title: 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.
abstract: 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/m(2)) 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 < or = 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 > or = 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.
authors.affiliation: FCP(SA), FRCPC, The Ottawa Hospital Cancer Centre, 501 Smyth Rd, Ottawa ON K1H 8L6, Canada. ggoss@ottawahospital.on.ca
authors.forename: Glenwood D
authors.initials: GD
authors.lastname: Goss
authors.forename: Andrew
authors.initials: A
authors.lastname: Arnold
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Mircea
authors.initials: M
authors.lastname: Dediu
authors.forename: Tudor-Eliade
authors.initials: TE
authors.lastname: Ciuleanu
authors.forename: David
authors.initials: D
authors.lastname: Fenton
authors.forename: Mauro
authors.initials: M
authors.lastname: Zukin
authors.forename: David
authors.initials: D
authors.lastname: Walde
authors.forename: Francis
authors.initials: F
authors.lastname: Laberge
authors.forename: Mark D
authors.initials: MD
authors.lastname: Vincent
authors.forename: Peter M
authors.initials: PM
authors.lastname: Ellis
authors.forename: Scott A
authors.initials: SA
authors.lastname: Laurie
authors.forename: Keyue
authors.initials: K
authors.lastname: Ding
authors.forename: Eliot
authors.initials: E
authors.lastname: Frymire
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gauthier
authors.forename: Natasha B
authors.initials: NB
authors.lastname: Leighl
authors.forename: Cheryl
authors.initials: C
authors.lastname: Ho
authors.forename: Jonathan
authors.initials: J
authors.lastname: Noble
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Lee
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D010919:Placebos; D011799:Quinazolines / Q000008:administration & dosage; D007211:Indoles
chemical_list: D016190:Carboplatin; D017239:Paclitaxel; D010919:Placebos; D011799:Quinazolines; C500926:cediranib; D007211:Indoles