Abstract 5358: Pediatric preclinical testing program (PPTP) evaluation of the non-camptothecin topoisomerase 1 targeted agent Genz644282
Authors: Peter J. Houghton, Richard B. Lock, Hernan Carol, Christopher L. Morton, Richard Gorlick, E. Anders Kolb, Stephen T. Kier, C. Patrick Reynolds, Min H. Kang, John M. Maris, Catherine A. Billups, Malcolm A. Smith
Journal: Cancer Research (2011)

Abstract Background: Genz644282, a non camptothecin topoisomerase I poison, was developed from a lead compound 8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxy-5-H-dibenzo[c,h] [1,6]naphthyridin-6-one (ARC111, topovale). In non-clinical testing ARC111 had equivalent or superior activity to irinotecan, and induced regression in a topotecan insensitive tumor xenograft. ARC111 also differentiated itself from other camptothecin derivatives in that it was not a substrate for the ABCG2 drug transporter. Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). Genz664282 (provided by Genzyme Corporation) was tested in vitro at concentrations from 0.1 nM to 1 μM with 96 hr exposure to drug. Genz664282 was administered IP, three times weekly for 2 weeks at a dose of 1 – 4 mg/kg for either 1 or two cycles. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a treated to control (T/C) tumor volume measure; and 3) a time to event (4-fold increase in tumor volume) measure based on the median event-free survival (EFS) of treated and control animals for each xenograft. Results: In vitro Genz644282 exerted potent cytotoxic activity with a median IC50 of 1.19 nM (range 0.186 – 23.3 nM). There was no cell type selectivity. In vivo at 4 mg/kg (MTD) for two cycles, Genz644282 induced maintained complete responses (MCR) in 8/8 models including tumor lines poorly responsive to topotecan. Dose response evaluation (1 cycle of treatment) against 3 tumor lines least sensitive to topotecan showed Genz644282 induced 2MCR and 1CR at 4 mg/kg, and 2CR and 1 MCR at 2 mg/kg, but no regressions were observed at 1 mg/kg, suggesting a steep dose response relationship. Further testing at 2 mg/kg (1 cycle) induced 4MCR, 1CR and 2PR in 17 tumor lines (41%), mainly in sarcoma models (6/7), particularly osteosarcoma (4/6). Conclusions: At the 2 mg/kg dose level administered for one cycle of treatment, Genz644282 demonstrated a high level of activity inducing regressions in 7 of 17 models evaluated, with particularly high activity in osteosarcoma models. The models included tumors intrinsically insensitive to topotecan. As with other topoisomerase I poisons, how accurately this data will translate to clinical activity will depend upon the drug exposures that can be achieved in children treated with this agent. (Supported by NO1-CM91003-03) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5358. doi:10.1158/1538-7445.AM2011-5358