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

This study has been terminated.
(Administratively complete.)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00042796
First received: August 5, 2002
Last updated: January 22, 2013
Last verified: January 2013
  Purpose

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 Intervention 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

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study Of Decitabine (DAC) (IND # 50733) In Children With Relapsed Or Refractory Acute Leukemia

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

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 [ Time Frame: 4 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • CR rate [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Will be estimated by proportions.

  • PR rate [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Will be estimated by proportions.

  • DNA methylation [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Pearson correlation will be used.

  • Gene expression profiles [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Will be analyzed using hierarchical clustering.

  • HDAC/HAT activity [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Pearson correlation coefficient analysis will be used.

  • Presence of mutant helicases [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

Enrollment: 21
Study Start Date: December 2002
Primary Completion Date: October 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   up to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00042796

Locations
United States, California
Children's Oncology Group
Arcadia, California, United States, 91006-3776
Sponsors and Collaborators
Investigators
Principal Investigator: Norman Lacayo Children's Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00042796     History of Changes
Other Study ID Numbers: NCI-2012-01873, ADVL0114, U01CA097452, CDR0000069471
Study First Received: August 5, 2002
Last Updated: January 22, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia
Leukemia, Promyelocytic, Acute
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 30, 2014