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

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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