Phase I/II Study of Decitabine and Valproic Acid in Relapsed/Refractory Leukemia or Myelodysplastic Syndromes

Recent studies have shown synergy between demethylating agents and histone deacetylase
inhibitors. It has been shown that both DNA methylation and histone deacetylation work
together in affecting gene expression.

Therefore, drugs that inhibit DNA methylation and those that inhibit histone deacetylase can
reactivate silenced genes in combination better than they can individually. Decitabine (5
aza-2'deoxycytidine), a drug that produces marked DNA hypomethylator, has demonstrated
antileukemic activity at low doses. There are several drugs that have been shown to have
histone acetylase activity. One of these is valproic acid that has been used safely for many
years as an anti-seizure medication.

Inclusion Criteria:

1. FOR PHASE I COMPONENT OF THE STUDY: Patients with refractory or relapsed: acute
myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic
syndrome (MDS) are eligible. Patients with chronic lymphocytic leukemia (CLL) are
eligible if fludarabine based therapy has failed. Patients with chronic myeloid
leukemia (CML) are eligible if they have documented hematologic resistance to imatinib
mesylate or have not achieved or lost any cytogenetic response to imatinib mesylate
after 12 months of therapy.

2. Untreated patients older than 60 years of age with AML or MDS who refuse or are not
eligible for frontline chemotherapy, are eligible.

3. Performance status of =/< 2 by the ECOG scale.

4. Signed informed consent indicating that patients are aware of the investigational
nature of this study in keeping with the policies of UTMDACC.

5. Age > 2 years.

6. Patients must have been off chemotherapy for 2 weeks prior to entering this study and
recovered from the toxic effects of that therapy, unless there is evidence of rapidly
progressive disease. Use of hydroxyurea for patients with rapidly proliferative
disease is allowed for the first two weeks on therapy. Imatinib mesylate (Gleevec) and
anagrelide must also be stopped 2 weeks prior to entering this study.

7. Adequate liver function (bilirubin of < 2mg%, SGPT < 3 x ULN) and renal function
(creatinine < 2mg%).

8. Women of childbearing potential must practice contraception. Men and women must
continue birth control for the duration of the trial.

9. INCLUSION OF PHASE II PORTION OF THE STUDY: As in the phase I portion but only
patients with AML or high-risk MDS (blasts > or = 10%), including untreated patients
older than 60 years of age with AML or MDS who refuse or are not eligible for
frontline chemotherapy, will be eligible in this portion of the study.

Exclusion Criteria:

1. Nursing and pregnant females are excluded.

2. Patients with active and uncontrolled infections are excluded.

3. Patients with a known ornithine transcarbamylase disorder, history of unexplained coma
or a family history of ornithine transcarbamylase disorder are excluded from this
study.

4. Uncontrolled intercurrent illness including, but not limited to symptomatic congestive
heart failure, unstable angina pectoris, pancreatitis, psychiatric illness that would
limit compliance with study requirements.

5. Patients with history of hepatitis B, C, alcoholic liver disease or evidence of
hepatopathy will be excluded.

6. Patients already receiving valproic acid or receiving other anticonvulsivants will be
excluded.

7. Untreated patients younger than 60 years will not be candidates for this study.