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A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma

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Abstract

Purpose

We studied the safety and effectiveness of TSU-68, an oral tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor and fibroblast growth factor receptor, in patients with advanced hepatocellular carcinoma (HCC).

Methods

Patients with unresectable or metastatic HCC were eligible for enrollment. In phase I, the safety, tolerability and pharmacokinetics were assessed in patients stratified based on liver function, from no cirrhosis to Child–Pugh class B. The safety and effectiveness were assessed in phase II at the dose determined in phase I.

Results

Twelve patients were enrolled in phase I. Dose-limiting toxicities were found with TSU-68 at the dose of 400 mg bid in Child–Pugh B patients, and 200 mg bid was established as the phase II dose. Phase II included 23 additional patients, and the safety and efficacy were evaluated in a total of 35 patients. One patient (2.9%) had a complete response. Two patients (5.7%) had a partial response, and 15 patients (42.8%) showed a stable disease. The median time to progression was 2.1 months, and the median overall survival was 13.1 months. Common adverse events were hypoalbuminemia, diarrhea, anorexia, abdominal pain, malaise, edema and AST/ALT elevation. The analysis of angiogenesis-related parameters suggests that serum-soluble vascular cell adhesion molecule-1 is a possible marker to show the response.

Conclusions

TSU-68 at a dose of 200 mg bid determined by stratification into liver function, showed promising preliminary efficacy with a high safety profile in patients with HCC who had been heavily pre-treated.

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Acknowledgments

We thank Tomonori Fujishima, Hideo Yoshida, Miwa Yamashita, Megumi Kawai and Atsuko Tamori for their contributions. We are also grateful to Yutaka Ariyoshi, Nagahiro Saijo and Yuh Sakata for their extramural review. This study was supported by Taiho Pharmaceutical.

Conflict of interest statement

The author(s) have nothing to disclose.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, University of Tokyo, Tokyo, Japan

    Fumihiko Kanai, Haruhiko Yoshida, Ryosuke Tateishi, Shinpei Sato, Takao Kawabe, Shuichiro Shiina & Masao Omata

  2. Department of Clinical Drug Evaluation, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Fumihiko Kanai

  3. Department of Hepatology, Kyoundo Hospital, Tokyo, Japan

    Shuntaro Obi

  4. Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan

    Yuji Kondo, Makoto Taniguchi & Kazumi Tagawa

  5. Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan

    Masafumi Ikeda, Chigusa Morizane & Takuji Okusaka

  6. Division of Medical Oncology, Yokohama Rosai Hospital, Yokohama, Japan

    Hitoshi Arioka

  7. Department of Gastroenterology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8677, Japan

    Fumihiko Kanai

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  1. Fumihiko Kanai
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  2. Haruhiko Yoshida
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Correspondence to Fumihiko Kanai.

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Kanai, F., Yoshida, H., Tateishi, R. et al. A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 67, 315–324 (2011). https://doi.org/10.1007/s00280-010-1320-2

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  • DOI: https://doi.org/10.1007/s00280-010-1320-2

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