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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Terminated

CT.gov ID

NCT00042796

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
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	Drug: decitabine Other: pharmacological study Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

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.
Determine the dose-limiting toxicity, pharmacokinetics, and antitumor activity of this drug in these patients.
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.
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.
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.
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 Design

Study Type:

Interventional

Actual Enrollment :

21 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Dec 1, 2002

Actual Primary Completion Date :

Oct 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (decitabine) 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 Given IV Other Names: 5-aza-dCyd 5AZA DAC Other: pharmacological study Correlative studies Other Names: pharmacological studies Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (decitabine)

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

Given IV

Other Names:

5-aza-dCyd

5AZA

DAC

Other: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 21 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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