Article date: June 2011
By: Xuexin He, Su Li, He Huang, Zhiming Li, Likun Chen, Sheng Ye, Jiajia Huang, Jing Zhan, Tongyu Lin, in Volume 71, Issue 6, pages 860-870
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 and syncope in patients who received doses ≥50 mg m−2.
WHAT THIS STUDY ADDS
• 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.
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.
DOI: 10.1111/j.1365-2125.2011.03928.x
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