A randomized, double-blind, phase IIa dose-finding study of Vandetanib (ZD6474) in Japanese patients with non-small cell lung cancer.
BACKGROUND
Vandetanib (ZACTIMA) is a once-daily, oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling. Vandetanib was evaluated as a monotherapy in a randomized, double-blind, dose-finding study in Japan.


METHODS
Eligible patients with locally advanced or metastatic (stage IIIB/IV) or recurrent non-small cell lung cancer, previously treated with chemotherapy, were randomized to receive once-daily oral vandetanib 100, 200, or 300 mg (1:1:1). The primary objective was to determine the objective response rate for each vandetanib dose.


RESULTS
Fifty-three patients received vandetanib (100 mg, n = 17; 200 mg, n = 18; 300 mg, n = 18). The objective response rate in each dose arm was 17.6% (3 of 17; 100 mg), 5.6% (1 of 18; 200 mg), and 16.7% (3 of 18; 300 mg). Common adverse events included rash, diarrhea, hypertension, and asymptomatic QTc prolongation. The adverse event profile was generally consistent with that reported previously for agents that inhibit the VEGFR or EGFR signaling pathways. Among the three responders evaluated for EGFR mutation, two had no mutation, and in one case, the EGFR mutation status could not be determined by direct DNA sequencing and amplification refractory mutation system assay of EGFR exons 19-21. Baseline plasma VEGF levels appeared to be lower in patients who experienced clinical benefit after vandetanib treatment.


CONCLUSIONS
In Japanese patients with advanced non-small cell lung cancer, vandetanib monotherapy (100-300 mg/d) demonstrated antitumor activity with an acceptable safety and tolerability profile.
Kiura
Katsuyuki
K
Okayama Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences and Okayama University Hospital, Okayama, Japan. kkiura@md.okayama-u.ac.jp
Nakagawa
Kazuhiko
K
Shinkai
Tetsu
T
Eguchi
Kenji
K
Ohe
Yuichiro
Y
Yamamoto
Nobuyuki
N
Tsuboi
Masahiro
M
Yokota
Soichiro
S
Seto
Takashi
T
Jiang
Haiyi
H
Nishio
Kazuto
K
Saijo
Nagahiro
N
Fukuoka
Masahiro
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000453:epidemiology / Q000556:secondary; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000453:epidemiology / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000453:epidemiology / Q000556:secondary; D004311:Double-Blind Method; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics
D014408:Biomarkers, Tumor; D010880:Piperidines; D011799:Quinazolines; D066246:ErbB Receptors; C452423:vandetanib