5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent: Phase I clinical and pharmacokinetic study

Abstract

The purpose of this phase I, dose-escalation study was to determine the toxicity, maximum tolerated dose, pharmacokinetics, and pharmacodynamic end points of 5,6-dimethylxanthenone acetic acid (DMXAA). In all, 46 patients received a total of 247 infusions of DMXAA over 15 dose levels ranging from 6 to 4900 mg m-2. The maximum tolerated dose was established at 3700 mg m-2; dose-limiting toxicities in the form of urinary incontinence, visual disturbance, and anxiety were observed at the highest dose level (4900 mg m-2). The pharmacokinetics of DMXAA were dose dependent. Peak concentrations and area under the curve level increased from 4.8 μM and 3.2 μM h, respectively, at 6 mg m-2 to 1290 μM and 7600 μM h at 3700 mg m-2, while clearance declined from 7.4 to 1.71 h-1 m-2 over the same dose range. The terminal half-life was 8. 1 ± 4.3 h. More than 99% of the drug was protein bound at doses up to 320 mg m-2; at higher doses the percent free drug increased to a maximum of 6.9% at 4900 mg m-2. Dose-dependent increases in the serotonin metabolite 5-hydroxyindoleacetic acid were observed at dose levels of 650 mg m-2 and above. There was one unconfirmed partial response at 1300 mg m-2. In conclusion, DMXAA is a novel vascular targeting agent and is well tolerated. © 2003 Cancer Research UK.