title: Randomized phase III placebo-controlled trial of carboplatin and paclitaxel with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 (vadimezan), when combined with first-line platinum-based chemotherapy, improves survival in patients with advanced non-small-cell lung cancer (NSCLC) versus chemotherapy alone.
  
  
  METHODS
  Patients with advanced stage IIIB or IV NSCLC, stratified by sex and tumor histology, were randomly assigned 1:1 to paclitaxel (200 mg/m(2)) and carboplatin (area under the curve, 6.0) with or without ASA404 (1,800 mg m(2)), given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR) and progression-free survival (PFS).
  
  
  RESULTS
  One thousand two hundred ninety-nine patients were randomly assigned. The trial was stopped for futility at interim analysis. At final analysis, there was no difference in OS seen between ASA404 (n = 649) and placebo (n = 650) arms: median OS was 13.4 and 12.7 months respectively (hazard ratio [HR], 1.01; 95% CI, 0.85 to 1.19; P = .535). Similarly, no OS difference was seen in the histologic (squamous or nonsquamous) and sex (male or female) strata. Median PFS was 5.5 months in both arms (HR, 1.04; P = .727), while ORR was 25% in both arms (P = 1.0). Overall rate of adverse events (AEs) was comparable between the ASA404 and placebo arms. Grade 4 neutropenia (27% v 19%) and infusion site pain (10% v 0.5%) were reported more frequently in the ASA404 arm.
  
  
  CONCLUSIONS
  The addition of ASA404 to carboplatin and paclitaxel, although generally well tolerated, failed to improve frontline efficacy in advanced NSCLC.
authors.affiliation: University of California, Davis Cancer Center, 4501 X St, Suite 3016, Sacramento, CA, USA. primo.lara@ucdmc.ucdavis.edu
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McKeage
authors.forename: Istvan
authors.initials: I
authors.lastname: Albert
authors.forename: György
authors.initials: G
authors.lastname: Losonczy
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.forename: Dae-Seog
authors.initials: DS
authors.lastname: Heo
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Fan
authors.forename: Abderrahim
authors.initials: A
authors.lastname: Fandi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scagliotti
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; 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* / Q000556:secondary; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D017239:Paclitaxel / Q000008:administration & dosage; D011788:Quality of Life; D011795:Surveys and Questionnaires; D017211:Treatment Failure; D044004:Xanthones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D044004:Xanthones; C066668:vadimezan; D016190:Carboplatin; D017239:Paclitaxel