title: Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors.
abstract: BACKGROUND
  ZD6474 selectively inhibits the tyrosine kinase activity of vascular endothelial growth factor receptor and epidermal growth factor receptor. The safety, tolerability and pharmacokinetics of ZD6474 were assessed in a phase I dose-escalation study of patients with advanced solid tumors.
  
  
  METHODS
  Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50-600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed.
  
  
  RESULTS
  Seventy-seven patients were treated at doses of 50 mg (n=9), 100 mg (n=19), 200 mg (n=8), 300 mg (n=25), 500 mg (n=8), and 600 mg (n=8). Adverse events were generally mild, and the most common dose-limiting toxicities (DLT) were diarrhea (n=4), hypertension (n=4), and rash (n=3). The incidence of most adverse events appeared to be dose-dependant. In the 500 mg/day cohort, 3/8 patients experienced DLT and this dose was therefore considered to exceed the maximum tolerated dose. Pharmacokinetic analysis confirmed that ZD6474 was suitable for once-daily oral dosing.
  
  
  CONCLUSIONS
  Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase II trials.
authors.affiliation: University of Colorado Cancer Center, Aurora, CO, USA. hurwi004@mc.duke.edu
authors.forename: S N
authors.initials: SN
authors.lastname: Holden
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: R
authors.initials: R
authors.lastname: Basser
authors.forename: R
authors.initials: R
authors.lastname: de Boer
authors.forename: D
authors.initials: D
authors.lastname: Rischin
authors.forename: M
authors.initials: M
authors.lastname: Green
authors.forename: M A
authors.initials: MA
authors.lastname: Rosenthal
authors.forename: C
authors.initials: C
authors.lastname: Wheeler
authors.forename: A
authors.initials: A
authors.lastname: Barge
authors.forename: H I
authors.initials: HI
authors.lastname: Hurwitz
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010880:Piperidines; D011799:Quinazolines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib