Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group.
OBJECTIVE
AZD2171 is a potent inhibitor of vascular endothelial growth factor receptors that showed broad antitumor activity in preclinical models. Doses of up to 45 mg/d of AZD2171 are tolerable when administered alone. This study evaluated escalating doses of AZD2171 in combination with standard chemotherapy in patients with advanced non-small-cell lung cancer.


METHODS
Eligible patients received carboplatin targeted to an area under the concentration time curve of 6 mg . min/mL and paclitaxel 200 mg/m(2), both on day 1 of a 3-week cycle; daily oral AZD2171 at either 30 mg or 45 mg commenced day 2 of cycle 1. Pharmacokinetics of all drugs were performed, and tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST).


RESULTS
Twenty patients were enrolled. No dose-limiting toxicities were observed during cycle 1 at either dose. Fatigue, diarrhea, anorexia, and granulocytopenia were common; hypertension was manageable with a treatment algorithm designed for this protocol. No clinically significant drug-related bleeding was observed. At 45 mg/d, fatigue and diarrhea were increased, and headache and hoarseness were observed. Paclitaxel clearance decreased during cycle 2, but no other significant pharmacokinetic interactions were observed. After radiology review, confirmed responses were observed in nine patients (response rate, 45%; 95% CI, 23% to 68%); all but one enrolled patient showed evidence of tumor shrinkage, some with cavitation.


CONCLUSIONS
AZD2171 can be combined with standard doses of carboplatin/paclitaxel with encouraging antitumor activity. Toxicity is increased, but predictable and manageable.
Laurie
Scott A
SA
The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa ON K1H 8L6, Canada. slaurie@ottawahospital.on.ca
Gauthier
Isabelle
I
Arnold
Andrew
A
Shepherd
Frances A
FA
Ellis
Peter M
PM
Chen
Eric
E
Goss
Glenwood
G
Powers
Jean
J
Walsh
Wendy
W
Tu
Dongsheng
D
Robertson
Jane
J
Puchalski
Thomas A
TA
Seymour
Lesley
L
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D007211:Indoles
D016190:Carboplatin; D017239:Paclitaxel; D011505:Protein-Tyrosine Kinases; D011799:Quinazolines; D040301:Vascular Endothelial Growth Factor Receptor-2; C500926:cediranib; D007211:Indoles