Abstract 3859: Evaluation of addition of the tumor-vascular disrupting agent ASA404 (vadimezan) to paclitaxel and carboplatin and the influence of subsequent ASA404 maintenance therapy using a human NSCLC xenograft model
Authors: Dean B. Evans, Robert Cozens
Journal: Cancer Research (2010)

Abstract The tumor vasculature is essential for maintaining tumor growth and regulating the tumor microenvironment through the supply of nutrients and oxygen. ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid) is a flavonoid, non-tubulin-binding Tumor-Vascular Disrupting Agent (Tumor-VDA) that induces breakdown of the established tumor vasculature resulting in the inhibition of tumor blood flow leading to tumor ischemia and extensive necrosis of the tumor core. Unlike anti-angiogenics, ASA404 (ASA) has limited effects on angiogenesis at the tumor periphery and as a consequence the remaining peripheral tumor rim represents a source of viable cells for regrowth of the tumor upon cessation of ASA treatment. Preclinical and clinical studies have highlighted the effectiveness of combining chemotherapies, particularly taxanes, with ASA for marked tumor inhibition. The ongoing ATTRACT-1 Phase III trial in NSCLC is evaluating the effect of adding ASA to the paclitaxel (P) and carboplatin (C) standard of care (SOC). In the present studies, the influence of adding ASA to P+C was examined in the human A549 NSCLC xenograft model. A549 NSCLC cells (5 × 107 in PBS containing 50% matrigel) were implanted sc into the right flank of female athymic nu/nu Harlan nude mice. Treatment schedules were as follows: ASA (18.6 mg/kg, iv on days 1, 5 and 9), P (15 mg/kg, iv qwk x3) and C (80 mg/kg, ip qwk x3). Tumor growth inhibition (TGI) was determined on day 21 and expressed as T/C (%). ASA alone resulted in a significant TGI of 17% T/C as compared to vehicle controls. P+C had a non-significant effect resulting in 82% T/C. The triple combination of ASA+P+C led to an improved TGI with a T/C of 12% being observed which was significant compared to vehicle controls and non-significant versus ASA alone, although by Clark's method, an additive effect was indicated. The influence of an additional maintenance cycle administration of ASA following ASA+P+C was then examined in a separate study. In addition to TGI (T/C %) determined at day 28, the median time to treatment endpoint (TTE) was measured based on the number of days taken until a preassigned tumor volume of 800 mm3 was reached. ASA+P+C resulted in a significant TGI of 22% T/C compared to vehicle controls. The TTE was extended from 24.8 days seen in controls to 63.5 days with the triple combination with 1 partial regression (PR). The influence of a subsequent cycle of ASA given alone (on days 21, 25 and 29) resulted in a further TGI with tumor regression being observed (T/T0 −13%), a TTE of 119 days and 3 PR. These studies demonstrate the value of the addition of ASA404 (vadimezan) to a current SOC composed of P+C and the potential of ASA404 maintenance therapy for added therapeutic benefit. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3859.