title: Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent.
abstract: OBJECTIVE
  CYT997 is a novel microtubule inhibitor and vascular disrupting agent. This phase I trial examined the safety, tolerability, pharmacokinetics and vascular-disrupting effects of orally-administered CYT997.
  
  
  METHODS
  We performed a phase I accelerated dose-escalation study of CYT997 given orally once every 2 to 3 weeks in patients with advanced solid tumours. Vascular disruption was assessed by measurement of plasma von Willebrand factor (vWF) levels and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
  
  
  RESULTS
  A total of 56 doses were administered to 21 patients over 8 dose levels (15-164 mg/m(2)). Grade 3 fatigue and grade 3 hypoxia were dose limiting. Oral bioavailability was observed with approximate linear pharmacokinetics over the 11-fold dose range. At doses of 84 mg/m(2) and above, plasma vWF levels increased above baseline and DCE-MRI scans showed reductions in tumour K(trans) in some patients.
  
  
  CONCLUSIONS
  CYT997 is orally bioavailable. The 118 mg/m(2) dose level should be used to guide dosing in future studies.
authors.affiliation: Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, Queensland 4029, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Burge
authors.forename: Alessandra B
authors.initials: AB
authors.lastname: Francesconi
authors.forename: Dusan
authors.initials: D
authors.lastname: Kotasek
authors.forename: Rosa
authors.initials: R
authors.lastname: Fida
authors.forename: Gregg
authors.initials: G
authors.lastname: Smith
authors.forename: Andrew
authors.initials: A
authors.lastname: Wilks
authors.forename: Paul A
authors.initials: PA
authors.lastname: Vasey
authors.forename: Jason D
authors.initials: JD
authors.lastname: Lickliter
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001682:Biological Availability; D003603:Cytotoxins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; C543949:CYT997; D003603:Cytotoxins; D011725:Pyridines; D011743:Pyrimidines; D050257:Tubulin Modulators