Originally published as JCO Early Release 10.1200/JCO.2009.22.9427 on November 16 2009

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Randomized, Double-Blind Trial of Carboplatin and Paclitaxel With Either Daily Oral Cediranib or Placebo in Advanced Non–Small-Cell Lung Cancer: NCIC Clinical Trials Group BR24 Study

From the National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada.

Corresponding author: Glenwood Goss, MD, FCP(SA), FRCPC, The Ottawa Hospital Cancer Centre, 501 Smyth Rd, Ottawa ON K1H 8L6, Canada; e-mail: ggoss{at}ottawahospital.on.ca.

Purpose This phase II/III double-blind study assessed efficacy and safety of cediranib with standard chemotherapy as initial therapy for advanced non–small-cell lung cancer (NSCLC).

Patients and Methods Paclitaxel (200 mg/m²) and carboplatin (area under the serum concentration-time curve 6) were given every 3 weeks, with daily oral cediranib or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was the primary outcome of the phase II interim analysis; phase III would proceed if the hazard ratio (HR) for PFS 0.77 and toxicity were acceptable.

Results A total of 296 patients were enrolled, 251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher response rate (RR) for cediranib than for placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths in each arm. The study was halted to review imbalances in assigned causes of death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo (38% v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism, hand-foot syndrome, and GI toxicity. Hypoalbuminemia, age 65 years, and female sex predicted increased toxicity. Survival update (N = 296) 10 months after study unblinding favored cediranib over placebo (median of 10.5 months v 10.1 months; HR, 0.78; 95% CI, 0.57 to 1.06; P = .11). Causes of death in the cediranib 30-mg cohort were NSCLC (81%), protocol toxicity ± NSCLC (13%), and other (6%); for the placebo group, they were 98%, 0%, and 2%, respectively.

Conclusion The addition of cediranib to carboplatin/paclitaxel results in improved response and PFS, but does not appear tolerable at a 30-mg dose. Consequently, the National Cancer Institute of Canada Clinical Trials Group and the Australasian Lung Cancer Trials Group initiated a randomized, double-blind, placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced NSCLC.

Supported by the Canadian Cancer Society and a grant from AstraZeneca. AstraZeneca supplied cediranib and placebo for the study.

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

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