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A phase 1 and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors

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Abstract

Purpose

Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors.

Methods

LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m2/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia.

Results

Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/μl within 7 days. All patients at 4 and 5 mg/m2/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m2/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed.

Conclusions

The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m2/day in Japanese patients with advanced solid tumors.

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Acknowledgments

We thank the patients, their families and caregivers, and all personnel who contributed to patient care and data collection. This study was sponsored by Kyowa Hakko Kirin Co., Ltd.

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Authors and Affiliations

  1. Department of Thoracic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hiroshi Wakui, Noboru Yamamoto, Satoru Kitazono, Hidenori Mizugaki, Shinji Nakamichi, Yutaka Fujiwara, Hiroshi Nokihara & Tomohide Tamura

  2. Department of Gastrointestinal Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Yasuhide Yamada

  3. Development Division, Kyowa Hakko Kirin Co., Ltd, 1-6-1, Ohtemachi, Chiyoda-ku, Tokyo, 100-8185, Japan

    Kohei Suzuki, Hironori Kanda & Shiro Akinaga

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  1. Hiroshi Wakui
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  2. Noboru Yamamoto
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Correspondence to Tomohide Tamura.

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Wakui, H., Yamamoto, N., Kitazono, S. et al. A phase 1 and dose-finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 74, 15–23 (2014). https://doi.org/10.1007/s00280-014-2467-z

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  • DOI: https://doi.org/10.1007/s00280-014-2467-z

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