Hiroshi Nokihara1, Yasuhide Yamada2, Yutaka Fujiwara3, Noboru Yamamoto3, Hiroshi Wakui3, Shinji Nakamichi3, Satoru Kitazono3, Kohei Inoue4,5, Akiko Harada4, Tillmann Taube6, Yoshito Takeuchi4, Tomohide Tamura3,7. 1. Department of Thoracic Oncology, National Cancer Centre Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. hnokihar@ncc.go.jp. 2. Division of Gastrointestinal Oncology, National Cancer Centre Hospital, Tokyo, Japan. 3. Department of Thoracic Oncology, National Cancer Centre Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. 4. Medical Division, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan. 5. Statistics Analysis Department 1, EPS Corporation, Tokyo, Japan. 6. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. 7. Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.
Abstract
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.
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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