Plasma levels of 5-hydroxyindole-3-acetic acid (5HIAA) as a pharmacodynamic marker of blood flow changes induced by the vascular targeting agent (VTA) 5,6 dimethyl xanthenone acetic acid, DMXAA

• DOI: 10.1200/jco.2005.23.16_suppl.3123
• Publication Date: 2017-02-23T13:55:09Z
• Authors: L. R. Kelland; B. C. Baguley; L. Zhao; Q. Ding; P. Kestell; M. Ravic; M. B. Jameson; M. J. McKeage
• Keywords: Extravasation; Pharmacodynamics

3123 Background: VTAs now undergoing clinical trials include those that interact with tubulin (e.g. combretastatins and ZD6126) the distinct tubulin-independent based flavonoid DMXAA (AS1404). induces both direct apoptosis of tumor vascular endothelial cells a secondary induction vasoactive agents such as serotonin (from platelets aggregating to damaged vasculature) necrosis factor (TNFα). The study objective was determine whether plasma levels metabolite, 5HIAA, correlated induced blood flow changes, first in mouse models then patients. Methods: 5HIAA from blood, were determined by HPLC. Mice, bearing syngeneic colon 38 subcutaneous tumors, given single doses (up ∼150mg/m2). Within recently completed Phase I double-blind randomised refractory tumors; DART) patients received 20 minute intravenous infusions at 300 3000 mg/m2. Results: mice measured 4hr post showed significant linear correlation increased extravasation albumin binding Evans Blue tumors (r=0.82; P<0.05); significantly reduced (r = 0.88; P<0.01). In same mice, no change seen normal skin. patients, peak occurred dosing dose >600mg/m2. Notably, there positive between up 1200mg/m2 but thereafter plateau observed (even though free linearly 3000mg/m2). Conclusions: Increased may represent sensitive biological marker changes VTA, DMXAA. Dose-response data trial receiving show optimum cause flow/5HIAA is range 1200mg/m2, is, well below maximum tolerated dose. Consequently, this are being studied II combination taxanes (where marked synergy various preclinical models) platins. Author Disclosure Employment or Leadership Consultant Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisoma