title: Phase I trial of CYT997, a novel cytotoxic and vascular-disrupting agent.
abstract: BACKGROUND
  CYT997 is a novel microtubule inhibitor and vascular-disrupting agent with marked preclinical anti-tumour activity.
  
  
  METHODS
  This phase I dose-escalation study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of CYT997 administered by continuous intravenous infusion over 24 h every 3 weeks to patients with advanced solid tumours.
  
  
  RESULTS
  Thirty-one patients received CYT997 over 12 dose levels (7-358 mg m(-2)). Doses up to 202 mg m(-2) were well tolerated. Dose-limiting toxicities were observed at 269 and 358 mg m(-2), consisting of grade 3 prolonged corrected QT interval in two patients and grade 3 hypoxia and grade 4 dyspnea in one patient. All toxicities were reversible. The pharmacokinetics of CYT997 were linear over the entire dose range. Dynamic contrast-enhanced magnetic resonance imaging scans showed significant changes in tumour K(trans) values consistent with vascular disruption in 7 out of 11 evaluable patients treated at CYT997 doses of >or=65 mg m(-2). Moreover, plasma levels of von Willebrand factor and caspase-cleaved cytokeratin-18 increased post-treatment at higher dose levels. Among 22 patients evaluable for response, 18 achieved stable disease for >2 cycles.
  
  
  CONCLUSIONS
  CYT997 was well tolerated at doses that were associated with pharmacodynamic evidence of vascular disruption in tumours.
authors: Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston 4029, Queensland, Australia. jason.lickliter@med.monash.edu.au
authors: J D
authors: JD
authors: Lickliter
authors: A B
authors: AB
authors: Francesconi
authors: G
authors: G
authors: Smith
authors: M
authors: M
authors: Burge
authors: A
authors: A
authors: Coulthard
authors: S
authors: S
authors: Rose
authors: M
authors: M
authors: Griffin
authors: R
authors: R
authors: Milne
authors: J
authors: J
authors: McCarron
authors: T
authors: T
authors: Yeadon
authors: A
authors: A
authors: Wilks
authors: A
authors: A
authors: Cubitt
authors: D K
authors: DK
authors: Wyld
authors: P A
authors: PA
authors: Vasey
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002452:Cell Count; D042783:Endothelial Cells; D005260:Female; D006801:Humans; D053538:Keratin-18 / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014841:von Willebrand Factor / Q000032:analysis / Q000276:immunology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C543949:CYT997; D053538:Keratin-18; D011725:Pyridines; D011743:Pyrimidines; C029417:Von Willebrand antigen; D014841:von Willebrand Factor