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.
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
- Patients with MDS of any risk group who have, just immediately prior to being entered
into this study, already received at least six cycles of 5-azacytidine and have
failed, either due to no response or to disease relapse despite being still on
5-azacytidine, or patients whose MDS has progressed while on 5-azacytidine,
irrespective of the number of cycles the patient has received. We have specifically
chosen to be very stringent about our patient population in order to address our
question of whether clofarabine can be used to salvage patients who have failed
5-azacytidine with only a small patient population, i.e. 10 patients in each cohort.
- ECOG Performance status of 0 - 2
- Recombinant erythropoietin is allowed, if the patients are already receiving
erythropoietin. G-CSF can be given during the neutropenic stage following therapy
since this would not affect evaluation of response because the response will be made
based on CBC and bone marrow changes upon recovery from clofarabine.
- Patients must have been at least four weeks after the last course of 5-azacytidine
- Age over 18 years
- Have adequate renal and hepatic functions as indicated by the following laboratory
- Serum creatinine 1.0 mg/dL; if serum creatinine 1.0 mg/dL, then the estimated
glomerular filtration rate (GFR) must be 60 mL/min/1.73 m2 as calculated by the
Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73
m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient
is female) x (1.212 if patient is black)
- Serum bilirubin ≤1.5 mg/dL × upper limit of normal (ULN)
- Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 × ULN
- Alkaline phosphatase 2.5 × ULN
- Capable of understanding the investigational nature, potential risks and benefits of
the study, and able to provide signed informed consent.
- Female patients of childbearing potential must have a negative serum pregnancy test
within 2 weeks prior to enrollment.
- Male and female patients must use an effective contraceptive method during the study
and for a minimum of 6 months after study treatment.
- Nursing or pregnant women
- Prior clofarabine therapy
- Life expectancy of less than 3 months due to other intercurrent illness.
- Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as
specified in the protocol.
- Use of investigational agents within 30 days or any anticancer therapy within 4 weeks
before study entry with the exception of hydroxyurea. The patient must have recovered
from all acute toxicities from any previous therapy.
- Have any other severe concurrent disease, or have a history of serious organ
dysfunction or disease involving the heart, kidney, liver, or other organ system that
may place the patient at undue risk to undergo treatment.
- Patients with a systemic fungal, bacterial, viral, or other infection not controlled
(defined as exhibiting ongoing signs/symptoms related to the infection and without
improvement, despite appropriate antibiotics or other treatment).
- Any significant concurrent disease, illness, or psychiatric disorder that would
compromise patient safety or compliance, interfere with consent, study participation,
follow up, or interpretation of study results.