title: A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours.
abstract: BACKGROUND
  Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). This phase I dose-escalation study evaluated the maximum tolerated dose (MTD) of volasertib, safety and efficacy, and pharmacokinetic (PK) parameters.
  
  
  METHODS
  This trial followed an open-label, toxicity-guided dose-titration design. Patients with progressive advanced or metastatic solid tumours received a single 1-h infusion of volasertib every 3 weeks. A total of 65 patients were treated at doses of 12-450 mg.
  
  
  RESULTS
  Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3: 8%), neutropenia (15%; grade 3/4: 14%), fatigue (15%; grade 3: 2%), and thrombocytopenia (14%; grade 3/4: 14%) were the most frequent drug-related adverse events. The MTD was 400mg; however, 300 mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1 year. PK analysis showed no indication of deviation from 'dose-linear PK' behaviour, a large volume of distribution (>4000 l), moderate clearance and a long half-life (~111 h).
  
  
  CONCLUSIONS
  This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing.
authors: Department of General Medical Oncology and Laboratory of Experimental Oncology, University Hospitals, Leuven Cancer Institute, Leuven, Belgium.
authors: Patrick
authors: P
authors: Schöffski
authors: Ahmad
authors: A
authors: Awada
authors: Herlinde
authors: H
authors: Dumez
authors: Thierry
authors: T
authors: Gil
authors: Sylvie
authors: S
authors: Bartholomeus
authors: Pascal
authors: P
authors: Wolter
authors: Martine
authors: M
authors: Taton
authors: Holger
authors: H
authors: Fritsch
authors: Patricia
authors: P
authors: Glomb
authors: Gerd
authors: G
authors: Munzert
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011621:Pteridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C541363:BI 6727; D047428:Protein Kinase Inhibitors; D011621:Pteridines