5,6-Dimethylxanthenone-4-acetic acid in the treatment of refractory tumors: a phase I safety study of a vascular disrupting agent

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 K-trans and k(ep) were observed but V, a secondary dynamic contrast - enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m(-2), the C-max and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 +/- 25.8 mu g/mL, 29 +/- 6.4 mu g/mL.d, 8.0 +/- 1.77 mu g/mL, and 0.43 +/- 0.07 mu g/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 1,2 00 mg m(-2), with a plateau thereafter. Doses in the range of 1,200 mg m-2 have been selected for further studies (phase 11 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.