title: Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer.
abstract: ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive </=6 cycles of carboplatin area under the plasma concentration-time curve 6 mg ml(-1) min and paclitaxel 175 mg m(-2) (CP, n=36) or standard therapy plus ASA404 1200 mg m(-2) (ASA404-CP, n=37). There was little change in the systemic exposure of either total or free carboplatin or paclitaxel on addition of ASA404. Safety profiles were similar and manageable in both groups, with most adverse effects attributed to standard therapy. Tumour response rate (31 vs 22%), median time to tumour progression (5.4 vs 4.4 months) and median survival (14.0 vs 8.8 months, hazard ratio 0.73, 95% CI 0.39, 1.38) were improved in the ASA404 combination group compared with the standard therapy group. In conclusion, this study establishes the feasibility of combining ASA404 with carboplatin and paclitaxel in patients with previously untreated, advanced NSCLC, demonstrating a manageable safety profile and lack of adverse pharmacokinetic interactions. The results indicate that there may be a benefit associated with ASA404, but this needs to be evaluated in a larger trial.
authors.affiliation: University of Auckland, 85 Park Road, Grafton, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: M J
authors.initials: MJ
authors.lastname: McKeage
authors.forename: J
authors.initials: J
authors.lastname: Von Pawel
authors.forename: M
authors.initials: M
authors.lastname: Reck
authors.forename: M B
authors.initials: MB
authors.lastname: Jameson
authors.forename: M A
authors.initials: MA
authors.lastname: Rosenthal
authors.forename: R
authors.initials: R
authors.lastname: Sullivan
authors.forename: D
authors.initials: D
authors.lastname: Gibbs
authors.forename: P N
authors.initials: PN
authors.lastname: Mainwaring
authors.forename: M
authors.initials: M
authors.lastname: Serke
authors.forename: J-J
authors.initials: JJ
authors.lastname: Lafitte
authors.forename: C
authors.initials: C
authors.lastname: Chouaid
authors.forename: L
authors.initials: L
authors.lastname: Freitag
authors.forename: E
authors.initials: E
authors.lastname: Quoix
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016190:Carboplatin / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome; D044004:Xanthones / Q000627:therapeutic use*
chemical_list: D044004:Xanthones; C066668:vadimezan; D016190:Carboplatin; D017239:Paclitaxel