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 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.
Interventional
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Stefan Faderl, MD
Principal Investigator
M.D. Anderson Cancer Center
United States: Food and Drug Administration
ID03-0139
NCT00065143
June 2003
February 2006
Name | Location |
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The University of Texas M.D. Anderson Cancer Center | Houston, Texas |