title: Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Thoracic Oncology, National Cancer Centre Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. hnokihar@ncc.go.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Centre Hospital, Tokyo, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Thoracic Oncology, National Cancer Centre Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Thoracic Oncology, National Cancer Centre Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Thoracic Oncology, National Cancer Centre Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wakui
authors.affiliation: Department of Thoracic Oncology, National Cancer Centre Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nakamichi
authors.affiliation: Department of Thoracic Oncology, National Cancer Centre Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kitazono
authors.affiliation: Medical Division, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.|Statistics Analysis Department 1, EPS Corporation, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Medical Division, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Harada
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Taube
authors.affiliation: Medical Division, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Department of Thoracic Oncology, National Cancer Centre Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.|Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D044466:Asian People; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011621:Pteridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; C541363:BI 6727; D047428:Protein Kinase Inhibitors; D011621:Pteridines
keywords: Japanese; Pharmacokinetics; Phase I trial; Polo-like kinase inhibitor; Solid tumors; Volasertib