期刊
ANTI-CANCER DRUGS
卷 25, 期 4, 页码 462-471出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0000000000000070
关键词
adverse events; combretastatin A4 phosphate; tolerated dose
资金
- Chinese National Major Project for New Drug Innovation [2008ZX09312, 2012ZX09303012]
- Chinese National High Technology Research and Development Program of China [2011AA02A110]
- Beijing Municipal Science and Technology Commission [Z121107005112005, Z121102009212055]
- Special Funds for Central Health Authority [B2009B124]
Combretastatin A4 phosphate (CA4P) is a prodrug that selectively destroys tumor blood vessels, and has shown efficacy as a targeted anticancer drug in both animal models and clinical trials. The aims of this single-center, open label, phase I clinical trial were to investigate the safety and tolerability of CA4P administered intravenously to patients aged 18-65 years with advanced solid tumors. Using a dose-escalation protocol, patients were assigned to five groups that received injections with 20 (n=3), 33 (n=3), 50 (n=11), 65 (n=6), or 85 (n=2) mg/m(2) CA4P. Patients in the 20 and 85 mg/m(2) groups received a single dose and the other groups received multiple doses. Adverse events (AE), cardiovascular parameters, and biochemical investigations were studied, and the maximum tolerated dose was determined. Of twenty-five patients enrolled, eight were withdrawn/excluded (not because of AE). There were no deaths. A total of 394 AE occurred in the 25 patients, with 89.3% considered related/possibly related to the drug. AE included headache and dizziness (19.8%), tumor-induced pain (14.2%), vascular vagal excitation (10.7%), and vomiting (9.4%). Ninety-five percent of AE were mild (grades 0-II), with only 5% being grade III-IV. Drug administration was associated with biphasic changes in heart rate and blood pressure, and only limited abnormalities in the laboratory investigations performed. The maximum tolerated dose was 65 mg/m(2). We conclude that CA4P is generally well tolerated, with the vast majority of AE that occurred being of mild severity. Further studies will establish the role of CA4P in cancer therapy.
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