The investigators hypothesize that, in addition to its apoptotic effect, clofarabine induces DNA hypomethylation. If the investigators' hypothesis is correct, findings from the present proposal will not only contribute to information relating to the mechanisms of action of clofarabine but also provide the opportunity for combined epigenetic targeting of MDS using clofarabine with either another hypomethylating agent or a histone deacetylase inhibitor. Clofarabine has demonstrated anti-cancer activity through inhibition of DNA synthesis and repair, induction of apoptosis, and possibly through other mechanisms. Numerous responses have been observed after treatment with clofarabine in heavily pre-treated relapsed/refractory patients with ALL, AML and high risk MDS. In the present proposal, the investigators will study the clinical and laboratory effects of 2 different dosages of clofarabine in patients who have failed the hypomethylating agent, 5-azacytidine. This study will recruit patients who have received at least six cycles of 5-azacytidine without response or whose disease has progressed or relapsed while on 5-azacytidine. The first cohort of patients will receive clofarabine 10 mg/m2/day for five days and the second cohort of patients 5 mg/m2/day for five days, both every four to six weeks. The investigators will determine the frequency of response to the two dosages of nucleoside analog in this group of patients. Measurement of responses will include improvement in the peripheral blood count, reduction in the blood and platelet transfusion need and eradication of cytogenetically abnormal clones. Successful completion of this study will define the position of clofarabine in MDS in the era of epigenetic targeting.
Study Overview This study will recruit patients who have received at least six cycles of 5-azacytidine without response or whose disease has progressed or relapsed while on 5-azacytidine. The first cohort of patients will receive clofarabine 10 mg/m2/day for five days and the second cohort of patients 5 mg/m2/day for five days, both every four to six weeks. The investigators will determine the frequency of response to the two dosages of nucleoside analog in this group of patients. Measurement of responses will include improvement in the peripheral blood count, reduction in the blood and platelet transfusion need and eradication of cytogenetically abnormal clones. * Primary Objectives 1. To determine the frequency and duration of peripheral blood responses to IV clofarabine in MDS patients who have failed 5-azacytidine 2. To determine the frequency and duration of bone marrow responses to IV clofarabine, including CR + PR * Secondary Objectives To determine whether clofarabine exhibits a DNA hypomethylating property
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
10
10 mg/m2 x 5 days per 4 to 6 week cycles
5 mg/m2 x 5 days per 4 to 6 week cycles
Texas Oncology Cancer Center
Amarillo, Texas, United States
Improvement in Peripheral Blood Count and Reduction in Number of Transfusions
Hematologic improvement will be an increased Hemoglobin of 1.5 g/dL or a reduction in the need for PRBC transfusions by at least 4 units over an 8 week period, at least 100% increase and an ANC of \>0.5 x 10\^9/L and an absolut platelet count increase of \>30 x 10\^9/L for patients who start at \> 20 x 10\^9/L, or increase from \<20 x 10\^9/L to \>20 x 10\^9/L and by at least 100%.
Time frame: 2-3 months
Determine Frequency and Duration of Bone Marrow Responses to IV Clofarabine
The International Working Group response criteria was used. Complete remission is defined as \<5 % marrow blasts without evidence of dysplasia and normalization of the peripheral blood counts, including hemoglobin \>11 g/dL, neutrophil count of \>1 x 10\^9/L. and platelet count of \>100 x 10\^9/L. Patients must also be transfusion-independent and not require any recombinant erythropoietin. Partial remission (PR) is defined as: satisfying complete remission criteria if abnormal before treatment, except that blasts are reduced by 50% or more compared to pretreatment levels, but still \>5 %. Stable disease is defined as: failure to achieve at least a PR but without evidence of disease progression for at least 8 weeks.Progression of disease is defined as: disease progression with worsening cytopenias. Best response of these patients is used in the determination for this outcome below.
Time frame: 2-3 months
To Determine the Non-hematologic Toxicity Profile of This Dose Schedule (Grade 2 and Above)
Assess for adverse events in all the patients receiving the Clofarabine at the dose schedules described in the protocol (CTCAE 3.0 used).
Time frame: biweekly for duration of treatment , an average of 3 months
Number of Participants With DNA Hypomethylation During the Study
Since we previously observed decreases in DNA methylation in tumor cells after in vitro treatment with Clofarabine, we compared the long interspersednuclear element-1 methylation of genomic DNA obtained from CD3-depletedperipheral blood mononuclear cells between day 1 and day 5 of each cycle of Clofarabine.
Time frame: assessed twice per cycle
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