The effect of AMG 706, a novel multi-kinase inhibitor, on vascular permeability and blood flow as assessed by dynamic contrast enhanced magnetic resonance imaging in an in vivo preclinical tumor model

Abstract

3134 Background: AMG 706 is a potent, oral, multi-kinase inhibitor with anti-angiogenic and anti-tumor activity achieved by selectively targeting all known VEGF, PDGF, Kit and Ret receptors. In previous experiments, AMG 706 treatment resulted in regression of large, established A431 epidermoid carcinoma tumors within seven days of the initiation of treatment. The present experiments were carried out to relate the therapeutic effect to changes in vascular permeability and blood flow, with the intent of identifying a pharmacodynamic marker for use in clinical trials. Methods: After an initial dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) baseline scan, mice bearing A431 xenografts (300 mm3) were dosed with either vehicle or AMG 706 at dose levels ranging between 10 and 75 mg/kg. DCE-MRI was repeated after 24, 48 or 96 hrs of treatment. All MRI studies were performed at 4.7 Tesla (Bruker Biospin, Billerica, MA). During the DCE-MRI scans, 0.2 mmol/kg gadopentetate dimeglumine was injected intravenously via a tail vein catheter. Results: DCE-MRI analysis identified a statistically significant (p = 0.0235) decrease in contrast agent uptake (AUC relative to baseline), occurring in a dose dependent fashion in the interior region of the tumor after only 24 hrs of treatment with AMG 706. The effect seen at 24 hrs is consistent with the previous observation that tumor endothelial cell apoptosis occurs within 12 hrs of initiation of treatment, and indicates a statistically significant treatment related reduction in tumor blood flow and vascular permeability in the A431 tumor model. Conclusions: Oral administration of AMG 706 produced a statistically significant reduction in vascular blood flow and/or permeability in the A431 human tumor xenograft model as early as 24 hrs of treatment. These results are consistent with previous observations indicating the destruction of tumor blood vessels as the mechanism of action of AMG 706, and support the use of DCE-MRI to obtain pharmacodynamic information in clinical trials of AMG 706. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen