The goal of this proposal is to further characterize the role of clofarabine in combination with cytarabine (ara-C) in the treatment of patients with acute leukemias who have relapsed or have become refractory to conventional therapy. Clofarabine is a novel nucleoside analog that was found to be active in phase I clinical trials of patients with hematologic malignancies. Activity in patients with advanced acute leukemias has been confirmed in phase II studies which are currently ongoing. Clofarabine acts through inhibition of DNA synthesis and repair. Importantly, clofarabine is also a potent inhibitor of ribonucleotide reductase (RnR) and thus ideally suited for biochemical modulation strategies with other nucleoside analogs such as ara-C. We have previously shown that RnR inhibitors (fludarabine, cladribine) can be used successfully to modulate ara-C triphosphate accumulation in leukemic cells. We therefore hypothesize that inhibition of RnR by clofarabine will result in a decrease in the levels of deoxynucleotides causing a subsequent decrease in the feedback inhibition of deoxycytidine kinase, the rate-limiting step in the synthesis of ara-CTP. We further hypothesize that the combination of clofarabine with ara-C leads to increased retention of ara-CTP in leukemic cells so that the antileukemic activity of clofarabine is complemented by a biochemical synergy between these agents that should result in greater clinical efficacy. The biochemical properties of clofarabine and data of its clinical efficacy in our target population determine the aims of the study. Specifically, we plan to investigate the safety and efficacy of the combination of clofarabine with ara-C (Aim1). Pharmacodynamic and pharmacokinetic measurements will determine intracellular concentrations of clofarabine triphosphate, clofarabine-triphosphate-mediated inhibition of RnR, and modulation of ara-CTP accumulation in leukemia cells (Aim 2). The pharmacodynamic and pharmacokinetic endpoints will then be correlated with clinical response to create a valuable knowledge base for future investigations of this agent (Aim 3) This study constitutes a rationally-designed attempt to utilize new and effective nucleoside analogs for single and combination drug development to achieve optimum therapeutic efficacy in a poor-prognosis group of patients.
| Faderl, Stefan; Gandhi, Varsha; O'Brien, Susan et al. (2005) Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 105:940-7 |
| Faderl, Stefan; Gandhi, Varsha; Keating, Michael J et al. (2005) The role of clofarabine in hematologic and solid malignancies--development of a next-generation nucleoside analog. Cancer 103:1985-95 |
