Abstract 2465: A new polymer conjugated taxane shows improved efficacy in tumor xenograft models.
Authors: Fry Dennis G. , Brew Christine , Lee Steve , Hoch Ute , Zhang Wen , Kozlowski Antoni , Dahhani Fadil , Tangudu Nagabhusan , Harrison Stephen D. , Riggs-Sauthier Jennifer 
Published: August 2014

Abstract
Introduction: Microtubule inhibitors are a mainstay of cancer therapy despite limitations in efficacy and tolerability. Such deficiencies are typical of cytotoxic drugs and a variety of strategies have been investigated to improve them, including the use of polymer conjugates. For example, etirinotecan pegol (EP, formerly NKTR-102) is a topoisomerase I inhibitor-polyethylene glycol (PEG) conjugate engineered by attaching irinotecan molecules to PEG using a biodegradable linker. EP has been studied in multiple clinical oncology studies and showed significantly higher response rates and decreased bone marrow toxicity in Phase 2 compared to historical data for irinotecan. EP is currently in a Phase 3 trial (BEACON; NCT01492101) for metastatic breast cancer.
We here report a novel PEG-taxane conjugate, PEG-TX1, which exhibits improved tumor growth inhibition compared to a recently approved taxane, cabazitaxel (CBZ). We have explored the basis for the improved preclinical activity, and show increased intratumoral exposure of the released active taxane (TX1) following administration of PEG-TX1, compared with that achieved with CBZ.
Methods: Tumor growth inhibition was examined using subcutaneous NCI-H460 tumor xenografts in nu/nu athymic mice. Test articles were administered intravenously via tail vein, q7dx3, at the maximum tolerated dose with a study endpoint of 2000 mm3. In PK/PD experiments to determine tissue and plasma concentrations of CBZ, TX1, and PEG-TX1, a single dose of test article was administered intravenously, and samples were collected at various time points to 14 d. Drug concentrations in tissue and plasma were quantified using LC/MS.
Results: In the NCI-H460 xenograft model, PEG-TX1 (administered q7dx3) delayed tumor growth by 336%, producing 90% partial and 10% complete tumor regressions. In comparison, CBZ delayed tumor growth by 213% and produced only 40% partial tumor regressions and 0% complete regressions. Following a single administration of PEG-TX1 vs. CBZ, significantly greater tumor growth inhibition was observed for PEG-TX1. This improved activity correlated well with increased tumor accumulation of PEG-TX1 and TX1 than was achieved for CBZ. Throughout the study, the concentration of TX1 was at least 10-fold higher in tumor tissue than in plasma or all other tissues examined. CBZ did not show such a sustained increase in tumor exposure relative to other tissues.
Conclusions: We demonstrate that PEG-TX1, a PEG-taxane prodrug utilizing Nektar's proprietary polymer conjugation technology, achieved superior tumor growth suppression in a murine xenograft model. Tumor growth inhibition is consistent with the enhanced concentration of taxane detected in tumors following administration of PEG-TX1. These data further demonstrate the utility of polymer conjugation to modify the biodistribution of drug conjugates and thereby enhance the therapeutic properties of an active pharmacophore.
Citation Format: Dennis G. Fry, Christine Brew, Steve Lee, Ute Hoch, Wen Zhang, Antoni Kozlowski, Fadil Dahhani, Nagabhusan Tangudu, Stephen D. Harrison, Jennifer Riggs-Sauthier. A new polymer conjugated taxane shows improved efficacy in tumor 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 2465. doi:10.1158/1538-7445.AM2013-2465