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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

Scott A. Laurie, Isabelle Gauthier, Andrew Arnold, Frances A. Shepherd, Peter M. Ellis, Eric Chen, Glenwood Goss, Jean Powers, Wendy Walsh, Dongsheng Tu, Jane Robertson, Thomas A. Puchalski, Lesley Seymour

From the From the Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa; Juravinski Cancer Centre, McMaster University, Hamilton; Princess Margaret Hospital, University of Toronto, Toronto; National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada; and AstraZeneca, Macclesfield, United Kingdom

Corresponding author: Scott A. Laurie, MD, FRCPC, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa ON K1H 8L6, Canada; e-mail: slaurie{at}ottawahospital.on.ca

Purpose 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.

Patients and Methods Eligible patients received carboplatin targeted to an area under the concentration time curve of 6 mg · min/mL and paclitaxel 200 mg/m², 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.

Conclusion AZD2171 can be combined with standard doses of carboplatin/paclitaxel with encouraging antitumor activity. Toxicity is increased, but predictable and manageable.

Supported by a grant from the Canadian Cancer Society. AstraZeneca Canada provided AZD2171 for this trial as well as partial funding.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA; the 8th International Symposium on Angiogenesis, February 3-5, 2006, San Diego, CA; and the 17th European Organisation for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research Symposium on Molecular Targets and Cancer Therapeutics, November 14-17, 2005, Philadelphia, PA.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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