Phase I study of intravenous ASA404 (vadimezan) administered in combination with paclitaxel and carboplatin in Japanese patients with non-small cell lung cancer.

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.