Plerixafor and Granulocyte Colony-stimulating Factor (G-CSF) in Combination With Azacitidine for the Treatment of Myelodysplastic Syndrome (MDS)

The interaction of normal stem cells with the bone marrow microenvironment is mediated by a
number of factors. These interactions have been implicated in protecting malignant
hematopoietic cells from spontaneous apoptosis and genotoxic stresses such as chemotherapy.
Key elements are CXCR4, which is expressed on normal stem cells and leukemic blasts, and its
ligand, stromal derived factor 1 (SDF-1) expressed by bone marrow stromal cells and
osteoblasts. The CXCR4/SDF-1 axis is essential for homing, retention and mobilization of
stem cells from the bone marrow microenvironment. Plerixafor is a bicyclam small molecule
inhibitor of CXCR4 and has been extensively studied by our group and others as a potent stem
cell mobilization agent both in combination with G-CSF or alone (25, 62). Plerixafor is
currently being investigated in a phase I/II trial in combination with salvage chemotherapy
for relapsed AML in an attempt to sensitize leukemia stem cells to chemotherapy. The goal of
this study is to determine the optimal dose of plerixafor for the treatment of patients with
high-risk myelodysplastic syndrome (MDS) in combination with G-CSF and azacitidine. We
hypothesize that plerixafor in combination with G-CSF will detach MDS blasts from the bone
marrow microenvironment resulting in their increased proliferation and sensitivity to
azacitidine; thus, improving complete and partial response rates (CR/PR).

Inclusion Criteria:

- Patients must have histologically confirmed MDS with 5-20% blasts on bone marrow
aspirate at the time of study enrollment AND at least one cytopenia.

- MDS is defined by the WHO criteria

- Previous therapy with decitabine or azacitidine will be allowed but patients must be
at least 4 weeks from prior chemotherapy or radiation.

- Age >=18 years. Because no dosing or adverse event data are currently available on
the use of plerixafor in combination with G-CSF or azacitidine in patients <18 years
of age, children are excluded from this study; however, they will be eligible for
future pediatric phase II combination trials.

- Life expectancy of greater than 2 months.

- ECOG performance status <= 2 (Karnofsky >=60%; see Appendix 1).

- Patients must have normal organ function as defined below:

- total bilirubin ≤ 1.5 X institutional upper limit of normal

- AST ≤ 2.0 X institutional upper limit of normal

- creatinine within normal institutional limits OR

- creatinine clearance >=60 mL/min/1.73 m2 for patients with creatinine levels above
institutional normal

- Ability of the patient (or legally authorized representative, if applicable) to
understand and the willingness to sign a written informed consent document.

- Females of child bearing potential must agree to abstain from sexual activity or to
use a medically approved contraceptive measure/regimen during and for 3 months after
the treatment period. Women of child bearing potential must have a negative serum or
urine pregnancy test at the time of enrollment. Acceptable methods of birth control
include oral contraceptive, intrauterine device (IUD), transdermal/implanted or
injected contraceptives and abstinence. Males must agree to abstain from sexual
activity or agree to utilize a medically approved contraception method during and for
3 months after the treatment period. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

Exclusion Criteria:

- Patients with untreated 5q minus syndrome MDS

- Patients who have had G-CSF or GM-CSF within 2 weeks of the start of study

- Patients receiving any other investigational agents.

- Patients with known brain metastases. (These patients should be excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events.)

- History of severe allergic or anaphylactic reactions attributed to compounds of
similar chemical or biologic composition to plerixafor, azacitidine, G-CSF, or
mannitol.

- History of sickle cell anemia. (G-CSF may initiate pain crises.)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because plerixafor, G-CSF, and
azacitidine are agents with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with azacitidine, G-CSF, or plerixafor,
breastfeeding should be discontinued. These potential risks may also apply to other
agents used in this study.

- Known HIV-positive patients on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with plerixafor. In
addition, these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.

- Patients with advanced malignant hepatic tumors

- History of cardiac arrhythmia