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

Secondary Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00042796
• Other study ID #: NCI-2012-01873
• Secondary ID: ADVL0114U01CA097
• Status: Terminated
• Phase: Phase 1
• First received: August 5, 2002
• Last updated: January 22, 2013
• Start date: December 2002

Study information

• Verified date: January 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 21
• Est. primary completion date: October 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 21 Years

Eligibility

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 Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Childhood Acute Myeloblastic Leukemia With Maturation (M2)
• Childhood Acute Promyelocytic Leukemia (M3)
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Promyelocytic, Acute
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Recurrent Childhood Acute Lymphoblastic Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Secondary Acute Myeloid Leukemia

Intervention

Drug:
• decitabine
Given IV

Other:
• pharmacological study
Correlative studies
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Children's Oncology Group	Arcadia	California

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD defined as the highest dose at which fewer than one-third of patients experience DLT assessed using CTC version 2.0		4 weeks	Yes
Secondary	CR rate	Will be estimated by proportions.	Up to 3 years	No
Secondary	PR rate	Will be estimated by proportions.	Up to 3 years	No
Secondary	DNA methylation	Pearson correlation will be used.	Up to 3 years	No
Secondary	Gene expression profiles	Will be analyzed using hierarchical clustering.	Up to 3 years	No
Secondary	HDAC/HAT activity	Pearson correlation coefficient analysis will be used.	Up to 3 years	No
Secondary	Presence of mutant helicases		Up to 3 years	No