ABSTRACT

This chapter reviews the currently available data with nilotinib, including preclinical findings, pharmacokinetic data, results from phase I and phase II trials, possible indications beyond Chronic Myelogenous Leukemia (CML), and potential for use in combination therapy. Nilotinib was developed using a rational design strategy based on the premise that breakpoint cluster region-Abelson (Bcr-Abl) inhibitors are more potent and selective than imatinib could be developed by making modest changes in this molecule. Studies investigating the induction of mutants after exposure to imatinib under conditions that favor mutagenesis using a cell-based screen indicated that resistance to nilotinib was associated with a limited spectrum of Bcr-Abl kinase mutations, mostly affecting the P-loop and T315I. The efficacy of nilotinib has been documented in in-vivo models of CML, such as mice with Bcr-Abl–positive leukemias, both imatinib-sensitive and resistant. An ongoing, open-label phase II trial is evaluating nilotinib 400 mg BID in CML postresistance to or intolerance of imatinib.