Myelodysplastic Syndromes Clinical Trial
Official title:
A Phase II Study of Clofarabine in Combination With Cytarabine (Ara-C) in Patients >/= 50 Years With Newly Diagnosed and Previously Untreated Acute Myeloid Leukemia (AML) and High-risk Myelodysplastic Syndrome (MDS) (>/= 10% Bone Marrow Blasts)
The goal of this clinical research study is to learn if clofarabine, when given in combination with ara-C (cytarabine), can help to improve the disease's response to therapy and to increase the duration of response in patients who are 50 years or older with leukemia. The safety of this combination treatment will also be studied.
The treatment of acute myeloid leukemia (AML) in older patients has not improved
significantly in recent years when compared with the considerable progress that has been made
in younger patients. Hence, new drugs and approaches are needed in this poor-prognosis group
of patients with AML.
Nucleoside analogs are among the most active antileukemic agents available. Clofarabine was
synthesized as a rational extension of the experience with other deoxyadenosine analogs.
Clofarabine is converted to the monophosphate form by the enzyme deoxycytidine kinase which
represents the major metabolite of clofarabine. Phosphorylation of clofarabine is
substantially more efficient than that of other nucleosides such as fludarabine and so is
intracellular retention of the triphosphate form of clofarabine. Mechanisms of action include
inhibition of DNA synthesis, inhibition of DNA polymerases, and potent inhibition of
ribonucleotide reductase (RNR) resulting in depletion of normal nucleotides and increased DNA
uptake of the analog. Single agent clofarabine has shown activity in phase I studies in AML
and ALL. As a potent inhibitor of RNR, however, clofarabine is ideal to be incorporated into
biochemical modulation strategies such as have been tested and validated with fludarabine and
ara-C in AML. By combining clofarabine with ara-C, inhibition of RNR by clofarabine will
result in a drop of deoxynucleotides causing a decrease in the feedback inhibition of
deoxycytidine kinase which is the rate-limiting step in the synthesis of ara-CTP leading to
increased retention of ara-CTP. Therefore, the activity of clofarabine and ara-C in leukemic
cells would be complemented by a biochemical synergism between these agents that should
result in better clinical efficacy. We have established the safety of the combination in
salvage patients with acute leukemias.
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