Testing of the topoisomerase 1 inhibitor Genz-644282 by the pediatric preclinical testing program

Background: Genz-644282 is a novel non-camptothecin topoisomerase I poison that is in clinical development. Procedures: Genz-644282 was tested against the PPTP in vitro panel (0.1nM to 1μM), and in vivo using three times per week×2 schedule repeated at day 21 at its maximum tolerated dose (MTD) of 4mg/kg. Subsequently Genz-644282 was tested at 4, 3, 2, and 1mg/kg in 3 models to assess the dose-response relationship. mRNA gene signatures predictive for Genz-644282 response in vitro were applied to select 15 tumor models that were evaluated prospectively. Results: In vitro, Genz-644282 demonstrated potent cytotoxic activity with a median IC ₅₀ of 1.2nM (range 0.2-21.9nM). In vivo, Genz-644282 at its MTD (4mg/kg) induced maintained complete responses (MCR) in 6/6 evaluable solid tumor models. At 2mg/kg Genz-644282 induced CR or MCR in 3/3 tumor models relatively insensitive to topotecan, but there were no objective responses at 1mg/kg. Further testing at 2mg/kg showed that Genz-644282 induced objective regressions in 7 of 17 (41%) models. There was a significant correlation between predictive response scores based on Affymetrix U133Plus2 baseline tumor expression profiles and the observed in vivo responses to Genz-644282. Conclusions: Genz-644282 was highly active within a narrow dose range (2-4mg/kg), typical of other topoisomerase I poisons. As with other topoisomerase I poisons, how accurately these data will translate to clinical activity will depend upon the drug exposures that can be achieved in children treated with this agent.