Brief Title
Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia
Official Title
A Phase I Study Of Decitabine (DAC) (IND # 50733) In Children With Relapsed Or Refractory Acute Leukemia
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.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
MTD defined as the highest dose at which fewer than one-third of patients experience DLT assessed using CTC version 2.0
Secondary Outcome
CR rate
Condition
Childhood Acute Myeloblastic Leukemia With Maturation (M2)
Intervention
decitabine
Study Arms / Comparison Groups
Treatment (decitabine)
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
21
Start Date
December 2002
Primary Completion Date
October 2005
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
Gender
All
Ages
N/A - 21 Years
Accepts Healthy Volunteers
No
Contacts
Norman Lacayo, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00042796
Organization ID
NCI-2012-01873
Secondary IDs
ADVL0114
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
Norman Lacayo, Principal Investigator, Children's Oncology Group
Verification Date
January 2013