A pharmacokinetic and safety study of single dose intravenous combretastatin A4 phosphate in Chinese patients with refractory solid tumours

Abstract

AIMS: This trial was conducted to evaluate the safety and pharmacokinetics of combretastatin A4 phosphate (CA4P) given intravenously as a single dose to Chinese patients with refractory solid tumours. METHODS: Twenty-five patients were treated with single doses of CA4P according to a dose escalation scheme: 5, 10, 20, 33, 50, 65 and 85mgm -2 infused intravenously over 30min. RESULTS: CA4P was generally well tolerated at ≤65mgm -2. Transient, moderate increases in the heart rate-corrected QT interval occurred at all doses. CA4P produced a transient dose-dependent increase in neural and gastrointestinal toxicities. Acute renal failure occurred in one dehydrated patient who had also taken paracetamol. There were seven episodes of dose-limiting toxicity at doses ≥65mgm -2, including two episodes of reversible ataxia at 85mgm -2. For CA4P, at 50mgm -2, mean (SD) peak plasma concentration (C max) was 0.99 (0.33) μm, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) μmh and terminal elimination half-life (t 1/2) was 1.81 (0.61) h. At 65mgm -2, C max was 1.73 (0.62) μm, AUC(0,t) was 3.19 (1.47) μmh and t 1/2 was 1.90 (0.61) h. One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass. CONCLUSION: Doses ≤65mgm -2 given as 30min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50-65mgm -2 have been selected for further studies. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.