Clofarabine Plus Cytarabine in Patients With Previously Untreated Acute Myeloid Leukemia and High-risk Myelodysplastic Syndrome
Condition: Leukemia, Myeloid; Myelodysplastic Syndromes
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Myelodysplastic Syndromes; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): clofarabine; Ara-C
Intervention type(s): Drug; Drug
Intervention MeSH terms: Clofarabine
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Newly diagnosed and previously untreated acute myeloid leukemia (AML); High-risk myelodysplastic syndrome (MDS) (>/= 10% bone marrow blasts); Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS)