Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia

Study Overview
=================
Brief Summary
-----------------
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

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase I Study Of Decitabine (DAC) (IND # 50733) In Children With Relapsed Or Refractory Acute Leukemia

Conditions
-----------------
Childhood Acute Myeloblastic Leukemia With Maturation (M2), Childhood Acute Promyelocytic Leukemia (M3), Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia

Intervention / Treatment
-----------------
* Drug: decitabine
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed acute myeloid leukemia (AML) or acute lymphoblastic leukemia that is considered refractory to conventional therapy or for which no conventional therapy exists For patients with AML: M3 marrow M2 marrow with at least 15% blasts Secondary AML allowed CNS involvement allowed Performance status - Karnofsky 50-100% (age 17 to 21) Performance status - Lansky 50-100% (age 16 and under) At least 8 weeks See Chemotherapy WBC no greater than 30,000/mm^3 Patients with granulocytopenia, anemia, and/or thrombocytopenia are eligible but are not evaluable for hematological toxicity Bilirubin no greater than 1.5 times normal ALT no greater than 5 times normal Albumin at least 2 g/dL Creatinine no greater than 1.5 times normal Creatinine clearance or radioisotope glomerular filtration rate at least lower limit of normal Shortening fraction at least 27% by echocardiogram Ejection fraction at least 50% by MUGA scan No evidence of dyspnea at rest No exercise intolerance Oxygen saturation greater than 94% by pulse oximetry Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Concurrent seizure disorder allowed if well controlled on anticonvulsants No grade 2 or greater CNS toxicity No uncontrolled infection (i.e., infections associated with fever, dissemination, hemodynamic instability [requiring pressor support], and progression while on therapy) No active graft-versus-host disease (GVHD) GVHD well controlled on cyclosporine allowed Recovered from prior immunotherapy At least 1 week since prior biologic agents At least 6 months since prior allogeneic bone marrow transplantation (BMT) At least 3 months since prior autologous BMT No concurrent sargramostim (GM-CSF) No concurrent prophylactic filgrastim (G-CSF) during the first course of therapy Recovered from prior chemotherapy At least 4 weeks since prior cytarabine At least 24 hours since prior cytoreductive therapy with hydroxyurea (20-30 mg/kg/day for no more than 7 days) to lower the WBC to no greater than 30,000/mm^3 No concurrent intrathecal therapy during the first course of decitabine Recovered from prior radiotherapy At least 2 weeks since prior local palliative radiotherapy (small port) At least 6 weeks since prior cranial or craniospinal radiotherapy No concurrent medications that induce cytidine deaminase or deoxycytidine kinase (e.g., cytarabine) No concurrent medications that mask poor or deteriorating organ function No concurrent CNS prophylaxis during the first course of decitabine Concurrent anticonvulsants with no known interactions with decitabine allowed Concurrent antibacterial or antifungal therapies for controlled infections allowed

Ages Eligible for Study
-----------------
Maximum Age: 21 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (decitabine)<br>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. | Drug: decitabine<br>* Given IV<br>* Other names: DAC;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD defined as the highest dose at which fewer than one-third of patients experience DLT assessed using CTC version 2.0 |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR rate | Will be estimated by proportions. | Up to 3 years | 
| PR rate | Will be estimated by proportions. | Up to 3 years | 
| DNA methylation | Pearson correlation will be used. | Up to 3 years | 
| Gene expression profiles | Will be analyzed using hierarchical clustering. | Up to 3 years | 
| HDAC/HAT activity | Pearson correlation coefficient analysis will be used. | Up to 3 years | 
| Presence of mutant helicases |  | Up to 3 years |