title: A phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors.
abstract: BACKGROUND
  ZD6474 (vandetanib) is an orally available inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and RET receptor tyrosine kinase activity. This study assessed the safety and tolerability of escalating doses of ZD6474 in Japanese patients with solid, malignant tumors.
  
  
  METHODS
  Adult patients with solid tumors refractory to standard therapy received a once-daily oral dose of ZD6474 (100-400 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed.
  
  
  RESULTS
  Eighteen patients were treated at doses of 100 mg (n = 3), 200 mg (n = 6), 300 mg (n = 6), and 400 mg (n = 3). Dose-limiting toxicities at the completion of cycle 2 were hypertension (n = 3), diarrhea (n = 1), headache (n = 1), toxic skin eruption (n = 1), and alanine aminotransferase increase (n = 1). A dose of 400 mg/day was considered to exceed the maximum tolerated dose (MTD). Toxicities were manageable with dose interruption and/or reduction. Objective tumor response was observed in four of nine patients with non-small cell lung cancer (NSCLC) at doses of either 200 or 300 mg. Terminal half-life was about 90-115 hours. Plasma trough concentrations achieved steady-state conditions after approximately 1 month of daily dosing.
  
  
  CONCLUSIONS
  It was concluded that a dose of 400 mg/day was considered to exceed the MTD, and doses for phase II study were thought to be not more than 300 mg/day. The objective response observed in some NSCLC patients is encouraging for further studies in this tumor type.
authors.affiliation: National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. ttamura@ncc.go.jp
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tatsu
authors.initials: T
authors.lastname: Shimoyama
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Murakami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Horiike
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Fujisaka
authors.forename: Tetsu
authors.initials: T
authors.lastname: Shinkai
authors.forename: Makoto
authors.initials: M
authors.lastname: Tahara
authors.forename: Kenji
authors.initials: K
authors.lastname: Kawada
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Yasutsuna
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Haiyi
authors.initials: H
authors.lastname: Jiang
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007564:Japan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009367:Neoplasm Staging; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D018570:Risk Assessment; D016019:Survival Analysis; D013899:Thoracic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D010880:Piperidines; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib