Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. This phase I trial is studying the side effects and best dose of decitabine in treating children with relapsed or refractory acute myeloid leukemia or acute lymphoblastic leukemia
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of decitabine that is associated with consistent evidence of deoxyribonucleic acid (DNA) demethylation in children with relapsed or refractory acute myeloid leukemia or acute lymphoblastic leukemia. II. Determine the dose-limiting toxicity, pharmacokinetics, and antitumor activity of this drug in these patients. III. Determine the biologic correlates of decitabine-induced DNA demethylation by characterizing, before and after treatment, global and specific DNA methylation status (using methylation microarrays) and hemoglobin F levels in these patients. IV. Determine the biologic correlates of decitabine-induced DNA demethylation by characterizing, before and after treatment, global changes in gene expression profiles using cDNA microarrays and drug sensitivity of blast cells by MTT assays in these patients. V. Determine the biologic correlates of decitabine-induced DNA demethylation by characterizing, before and after treatment, deletions and single nucleotide polymorphisms in genomic DNA of deoxycytidine kinase and cytidine deaminase genes in these patients. VI. Determine the biologic correlates of decitabine-induced DNA demethylation by characterizing, before and after treatment, acetylation and methylation of histones H3 and H4 and helicase protein expression in these patients. OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to disease type (acute myeloid leukemia vs acute lymphoblastic leukemia). Patients receive decitabine IV over 1 hour on days 1-5 and 8-12. Treatment repeats every 4-6 weeks for a minimum of 4 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of decitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. PROJECTED ACCRUAL: A total of 15-21 patients will be accrued for this study within 7.5-21 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
21
Children's Oncology Group
Arcadia, California, United States
MTD defined as the highest dose at which fewer than one-third of patients experience DLT assessed using CTC version 2.0
Time frame: 4 weeks
CR rate
Will be estimated by proportions.
Time frame: Up to 3 years
PR rate
Will be estimated by proportions.
Time frame: Up to 3 years
DNA methylation
Pearson correlation will be used.
Time frame: Up to 3 years
Gene expression profiles
Will be analyzed using hierarchical clustering.
Time frame: Up to 3 years
HDAC/HAT activity
Pearson correlation coefficient analysis will be used.
Time frame: Up to 3 years
Presence of mutant helicases
Time frame: Up to 3 years
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