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

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

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

Study Overview

• Status: Terminated
• Conditions: Secondary Acute Myeloid Leukemia; Childhood Acute Myeloblastic Leukemia With Maturation (M2); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: decitabine

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 Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Arcadia, California, United States, 91006-3776
      • Children's Oncology Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: decitabine; Given IV; Other Names: DAC; 5-aza-dCyd; 5AZA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Norman Lacayo, Children's Oncology Group

Study record dates

Study Major Dates

• Study Start: December 1, 2002
• Primary Completion (Actual): October 1, 2005

Study Registration Dates

• First Submitted: August 5, 2002
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): January 23, 2013
• Last Update Submitted That Met QC Criteria: January 22, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Promyelocytic, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine; Azacitidine
• Other Study ID Numbers: NCI-2012-01873; U01CA097452 (U.S. NIH Grant/Contract); ADVL0114; CDR0000069471 (Registry Identifier: PDQ (Physician Data Query))