DART - A phase I safety and dose-finding study of the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in the treatment of refractory tumors

Abstract

3081 Background: DMXAA (AS1404) targets established tumor vasculature and induces hemorrhagic necrosis of the hypoxic central region of tumors. The drug causes damage to endothelial cells and apoptosis, resulting in exposure of basement membrane, aggregation and activation of platelets and release of vasoactive mediators, leading to capillary rupture, extravasation of contents and cessation of blood flow. In previous phase I studies, DMXAA was well tolerated across a wide range of doses; QTc prolongation and ocular effects were documented. This study was designed to confirm the safety profile and identify suitable doses of DMXAA for further trials. Methods: Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive 6 sequential doses of DMXAA (300, 600, 1200, 1800, 2400 and 3000 mg m−2), each given once weekly as a 20-min iv infusion. Clinical and laboratory analyses were performed regularly, including extensive ECG and ophthalmic measurements. Tumor blood flow parameters were assessed by DCE-MRI. Results: 14 patients completed the study, each receiving 6 doses of DMXAA. The drug was generally well tolerated. Transient, moderate increases in the heart rate-corrected cardiac QT (QTc) interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient visual disturbances occurred at the two highest dose levels. Ve, a DCE-MRI parameter indicative of vascular permeability, increased significantly after DMXAA, while no significant changes were observed in other blood flow parameters. Plasma levels of the vascular damage biomarker 5-hydroxyindoleacetic acid (5-HIAA) increased in the 4 hours after treatment in a dose-dependent fashion, with a plateau around 1200mg m−2. Conclusions: Doses in the range of 1200 mg m−2 have been selected for further studies (a program of phase II combination studies with taxanes and platins has now begun) because this dose produced no significant effect on the QTc interval, produced near maximum plasma concentrations of 5-HIAA and was well tolerated. DCE-MRI findings were consistent with increased vascular permeability after DMXAA. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisoma Antisoma