Trial Information

A PHASE I STUDY OF DECITABINE IN COMBINATION WITH VALPROIC ACID IN PATIENTS WITH SELECTED HEMATOLOGIC MALIGNANCIES

PRIMARY OBJECTIVES:

I. Determine the minimally effective pharmacological dose (MEPD) of decitabine in patients
with refractory or relapsed acute myeloid leukemia or with previously treated chronic
lymphocytic lymphoma or small lymphocytic lymphoma.

II. Determine the maximum tolerated dose (MTD) of valproic acid in combination with the MEPD
of decitabine in these patients.

III. Determine the MEPD of valproic acid in combination with decitabine in these patients.

IV. Determine the qualitative and quantitative toxic effects of decitabine alone and in
combination with valproic acid, in terms of organ specificity, time course, predictability,
and reversibility in these patients.

SECONDARY OBJECTIVES:

I. Determine the therapeutic response in patients treated with decitabine alone and in
combination with valproic acid.

II. Determine the pharmacokinetics of this regimen in these patients. III. Determine
kinetics of methyltransferase activity and re-expression of select target genes in AML [p15,
estrogen receptor (ER), WT-1, calcitonin, MYOD1] and in CLL/SLL [DERMO-1, DAPK, and ID4]
known to be methylated in primary tumor cells.

IV. Correlate baseline and post-treatment changes in DNA methyltransferases (MT1, MT3a, and
MT3b) expression with achievement of decitabine MEPD, toxicity, treatment resistance, and
disease response in these patients.

V. Determine kinetics of HDAC enzyme inhibition and changes in the acetylation status of
histones H3 or H4 following treatment with the combination. These parameters will be used to
define the MEPD of the combination.

VI. Examine baseline and post-therapy changes in the "histone code' in both AML and CLL
cells by assessment of the acetylation and methylation status of histones H3 and H4 lysine
residues using both Western Blot and Mass Spectrometry techniques.

OUTLINE: This is a dose-escalation study. Patients are stratified according to disease
(refractory or relapsed acute myeloid leukemia vs chronic lymphocytic leukemia or small
lymphocytic lymphoma).

Patients receive decitabine IV over 1 hour on days 1-5 or 1-10. Treatment repeats every 28
days.

Cohorts of 6 patients receive escalating doses of decitabine until the minimally effective
pharmacological dose (MEPD) is determined. The MEPD is defined as the dose at which at least
5 of 6 patients meet gene methylation criteria and no more than 1 of 6 patients experiences
dose-limiting toxicity (DLT).

Once the MEPD is determined, patients receive decitabine at that dose level administered as
above and oral valproic acid three times daily on days 5-21. Treatment repeats every 28
days.

Cohorts of 3-6 patients receive escalating doses of valproic acid until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
of 3 or 2 of 6 patients experience DLT. The MEPD of valproic acid is then determined using
established gene methylation and toxicity criteria. Treatment continues for up to 24 months
in the absence of disease progression or unacceptable toxicity.

Patients are followed for survival.