Phase I, Dose Escalation Study of Decitabine

Decitabine is a hypomethylating agent with significant anti-leukemic effect in MDS and AML.
Additionally, aberrant DNA methylation has been identified in high risk childhood ALL, and
therefore, DNA hypomethylating agents, such as decitabine, have been identified as
therapeutic agents. Moreover, decitabine has immunomodulatory effects by enhancement of class
I human leukocyte antigen (HLA) antigen expression on cancer cells, which increases their
susceptibility to immune surveillance mechanisms, such as graft-versus-leukemia effect of
donor cells in allogeneic transplantation and by augmentation of natural killer (NK), T and B
lymphocyte reactivity. We hypothesize that decitabine delivered after allo-HSCT in patients
with leukemia will enhance disease control by the allogeneic immune system and lead to a
longer disease free survival. However, a safety study is needed to determine appropriate
decitabine dosing in the post-transplant period. Low doses of decitabine are likely better
tolerated in the post-transplant setting given risks of myelosuppression. In addition, when
administered at lower doses, decitabine's hypomethylation effects are more pronounced in
relation to its pyrimidine analog cytotoxic effects. In this study low doses of decitabine
will be administered beginning 6 weeks to 100 days post-transplant. Measures of gene
methylation and immune reconstitution will be conducted to define biologically active doses.
Results from this trial will provide new clinical data regarding the effects of decitabine on
gene methylation and immunoreactivity, will establish a maximally tolerated dose in the
post-transplant setting, will define biologically active doses, and will serve as a basis for
future efficacy trials.

Inclusion Criteria:

- Age: greater than 1 and less than 31 years of age;

- Diagnosis: history of ALL, AML or MDS, currently in a complete remission (CR)
following allo-HSCT (bone marrow leukemic blasts less than 5% by morphology), with
high risk features including:

- Status post allogeneic HSCT

- GVHD prophylaxis:

- Karnofsky or Lansky performance scores more than 50%. Karnofsky scores will be used
for patients > 16 years of age and Lansky scores for patients ≤ 16 years of age;

- Platelet count ≥ 50,000 (untransfused);

- Absolute neutrophil count ≥ 1000; and;

- Hemoglobin ≥ 8 g/dL (un-transfused);

Exclusion Criteria:

- Progressive disease;

- Philadelphia chromosome positive ALL (these patients receive tyrosine kinase inhibitor
posttransplant);

- Known hypersensitivity to any components of decitabine;

- Uncontrolled grade 3-4 graft versus host disease;

- Uncontrolled infection;

- Serum creatinine > 2 mg/dL or glomerular filtration rate (GFR) less than 60
mL/min/1.73m2 ;

- Alanine Aminotransferase (ALT) greater than 3 times normal or serum total bilirubin
greater than 2 mg/dL;