title: Phase II study of ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800mg/m(2) combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer.
abstract: This single-arm phase II study evaluated the tumor-vascular disrupting agent ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800mg/m(2) plus standard therapy of carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). This ASA404 dose is 50% higher than that used in previous phase II studies. Thirty patients with histologically confirmed stage IIIb or IV NSCLC previously untreated with chemotherapy received carboplatin AUC 6mg/mlmin plus paclitaxel 175mg/m(2) plus ASA404 1800mg/m(2) every 21 days for up to six cycles. The addition of ASA404 1800mg/m(2) to standard therapy produced little change in the systemic exposure of either total or free carboplatin or paclitaxel, and was generally well-tolerated, with no cardiac serious adverse events or clinically relevant ophthalmic abnormalities. The best overall tumor response was partial response, which was seen in 37.9% of patients by independent assessment and in 46.7% by investigator assessment. Stable disease was seen in 48.3% of patients by independent assessment and in 43.3% by investigator assessment. Median time to tumor progression was 5.5 months by investigator assessment and median survival was 14.9 months. The data from this trial corroborate findings from a recent randomized phase II trial, which suggested improvements in efficacy variables, including survival, when ASA404 1200mg/m(2) was added to standard therapy for advanced NSCLC. The manageable safety profile, lack of adverse pharmacokinetic interactions and efficacy outcomes seen in this single-arm study suggest that ASA404 1800mg/m(2) is a viable dose for future combination studies.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, The University of Auckland, 85 Park Rd, Grafton, Private Bag 92019, Auckland 1142, New Zealand. m.mckeage@auckland.ac.nz
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McKeage
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jameson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rosenthal
authors.forename: David
authors.initials: D
authors.lastname: Gibbs
authors.forename: Paul N
authors.initials: PN
authors.lastname: Mainwaring
authors.forename: Lutz
authors.initials: L
authors.lastname: Freitag
authors.forename: Richard
authors.initials: R
authors.lastname: Sullivan
authors.forename: Joachim
authors.initials: J
authors.lastname: Von Pawel
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; 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; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D044004:Xanthones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D044004:Xanthones; C066668:vadimezan; D016190:Carboplatin; D017239:Paclitaxel