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Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with advanced solid tumors

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Summary

Purpose This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical effects of volasertib, a selective Polo-like kinase inhibitor that induces mitotic arrest and apoptosis, in Japanese patients with advanced solid tumors (NCT01348347; 1230.15). Methods In this phase I, open-label, dose-escalation trial, sequential patient cohorts (3 + 3 dose-escalation design) received volasertib (200–350 mg) as a single dose by intravenous infusion over 2 h on day 1 every 21 days until disease progression or unacceptable toxicity. The primary endpoint was the MTD of volasertib in Japanese patients with an advanced solid tumor; secondary endpoints included safety, pharmacokinetics, and clinical benefit. Results Fifteen patients with an advanced solid tumor were treated. Dose-limiting toxicities of grade 4 neutropenia for ≥7 days and grade 4 thrombocytopenia were both experienced by 2/6 patients in the 350 mg cohort. The MTD of volasertib in Japanese patients was 300 mg. The most common (≥3 patients) drug-related non-hematologic adverse events included fatigue, decreased appetite, and nausea. Exposure to volasertib and its metabolite increased with increasing doses. A partial response in a patient with gastric cancer and stable disease in eleven patients were observed. Conclusions Volasertib had a manageable safety profile up to the MTD determined as 300 mg. Exposure to volasertib and its metabolite increased with increasing doses. The safety profile of volasertib in Japanese patients is comparable with those previously obtained in Caucasian patients. These data support enrollment of Japanese patients in global clinical trials without dose modification.

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Acknowledgments

The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version. Medical writing assistance, financially supported by Boehringer Ingelheim, was provided by Victoria A. Robb of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.

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Author notes

  1. Tomohide Tamura

    Present address: Thoracic Center, St. Luke’s International Hospital, Tokyo, Japan

  2. Kohei Inoue

    Present address: Statistics Analysis Department 1, EPS Corporation, Tokyo, Japan

Authors and Affiliations

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

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

  2. Division of Gastrointestinal Oncology, National Cancer Centre Hospital, Tokyo, Japan

    Yasuhide Yamada

  3. Medical Division, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan

    Kohei Inoue, Akiko Harada & Yoshito Takeuchi

  4. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany

    Tillmann Taube

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  1. Hiroshi Nokihara
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Correspondence to Hiroshi Nokihara.

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Ethical approval and informed consent

The trial was approved by National Cancer Center Hospital’s Institutional Review Board and conducted in compliance with the principles laid down in the Declaration of Helsinki, in accordance with the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice (GCP) and in accordance with relevant Boehringer Ingelheim standard operating procedures and Japanese GCP. All participating patients gave written informed consent.

Conflict of interest

Hiroshi Nokihara received honoraria from Sanofi, Eli Lilly, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, and Ono Pharmaceutical, and research support from Merck Serono, Pfizer, Taiho Pharmaceutical, Esai Co., Ltd, Chugai Pharmaceutical Co., Ltd, Eli Lilly, Novartis, Daiichi Sankyo, GlaxoSmithKline, Yakult Pharmaceutical Industry Co., Ltd, Quintiles, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, and Ono Pharmaceutical. Yasuhide Yamada received honoraria from Taiho Pharmaceutical, Yakult Pharmaceutical Industry Co., Ltd, and Chugai Pharmaceutical Co., Ltd, and grants/patents from AstraZeneca, Novartis, Chugai Pharmaceutical Co., Ltd, Otsuka Pharmaceutical Co., Ltd, Taiho Pharmaceutical, Daiichi Sankyo, and Merck Serono. Noboru Yamamoto received honoraria from Chugai Pharmaceutical Co., Ltd, Eli Lilly, AstraZeneca, and Sanofi, and grants/patents from Chugai Pharmaceutical Co., Ltd, Eli Lilly, Taiho Pharmaceutical, Esai Co., Ltd, Quintiles, Astellas Pharma, Bristol-Myers Squibb, Novartis, Daiichi Sankyo, Pfizer, and Takeda Pharmaceutical Company Ltd. Tillmann Taube is an employee of Boehringer Ingelheim Pharma GmbH & Co KG. Tomohide Tamura received honoraria from Boehringer Ingelheim. All other authors disclose no potential conflicts of interest.

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Nokihara, H., Yamada, Y., Fujiwara, Y. et al. Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with advanced solid tumors. Invest New Drugs 34, 66–74 (2016). https://doi.org/10.1007/s10637-015-0300-0

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  • DOI: https://doi.org/10.1007/s10637-015-0300-0

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