PK Study of Oral and IV Clofarabine in High Risk Myelodysplasia+Acute Leukemias

Clofarabine is a second-generation adenosine nucleoside analog with activity in hematologic
malignancies. It has gained FDA-approval for use in children with relapsed-refractory ALL,
and early phase studies have shown activity in patients with AML and MDS. Clofarabine's
activity in acute leukemias and MDS has been established in multiple phase I and II studies,
both alone and in combination with cytosine arabinoside (araC), and in both
relapsed-refractory patients, and untreated older adults.

Pharmacokinetic investigations comparing I.V. and P.O. dosing within the same patient have
not been performed. Furthermore, the effect of OCT2 inhibition on clofarabine
pharmacokinetics in humans has not been investigated. The potential for enhanced drug
exposure and toxicity in the setting of OCT2 inhibition is of clinical importance as
clofarabine gains broader indications in hematologic oncology. In particular,
bioavailability and the OCT2 mechanism are important with prolonged drug exposure and oral
administration in older adults, who are likely to have impaired renal function and take
other drugs that interact with OCT2 such as metformin (a substrate) and trimethoprim (one of
several inhibitors). OCT2 is expressed on several solid tumor cell lines, and is thought to
play a role in tumor uptake of cationic cytotoxins. Whether OCT2 or other transporters are
expressed on leukemic blasts, or influence drug uptake has not been investigated. However,
variation in the expression of drug transporters could be one of several mechanistic
explanations for the fact that clofarabine-responsive patients accumulate intracellular
clofarabine triphosphate, whereas non-responders do not.

Single nucleotide polymorphisms have been identified in the gene encoding OCT2, which may
influence substrate uptake or inhibitor potency. Such polymorphisms may explain variation in
clofarabine pharmacokinetics and pharmacodynamics between individuals, but the potential for
this phenomenon has not previously been investigated.

Patients will receive clofarabine as induction therapy in five doses. Initially, and unless
dose escalation or de-escalation criteria are met, patients will be assigned to dose level 0
(IV Clofarabine 15mg/m2; Oral clofarabine 30mg/m2). The first three doses (on days 1, 3 and
5) will be administered followed by washout periods that extend until the next clofarabine
dose is administered. During the washout periods, frequent phlebotomy for PK sampling will
be performed in an outpatient setting at the UNC Clinical Translational Research Center
(CTRC). The duration of the induction period will be determined by time to recovery of
hematologic toxicity (platelets >50 x 109/liter, ANC >1.0x109/liter).

AML patients achieving CR, and MDS patients achieving CR, PR or hematologic improvement will
receive additional consolidation cycles of oral clofarabine daily on days 1 through 5 of
each subsequent cycle, with clofarabine dose according to assigned dose level (0: 30 mg/m2,
-1: 20 mg/m2, +1: 40 mg/m2). Consolidation cycles will begin no sooner than 28 days after
the first day of the previous clofarabine cycle. Patients will be evaluated for response
after each cycle, and will be continued on trial for up to 6 total cycles of therapy as long
as a response or lack of progression is maintained and no Grade 3-4 non-hematologic
toxicities have been observed in that patient.

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