title: Phase I study of intravenous ASA404 (vadimezan) administered in combination with paclitaxel and carboplatin in Japanese patients with non-small cell lung cancer.
abstract: ASA404 (5,6-dimethylxanthenone-4-acetic acid, vadimezan), a flavone-8-acetic acid analogue, is a novel tumor-vascular disrupting agent. In this study, the safety and tolerability, pharmacokinetics and pharmacodynamics of ASA404 in combination with standard therapy of paclitaxel and carboplatin (P/C) were assessed. A total of 15 Japanese patients with stage IV advanced non-small cell lung cancer were enrolled and P/C plus ASA404 at three dose levels (600-1800 mg/m(2)) was administered every 3 weeks. Dose limiting toxicities were observed in two patients during Cycle 1 of ASA404 treatment (Grade 3 febrile neutropenia at ASA404 1200 mg/m(2) and Grade 3 QT prolongation at ASA404 1800 mg/m(2)) and the incidence of dose limiting toxicity was ≤1/3. The most frequently reported adverse events were injection site pain, peripheral sensory neuropathy, alopecia, neutropenia, nausea, anorexia and arthralgia, which were similar to those seen in previous Phase I/II studies. Pharmacokinetic analysis revealed the plasma area under the curve (AUC) of total ASA404 increased in a mostly dose-proportional manner within the dose range investigated. Administration of ASA404 raised plasma 5-hydroxyindole-3-acetic acid level dose-dependently by 116 and 204% after 1200 and 1800 mg/m(2) doses, respectively. Partial response was observed in four patients (27%), and seven patients (47%) exhibited stable disease. Overall, the safety and preliminary efficacy profiles were comparable to those seen in non-Japanese patients in previous Phase I and Phase II studies, and support the further evaluation of ASA404 (1800 mg/m(2)) in Phase III studies in combination with P/C in Japanese patients with advanced non-small cell lung cancer.
authors.affiliation: Aichi Cancer Center Hospital, Aichi, Japan. 107974@aichi-cc.jp
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tamiya
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hirashima
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horai
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tanii
authors.forename: Michael M
authors.initials: MM
authors.lastname: Shi
authors.forename: Ken
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Horio
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D012074:Remission Induction; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome; D044004:Xanthones / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; D044004:Xanthones; C066668:vadimezan; D016190:Carboplatin; D017239:Paclitaxel