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

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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 85 mg m−2 infused intravenously over 30 min.

RESULTS

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 CA4P, at 50 mg m−2, mean (SD) peak plasma concentration (Cmax) 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) μm h and terminal elimination half-life (t1/2) was 1.81 (0.61) h. At 65 mg m−2, Cmax was 1.73 (0.62) μm, AUC(0,t) was 3.19 (1.47) μm h and t1/2 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 ≤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.

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