title: Open-label, non-randomised, inter-individual dose escalation of ZK 304709 with the evaluation of safety, tolerability, pharmacokinetics, oral bioavailability and orientating efficacy after daily administration in patients with advanced cancer (7 d treatment and 14 d recovery).
abstract: OBJECTIVE
  The primary objectives of this study were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of ZK 304709, a novel multi-targeted growth inhibitor (MTGI(trade mark)), in man. Secondary end-points included safety evaluation, tolerability, pharmacokinetic profiling and assessment of response using standard and novel surrogate pharmacodynamic end-points.
  
  
  METHODS
  Patients (n=40) with advanced solid malignancies were treated with ZK 304709, administered orally once daily for 7 d with 14 d recovery. Doses were escalated in sequential cohorts of three patients with expansion to 6-7 patients should a dose-limiting toxicity occur.
  
  
  RESULTS
  ZK 304709 was safely administered up to 360mg. However, above 90mg blood concentrations increased only slightly. As this dose was not deemed likely to result in meaningful pharmacologic or clinical activity, the trial was stopped before the MTD was ascertained. It was therefore not possible to make a reliable assessment of efficacy or pharmacodynamic end-points.
  
  
  CONCLUSIONS
  Due to the lack of further increment in blood concentrations above a dose of 90mg, which was felt from previous animal studies to be unlikely to result in meaningful pharmacologic or clinical activity, this study was stopped early.
authors.affiliation: Cancer Research UK, Department of Medical Oncology, University of Glasgow, Glasgow G61 1BD, UK. j.graham@imperial.ac.uk
authors.forename: Janet S
authors.initials: JS
authors.lastname: Graham
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
authors.forename: Candice
authors.initials: C
authors.lastname: McCoy
authors.forename: Kristin
authors.initials: K
authors.lastname: Kowal
authors.forename: Herbert
authors.initials: H
authors.lastname: Wiesinger
authors.forename: Katharina
authors.initials: K
authors.lastname: Detjen
authors.forename: Hilary
authors.initials: H
authors.lastname: Calvert
authors.forename: Bertram
authors.initials: B
authors.lastname: Wiedenmann
authors.forename: Jim
authors.initials: J
authors.lastname: Cassidy
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity*; D001682:Biological Availability; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D018579:Patient Selection; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use / Q000633:toxicity; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors