A Phase I Study of 5-Azacytidine in Combination With Chemotherapy for Children With Relapsed or Refractory ALL or AML

Inclusion Criteria:

Patients must be ≥ 1 and ≤ 21 years of age.

Diagnosis

1. Patients with AML must have ≥5% blasts (by morphology) in the bone marrow.

2. Patients with ALL must have an M2 or M3 marrow (≥5% blasts by morphology).

3. Patients may have disease in the central nervous system (CNS) or other sites of
extramedullary disease. No cranial irradiation is allowed during the protocol
therapy.

4. Patients with secondary AML are eligible.

5. Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia,
Bloom syndrome) are excluded.

Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of
age.

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

Myelosuppressive chemotherapy - the eligibility criteria is different between phase I and
expansion phase

1. Phase I

- Any patient with AML in 1st or greater relapse, OR

- Any patient with ALL in 2nd or greater relapse, OR

- Patients with AML or ALL failed to go into remission after first or greater
relapse, OR

- Patients with AML or ALL failed to go into remission from original diagnosis
after two or more courses of induction attempts.

2. Expansion phase - will be restricted to AML patients only

3. Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours
prior to the start of azacytidine. It is recommended to use hydroxyurea in patients
with significant leukocytosis (WBC > 50,000/L) to control blast count before
initiation of systemic protocol therapy.

4. Patients who relapsed while they are receiving cytotoxic therapy (including AZA ,
decitabine, or vorinostat) At least 14 days must have elapsed since the completion of
the cytotoxic therapy.

Hematopoietic stem cell transplant: Patients who have experienced their relapse after a
stem cell transplant are eligible, provided they have no evidence of acute or chronic
Graft-versus-Host Disease (GVHD) and are at least 90 days post-transplant at the time of
enrollment.

Hematopoietic growth factors: It must have been at least 7 days since the completion of
therapy with filgrastim or other growth factors at the time of enrollment. It must have
been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).

Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent.
For agents that have known adverse events occurring beyond 7 days after administration,
this period must be extended beyond the time during which adverse events are known to
occur. The duration of this interval must be discussed with the study chair

Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the
last dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days)

Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g.
tumor vaccines.

Radiation Therapy (XRT): Craniospinal XRT is prohibited during protocol therapy. No
washout period is necessary for radiation given to non-CNS chloromas; ≥ 90 days must have
elapsed if prior total body radiation or craniospinal radiation.

Renal and hepatic function

Patients must have adequate renal and hepatic functions as indicated by the following
laboratory values:

- Patient must have a calculated creatinine clearance or radioisotope glomerular
filtration rate (GFR) greater than or equal to 70ml/min/1.73m2 OR a normal serum
creatinine based on age/gender.

- Direct bilirubin < 1.5 x upper limit of normal (ULN) for age or normal, AND alanine
transaminase (ALT) < 5 x ULN for age.

Adequate Cardiac Function Defined as: Shortening fraction greater than or equal to 27% by
echocardiogram, OR ejection fraction greater than or equal to 50% by radionuclide
angiogram (MUGA).

Reproductive Function

- Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed within 2 weeks 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 and for a
minimum of 6 months after study treatment.

Patients and/or their parents or legal guardians must be capable of understanding the
investigational nature, potential risks and benefits of the study. All patients and/or
their parents or legal guardians must sign a written informed consent.

Exclusion Criteria:

Patients will be excluded if they have a known allergy to any of the drugs used in the
study.

Patients will be excluded if they have a systemic fungal, bacterial, viral or other
infection that is exhibiting ongoing signs/symptoms related to the infection without
improvement despite appropriate antibiotics or other treatment. The patient needs to be
off pressors and have negative blood cultures for 48 hours.

Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
radiation therapy, or immunotherapy during the study period.

Patients will be excluded if they have significant concurrent disease, illness,
psychiatric disorder or social issue that would compromise patient safety or compliance
with the protocol treatment or procedures, interfere with consent, study participation,
follow up, or interpretation of study results.

Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom
syndrome) are excluded.