Clofarabine With Cytarabine for Patients With Minimal Residual Disease Positive Leukemia

Recent studies have demonstrated that even low levels of minimum residual disease (MRD)
(>0.01% abnormal blasts) after aggressive re-induction therapy indicate a relatively poor
outcome in relapsed acute lymphoblastic leukemia (ALL) patients, including those who proceed
to allogeneic stem cell transplant (alloSCT). A similarly poor prognosis was seen in
pediatric acute myelogenous leukemia patients with sub-morphologic disease prior to alloSCT.
Studies to identify therapies that can eliminate persistent leukemia, have low toxicity
profiles and can serve as a bridge to transplant are needed.

This study will test the ability of clofarabine + cytarabine to eliminate minimal residual
disease (MRD) in acute myelogenous leukemia and acute lymphoblastic leukemia patients whose
bone marrows exhibit complete remission by morphology. The toxicity profile of this regimen
will be evaluated in addition to toxicity experienced by patients who proceed to stem cell
transplant. Overall length of remission will also be collected.

Inclusion Criteria: Patients must meet all of the following criteria to be eligible to
participate in the study.

Patients must be ≥1 and ≤ 21 years of age when enrolled onto this study.

- Diagnosis (Patient must have all of the following)

- Patients must have a diagnosis of relapsed acute myelogenous leukemia (AML) or
acute lymphoblastic leukemia (ALL)

- Patient must have an M1 marrow based upon a recovered marrow with less than 5%
blasts by conventional morphology

- Patient must have minimal residual disease (MRD) detected by either
multidimensional or conventional flow cytometry greater than 0.1% and less than
5% following any re-induction attempt

- Patients must have a central nervous system (CNS) disease status of 1

- Patient must have an absolute neutrophil count (ANC) >500/μL off cytokine support for
at least 24 hours and platelets >50,000 K/μL without platelet transfusion in the past
seven days

- Karnofsky > 50% for patients > 10 years of age and Lansky > 50% for patients ≤ 10
years of age.

- Patient must have adequate venous access.

- Patients must have fully recovered from the acute toxic effects of all prior
chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

- At least 21 days must have elapsed from prior chemotherapy, at least 7 days must have
elapsed since receiving biological therapy.

- It must be at least 90 days from any higher dose cytarabine therapy (>1 gm/ m2/day).

- Patients must have a normal calculated creatinine clearance

- Patient must have

1. Conjugated (direct) serum bilirubin ≤ 1.5 x upper limit of normal (ULN) for age.

2. Alanine transaminase (ALT) ≤ 2.5 × ULN for age.

3. Alkaline phosphatase ≤ 2.5 × ULN for age.

4. Serum amylase ≤ 1.5 ULN for age.

5. Serum Lipase is ≤ ULN for age.

- Patient must have a shortening fraction > 28% or an ejection fraction > 50%.

- Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed prior to enrollment.

- Female patients with infants must agree not to breastfeed their infants while on this
study.

- Male and female patients of child-bearing potential must agree to use an effective
method of contraception approved by the investigator during the study.

- Patient must agree to submission of blood and bone marrow for assessment of minimal
residual disease (MRD).

- All patients and/or their parents or legal guardians must sign a written informed
consent.

Exclusion Criteria:Patients who meet any of the following criteria will be excluded from
participating in the study.

- Patients with previous hematopoietic stem cell transplant (HSCT) within previous six
months.

- Patients who have had prior treatment with clofarabine.

- Patients with CNS2 or CNS 3 disease or bulky chloromatous disease.

- Patients with Down Syndrome.

- Patients with a previous history of veno-occlusive disease (VOD) or findings
consistent with a diagnosis of VOD.

- Patients with a systemic fungal, bacterial, viral, or other infection not controlled.

- Use of investigational agents within 30 days of planned treatment on this protocol.

- Patient is receiving or plans to receive concomitant chemotherapy, radiation therapy,
immunotherapy or other anti-cancer therapy other than is specified in the protocol.

- Pregnant or lactating patients.

- Any significant concurrent disease, illness, psychiatric disorder or social issue
that would compromise patient safety or compliance, interfere with consent, study
participation, follow up, or interpretation of study results.

- Have had a diagnosis of another malignancy, unless the patient has been disease-free
for at least 3 years following the completion of curative intent therapy with the
following exceptions:

1. Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical
intra-epithelial neoplasia, regardless of the disease-free duration, are
eligible for this study if definitive treatment for the condition has been
completed.

2. Patients with organ-confined prostate cancer with no evidence of recurrent or
progressive disease based on prostate-specific antigen (PSA) values are also
eligible for this study if hormonal therapy has been initiated or a radical
prostatectomy has been performed.