5,6-Dimethylxanthenone-4-acetic acid in the treatment of refractory tumors: a phase I safety study of a vascular disrupting agent
| Autor: | Mark J. McKeage, Bruce C. Baguley, Michael B. Jameson, Mark Jeffery, Miroslav Ravic, Peter C.C. Fong, Phil Kestell |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Xanthones Cmax Antineoplastic Agents Blood Pressure Pharmacology QT interval Electrocardiography Therapeutic index Refractory Vadimezan Neoplasms Tremor medicine Humans Infusions Intravenous Aged Cross-Over Studies Dose-Response Relationship Drug business.industry Headache Nausea Middle Aged Crossover study Surgery Dose–response relationship Long QT Syndrome Treatment Outcome Oncology Drug Resistance Neoplasm Area Under Curve Toxicity Female business |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 12(6) |
| ISSN: | 1078-0432 |
| Popis: | This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) for combination studies. Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive six sequential doses of DMXAA (300, 600, 1,200, 1,800, 2,400, and 3,000 mg m−2), each given once-weekly as a 20-minute i.v. infusion. The drug was generally well tolerated. Transient, moderate increases in the heart rate–corrected cardiac QT interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient, dose-related visual disturbances occurred at the two highest doses. No significant changes in Ktrans and kep were observed but Ve, a secondary dynamic contrast–enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m−2, the Cmax and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 ± 25.8 μg/mL, 29 ± 6.4 μg/mL·d, 8.0 ± 1.77 μg/mL, and 0.43 ± 0.07 μg/mL·d, respectively. Plasma levels of the vascular damage biomarker 5-hydroxyindoleacetic acid increased in the 4 hours after treatment in a dose-dependent fashion up to 1,200 mg m−2, with a plateau thereafter. Doses in the range of 1,200 mg m−2 have been selected for further studies (phase II combination studies with taxanes and platins are under way) because this dose produced no significant effect on heart rate–corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated. |
| Databáze: | OpenAIRE |
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