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

摘要: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • 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 syncope patients who received doses ≥50 mg m−2. WHAT STUDY ADDS • This is study East Asian patients. • There appeared to be a trend that Chinese metabolized CA4 more rapidly had greater neurotoxicity than countries. • We observed favourable clinical responses with refractory nasopharyngeal carcinoma. • CA4P-induced acute renal failure seen one dehydrated patient. AIMS This trial evaluate pharmacokinetics of (CA4P) given intravenously as single solid tumours. METHODS Twenty-five treated CA4P according escalation scheme: 5, 10, 20, 33, 50, 65 85 mg m−2 infused over 30 min. RESULTS generally well at ≤65 mg m−2. Transient, moderate increases heart rate-corrected QT interval occurred all doses. produced transient dose-dependent increase neural gastrointestinal toxicities. Acute patient also taken paracetamol. There seven episodes dose-limiting toxicity ≥65 mg m−2, including two reversible ataxia 85 mg m−2. For CA4P, 50 mg m−2, mean (SD) peak plasma concentration (Cmax) 0.99 (0.33) µm, area under curve from time zero last quantifiable (AUC(0,t)) 1.42 (0.30) µm h terminal elimination half-life (t1/2) 1.81 (0.61) h. At 65 mg m−2, Cmax 1.73 (0.62) AUC(0,t) 3.19 (1.47) t1/2 1.90 One carcinoma an obvious response central necrosis metastatic lung mass. CONCLUSION Doses ≤65 mg m−2 30 min infusions define patients, range 50–65 mg m−2 selected further studies.