Abstract 699: Optimized dosing strategies resulting in prolonged pathway inhibition enhance dinaciclib anti-tumor activity in preclinical xenograft models.

Abstract

Abstract Dinaciclib is a novel CDK1, 2, 5, and 9 inhibitor currently in clinical development for CLL. Preclinical studies indicate that dinaciclib may have activity in a wide variety of indications including hematologic malignancies and solid tumors. Clinically, dinaciclib is administered by 2 hour intravenous (iv) infusion and achieves plasma concentrations above 100nM for ∼6 hours; a concentration and duration of treatment which in vitro provides complete target engagement and induces apoptosis. Pre-clinically, dinaciclib is administered by intraperitoneal (ip) bolus injections and achieves plasma concentrations above 100nM for less than 2 hours. To determine whether prolonged plasma concentrations would enhance dinaciclib activity, we administered dinaciclib to COLO-320DM tumor bearing mice either as a 40 mg/kg single dose, or as two doses of 20 mg/kg separated by 2 hours. This 20-20 split dosing resulted in prolonged target engagement, phospho-RNA-Polymerase-2 reduction, decreased MCL-1, and increased apoptosis relative to the 40mg/kg single dose. Comparing the in vivo anti-tumor activity of dinaciclib dosed at 40 mg/kg ip every 4 days (q4d) vs. 20 mg/kg bid separated by 2 hours q4d demonstrated that the 20-20 split dose increased the anti-tumor activity of dinaciclib (25% Tumor Growth Inhibition (TGI) versus 66% TGI). Dinaciclib single vs. split dosing was further evaluated in 8 lung cancer xenograft models, 5 of which were insensitive to dinaciclib single dose (TGI >50%) and 3 of which were sensitive. 20-20 split dosing resulted in increased anti-tumor activity in all models tested. Split dosing resulted in <50% TGI in 4 of 5 insensitive models. Split dosing also increased anti-tumor activities in all 3 sensitive models tested resulting in stasis in 2 models, and sustained complete regressions in one lung cancer xenograft model. Body weight measurements revealed that split dosing increased body weight loss indicating that prolonged pathway inhibition can affect both anti-tumor activity and tolerability. Taken together, these data suggest that dinaciclib dosing paradigms that prolong pathway inhibition enhanced anti-tumor activity in pre-clinical xenograft models. Citation Format: Alwin Schuller, Robert Booher, Louise Cadzow, Minilik Angagaw, Lauren Harmonay, Xianlu Qu, Nathan Miselis, Vincenzo Pucci, Mark Ayers, Thorsten Graef, Ellie Im, Rebecca Blanchard, Brian Long, Leigh Zawel, peter strack. Optimized dosing strategies resulting in prolonged pathway inhibition enhance dinaciclib anti-tumor activity in preclinical xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 699. doi:10.1158/1538-7445.AM2013-699