Abstract 2614: Anti-tumor efficacy and pharmacokinetics of the novel aptamer AS1411 in a continuous infusion nude rat xenograft model

Abstract

AS1411 is a novel DNA aptamer that binds to the multi-functional protein nucleolin and induces cell death. AS1411 has shown activity at two different doses in combination with cytarabine in a phase II study of patients with AML. We have previously shown that AS1411 has activity against a range of solid and hematological cancer cell lines, with IC50 values between 1 and 10 μM, when cells are exposed to AS1411 continuously for more than 3 days. We have also demonstrated efficacy in vivo in both lung (A549) and renal (A498) mouse xenografts. However, it has been challenging to provide optimal continuous dosing of AS1411 in mice; use of osmotic pumps or intraperitoneal bolus injection have been associated with low drug exposure. In the current study, we optimized the continuous infusion model by using nude, athymic rats with a surgically implanted catheter in a two-cycle xenograft study. Plasma and tumor samples were collected for PK determination, allowing a correlation of PK with efficacy. The colorectal cell line HT29, which is sensitive to AS1411 in vitro, was used in this study. Cells (5×106) were implanted subcutaneously in the flank of female nude rats and tumors were allowed to grow to approximately 200 − 300 mm3 before surgical cannulation of the femoral vein. Following recovery, animals received AS1411 at 40, 80 or 180 mg/kg/day for two 7 day cycles of continuous infusion, 7 days apart. A vehicle control group received saline. Animals in the 80 and 180 mg/kg/day groups exhibited a significant (p<0.01) reduction in tumor volume compared to control animals at day 33 and at day 22 (interim analysis); this was not observed for animals in the 40mg/kg/day group (40mg kg/day in this model does not directly correlate to the clinical dose of the same name). AS1411 was well-tolerated by all animals in all dose groups. Plasma levels of AS1411 were measured at the three dose levels after one cycle of treatment. Mean AS1411 plasma concentrations were 0.7, 2.5 and 5.0 μM, for rats treated at 40, 80 and 180 mg/kg/day, respectively. The plasma concentrations in the two higher dose groups are within the range of the in vitro IC50 concentrations of a panel of cell lines. We conclude that AS1411 shows activity in vivo in the HT29 nude rat xenograft model. Doses associated with significant reductions in tumor volume were those that produced plasma concentrations close to the IC50 level for AS1411. This correlation has been used in planning further clinical development of AS1411, including a phase IIb study of patients with AML. 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 2614.