A phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors.
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.
Tamura
Tomohide
T
National Cancer Center Hospital, Chuo-ku, Tokyo, Japan. ttamura@ncc.go.jp
Minami
Hironobu
H
Yamada
Yasuhide
Y
Yamamoto
Noboru
N
Shimoyama
Tatsu
T
Murakami
Haruyasu
H
Horiike
Atsushi
A
Fujisaka
Yasuhito
Y
Shinkai
Tetsu
T
Tahara
Makoto
M
Kawada
Kenji
K
Ebi
Hiromichi
H
Sasaki
Yasutsuna
Y
Jiang
Haiyi
H
Saijo
Nagahiro
N
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
D010880:Piperidines; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib