Abstract #4523: The use of the nucleoside-prodrug EPD-clofarabine (HDP15.0022) in different xenograft models of solid tumors

Abstract

Clofarabine is a novel, second-generation, halogenated-adenosine analogue, which was approved by the FDA in 2004 for the treatment of acute lymphoblastic leukemia (ALL). In preclinical investigations clofarabine showed antitumoral activity in a limited number of solid tumor models after parenteral application. Its clinical efficacy, however, may be limited by undesirable pharmaceutical properties such as bone marrow toxicity, narrow therapeutic ratio and short biological half-life. EPD-clofarabine was designed to address these limitations. We applied our proprietory EPD technology to clofarabine with the goal to exploit its potential by significantly improving its pharmacokinetic, pharmacodynamic and toxicologic properties. EPD-clofarabine is activated by membrane associated specific hydrolases releasing the free nucleoside into the respective cells. In a comparative pharmacokinetic study using equimolar doses EPD-clofarabine revealed a 36-fold higher plasma exposure (AUC) and an increased terminal half-life but very low free clofarabine concentrations. EPD-clofarabine showed high efficacy in a variety of solid tumor xenograft models (e.g. PC-3, HCT-15, KB-3.1, MDA-MB231, Capan-2) demonstrating improved tolerability. A study in HCT-116 colon xenograft exhibited increased and sustained antitumoral growth inhibition of EPD-clofarabine compared to clofarabine. These results were supported by histological investigations using BrdU-labeling, showing sustained and higher antiproliferative activity in the tumor tissue. Efficacy studies in P-gp (Mdr-1) expressing and capecitabine-resistant xenografts demonstrate superior activity relative to clinical standards and clofarabine. In conclusion these results suggest that EPD-clofarabine (HDP15.0022) is an attractive clinical candidate for the 1st and 2nd line treatment of solid malignancies. Our data further support that our proprietary EPD-technology can be applied to nucleosides in order to widen the therapeutic window and the range of application.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4523.