Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Completed	Under 22	NCI	COG-ADVL0114 ADVL0114, NCT00042796

Objectives

1. 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.
2. Determine the dose-limiting toxicity, pharmacokinetics, and antitumor activity of this drug in these patients.
3. 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.
4. 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.
5. 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.
6. 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.

Entry Criteria

Disease Characteristics:

• 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

    OR

  • M2 marrow with at least 15% blasts
  • Secondary AML allowed



• CNS involvement allowed

Prior/Concurrent Therapy:

Biologic therapy

• 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

Chemotherapy

• 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/mm³
• No concurrent intrathecal therapy during the first course of decitabine

Endocrine therapy

• Not specified

Radiotherapy

• 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

Surgery

• Not specified

Other

• 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

Patient Characteristics:

Age

• Under 22

Performance status

• Karnofsky 50-100% (age 17 to 21)
• Lansky 50-100% (age 16 and under)

Life expectancy

• At least 8 weeks

Hematopoietic

• See Chemotherapy
• WBC no greater than 30,000/mm³
• Patients with granulocytopenia, anemia, and/or thrombocytopenia are eligible but are not evaluable for hematological toxicity

Hepatic

• Bilirubin no greater than 1.5 times normal
• ALT no greater than 5 times normal
• Albumin at least 2 g/dL

Renal

• Creatinine no greater than 1.5 times normal

  OR

• Creatinine clearance or radioisotope glomerular filtration rate at least lower limit of normal

Cardiovascular

• Shortening fraction at least 27% by echocardiogram

  OR

• Ejection fraction at least 50% by MUGA scan

Pulmonary

• No evidence of dyspnea at rest
• No exercise intolerance
• Oxygen saturation greater than 94% by pulse oximetry

Other

• 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

Expected Enrollment

A total of 15-21 patients will be accrued for this study within 7.5-21 months.

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.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Norman Lacayo, MD, Protocol chair		Ph: 650-723-5535 Email: lacayon@stanford.edu

Registry Information
Official Title		A Phase I Study Of Decitabine (DAC) (IND # 50733) In Children With Relapsed Or Refractory Acute Leukemia
Trial Start Date		2003-01-07
Registered in ClinicalTrials.gov		NCT00042796
Date Submitted to PDQ		2002-06-03
Information Last Verified		2005-11-02
NCI Grant/Contract Number		CA13539

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