title: A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies.
abstract: BACKGROUND
  Polo-like kinase 1 (Plk1) has an important role in mitosis. Volasertib (BI 6727), a potent and selective cell cycle kinase inhibitor, induces mitotic arrest and apoptosis by targeting Plk; this phase I study sought to determine its maximum tolerated dose (MTD) in Asian patients with advanced solid tumours.
  
  
  METHODS
  Patients were enrolled simultaneously into two 3-week schedules of volasertib: a 2-h infusion on day 1 (schedule A) or days 1 and 8 (schedule B). Dose escalation followed a 3+3 design. The MTD was determined based on dose-limiting toxicities (DLT) in the first treatment course.
  
  
  RESULTS
  Among 59 treated patients, the most common first course DLTs were reversible thrombocytopenia, neutropenia and febrile neutropenia; MTDs were 300 mg for schedule A and 150 mg for schedule B. Volasertib exhibited multi-exponential pharmacokinetics (PK), a long terminal half-life of ∼135 h, a large volume of distribution (>3000 l), and a moderate clearance. Partial responses were observed in two pre-treated patients (ureteral cancer; melanoma). Volasertib was generally well tolerated, with an adverse event profile consistent with its antimitotic mode of action and a favourable PK profile.
  
  
  CONCLUSIONS
  These data support further development of volasertib and a harmonised dosing for Asian and Caucasian patients.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S Road, Taipei 100, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, National Cheng Kung University, Medical College and Hospital, 138 Sheng-Li Road, Tainan 704, Taiwan.
authors.forename: W-C
authors.initials: WC
authors.lastname: Su
authors.affiliation: Department of Internal Medicine, National Cheng Kung University, Medical College and Hospital, 138 Sheng-Li Road, Tainan 704, Taiwan.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: 1] Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S Road, Taipei 100, Taiwan [2] Graduate Institute of Oncology and Cancer Research Centre, National Taiwan University College of Medicine, 2 Xuzhou Road, Taipei 100, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Hsu
authors.affiliation: Department of Internal Medicine, National Cheng Kung University, Medical College and Hospital, 138 Sheng-Li Road, Tainan 704, Taiwan.
authors.forename: W-P
authors.initials: WP
authors.lastname: Su
authors.affiliation: 1] Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S Road, Taipei 100, Taiwan [2] Graduate Institute of Oncology and Cancer Research Centre, National Taiwan University College of Medicine, 2 Xuzhou Road, Taipei 100, Taiwan.
authors.forename: K-H
authors.initials: KH
authors.lastname: Yeh
authors.affiliation: Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S Road, Taipei 100, Taiwan.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Lu
authors.affiliation: 1] Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S Road, Taipei 100, Taiwan [2] Graduate Institute of Oncology and Cancer Research Centre, National Taiwan University College of Medicine, 2 Xuzhou Road, Taipei 100, Taiwan.
authors.forename: A-L
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: Boehringer Ingelheim Taiwan Limited, 12F, 49/51 Min Sheng East Road, Taipei 100, Taiwan.
authors.forename: D C-L
authors.initials: DC
authors.lastname: Huang
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Fritsch
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG., Binger Strasse 173, Ingelheim, Germany 55216.
authors.forename: F
authors.initials: F
authors.lastname: Voss
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Taube
authors.affiliation: 1] Department of Oncology, National Taiwan University Hospital, 7 Chung Shan S Road, Taipei 100, Taiwan [2] Graduate Institute of Oncology and Cancer Research Centre, National Taiwan University College of Medicine, 2 Xuzhou Road, Taipei 100, Taiwan.
authors.forename: J C-H
authors.initials: JC
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016879:Salvage Therapy; D013624:Taiwan; D016896:Treatment Outcome; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C541363:BI 6727
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