A phase I clinical trial assessing the safety and tolerability of combretastatin A4 phosphate injections.

Abstract

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/m² CA4P. Patients in the 20 and 85 mg/m² 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 Of twenty-five patients enrolled, eight were withdrawn/excluded (not because of AE).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/m². 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.

• Authors: Peng Liu, Yan Qin, Lingying Wu, Sheng Yang, Nan Li, Haijun Wang, Haiyan Xu, Kelin Sun, Shuxiang Zhang, Xiaohong Han, Yan Sun, Yuankai Shi
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 25 Issue 4 Pg. 462-71 (Apr 2014) ISSN: 1473-5741 [Electronic] England
• PMID: 24500030 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Prodrugs
• Stilbenes
• fosbretabulin

Topics

• Adolescent
• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, therapeutic use)
• Female
• Humans
• Injections, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Prodrugs (administration & dosage, adverse effects, therapeutic use)
• Stilbenes (administration & dosage, adverse effects, therapeutic use)
• Treatment Outcome
• Young Adult