A Pharmacokinetic Study of Oral and Intravenous Clofarabine in Patients With High Risk Myelodysplasia and Acute Leukemias - Determination of Oral Bioavailability and the Effect of Cimetidine on Clofarabine Clearance

Inclusion Criteria:

- MDS patients age 18 and older with IPSS risk of intermediate-2 who have failed ≥ 1
prior regimen with a DNA methyltransferase inhibitor, or have ≥ 10% bone marrow
myeloblasts

- MDS patients age 18 and older with IPSS high risk

- Patients with CMML (chronic myelomonocytic leukemia) age 18 and older

- Untreated AML or Ph-negative ALL patients age 60 and over who are deemed not to be
candidates for intensive anthracycline based induction therapies based on age, organ
function or co-morbidities

- AML or Ph-negative ALL patients age 60 and over who have failed or relapsed following
initial induction therapy

- Provide signed written informed consent.

- Capable of understanding the investigational nature, potential risks and benefits of
the study, and able to provide valid informed consent.

- Have adequate renal and hepatic functions as indicated by the following laboratory
values:

- Serum creatinine 1.0 mg/dL, then the
estimated glomerular filtration rate (GFR) must be >60 mL/min as calculated by
the Cockcroft-Gault equation:

GFR (mL/min) = (140 - age) X (weight in kg) X (0.85 if female)/ 72 X serum creatinine in
mg/mL

- Serum bilirubin ≤1.5 mg/dL × upper limit of normal (ULN)

- Aspartate transaminase (AST)/alanine transaminase (ALT)
- Alkaline phosphatase 2.5 × ULN

- Female patients of childbearing potential must have a negative serum pregnancy
test within 1 week 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.

- INR ≤ 1.5 and APTT within the upper limits of normal (Patients on therapeutic
anticoagulation will be allowed to participate if anticoagulation can be changed
to parenteral medication or discontinued when platelet count is <50x109/liter)

Exclusion Criteria:

- 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 2 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).

- Pregnant or lactating patients.

- 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.

- Abnormal organ function as defined by ALT, AST or total bilirubin >1.5 x ULN, GFR<
60mL/minute by MDRD equation

- Active cardiac disease as manifest by: >class II NYHA congestive heart failure,
unstable angina or myocardial infarction within the last 6 months

- Hemorrhage or bleeding >/= CTCAE grade 3 within 4 weeks of enrollment

- Pulmonary hemorrhage >/= CTCAE grade 2 within 4 weeks of enrollment

- HIV infection

- Active Hepatitis B or Hepatitis C infection (defined as measurable viral load by PCR,
or liver function abnormalities attributed to viral hepatitis)

- Cerebrovascular accident or transient ischemic attack within 6 months of study
enrollment.

- Non-healing wound or ulcer, or major surgery or trauma within 4 weeks of study
enrollment

- Active graft versus host disease of any grade

- Active CNS disease that will require radiation therapy.

- Suspected or confirmed hypersensitivity to cimetidine or other histamine H2
antagonists.

- Have currently active gastrointestinal disease, or prior surgery that may affect the
ability of the patient to absorb oral clofarabine.

- 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:

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

- 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.

- Medical indication for therapy with one of the previously-documented human OCT2
inhibitors (table 4), for which cessation of the OCT2 inhibitor or conversion to an
alternate agent would pose unacceptable risk to the patient