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

Abstract

• Three pharmacokinetic and safety studies for combretastatin A4 phosphate (CA4P), the first vascular disrupting agent, have been conducted in Western countries. • The maximum tolerated dose (MTD) was approximately 60-68 mg m(-2). • CA4P-related grade 3 or 4 adverse events were tumour pain, dyspnoea, hypoxia and syncope in patients who received doses ≥ 50 mg m(-2). • This is the first pharmacokinetic and safety study conducted in East Asian patients. • There appeared to be a trend that Chinese patients metabolized CA4 more rapidly and had greater neurotoxicity than patients in Western countries. • We observed favourable clinical responses in patients with refractory nasopharyngeal carcinoma. • CA4P-induced acute renal failure was seen in one dehydrated Chinese patient. 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 85 mg m(-2) infused intravenously over 30 min. CA4P was generally well tolerated at ≤ 65 mg m(-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 ≥65 mg m(-2), including two episodes of reversible ataxia at 85 mg m(-2).For CA4, at 50 mg m(-2),mean (SD) peak plasma concentration (C(max) was 0.99 (0.33) mM, area under the curve from time zero to time of last quantifiable concentration (AUC(0,t)) was 1.42 (0.30) mM h and terminal elimination half-life (t(1/2)was 1.81 (0.61) h. At 65 mg m-2,C(max) was 1.73 (0.62) mM,AUC(0,t) was 3.19 (1.47) mM h and t (1/2) was 1.90 (0.61) h [corrected]One patient with nasopharyngeal carcinoma had an obvious clinical response with central necrosis in the metastatic lung mass. CONCLUSION Doses ≤ 65 mg m(-2) given as 30 min infusions define the maximum tolerated dose in East Asian patients, and doses in the range of 50-65 mg m(-2) have been selected for further studies.