, Setagaya-ku, Tokyo, 158-8531, Japan

    Yukihiro Koike

  8. 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 Imamura

  9. Clinical Research 1, Zeria Pharmaceutical Co., Ltd, 10-11 Nihonbashi Kobuna-cho, Chuo-ku, Tokyo, 103-8351, Japan

    Takayoshi Yamaguchi & Isamu Saida

  10. Yamanashi Prefectural Hospital Organization, 1-1-1 Fujimi, Kofu City, Yamanashi, 400-8506, Japan

    Masao Omata

Authors
  1. Fumihiko Kanai
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  2. Shuntaro Obi
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  3. Shigetoshi Fujiyama
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  4. Shuichiro Shiina
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  5. Hideyuki Tamai
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  6. Hitoshi Mochizuki
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  7. Yukihiro Koike
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  8. Jun Imamura
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  9. Takayoshi Yamaguchi
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  10. Isamu Saida
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  11. Osamu Yokosuka
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  12. Masao Omata
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Corresponding author

Correspondence to Fumihiko Kanai.

Additional information

The registered study number was NCT00731445 (clinicaltrials.gov).

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Kanai, F., Obi, S., Fujiyama, S. et al. An open-label phase I/II study of tamibarotene in patients with advanced hepatocellular carcinoma. Hepatol Int 8, 94–103 (2014). https://doi.org/10.1007/s12072-013-9459-7

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  • DOI: https://doi.org/10.1007/s12072-013-9459-7

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