Clinical Trials Directory

Trials / Completed

CompletedNCT01861002

A Phase I Study of 5-Azacytidine in Combination With Chemotherapy for Children With Relapsed or Refractory ALL or AML

Status
Completed
Phase
Phase 1
Study type
Interventional
Enrollment
15 (actual)
Sponsor
Therapeutic Advances in Childhood Leukemia Consortium · Academic / Other
Sex
All
Age
1 Year – 21 Years
Healthy volunteers
Not accepted

Summary

This is a Phase I study with a conditional cohort expansion phase to evaluate the feasibility of, and to obtain preliminary efficacy data about, pretreatment with Azacytidine (AZA) for 5 days followed by fludarabine/cytarabine chemotherapy regimen in pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients who are refractory to primary treatment or who relapsed.

Detailed description

Growing evidence indicates that aberrant DNA hypermethylation is associated with leukemia development, drug resistance, and relapse. It has been shown that pretreating leukemia cells with AZA or decitabine could partially reverse the aberrant DNA methylation, restore the expression of tumor suppressor gene important for apoptosis, and sensitize cells to subsequent killing by cytotoxic agent. Since cytarabine and decitabine share the same mechanisms of resistance, we use AZA to test the novel epigenetic "priming" approach. This is a phase I clinical study with expansion phase, using hypomethylating agent, 5-azacytidine (AZA), in sequential with chemotherapy to evaluate whether epigenetic "priming" can reverse aberrant DNA methylation, overcome drug resistance, and increase response in relapsed/refractory AML. The chemotherapy regimen to be used in this study is fludarabine and cytarabine. This regimen has substantial activity in leukemia and has been widely used in treating pediatric patients with relapsed/refractory AML and ALL in the past several decades. In BFM relapsed AML 2001/01 study, FLAG (fludarabine, cytarabine and G-CSF) chemotherapy regimen showed significant activity in AML with 4 year OS around 36%. Since the use of G-CSF in conjunction with fludarabine/cytarabine didn't improve the overall survival of patient in a randomized trial, only fludarabine and cytarabine will be used in this study to decrease the incidence of leukocytosis related complications. This regimen is very similar to the chemotherapy regimen proposed for the next relapsed AML trial within the Children's Oncology Group (COG). If this trial proves to be safe and active, it will provide the foundation and smooth transition to larger statistically powered nationwide phase II clinical trials by COG.

Conditions

Interventions

TypeNameDescription
DRUGAzacytidineDose assigned at study entry (75 mg/m2/day). Given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.
DRUGFludarabine30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses
DRUGCytarabine2000 mg/m2/dose intravenous infusion over 3 hours, starting 4 hours after the beginning of fludarabine, once daily, on days 6 to 10, total 5 doses.
DRUGIntrathecal (IT) CytarabineIntrathecally to AML patients on day 1 of course 1 and 2. * Omit on day 1 of course 1 if patient received IT therapy within 7 days prior to study enrollment * IT therapy may be given during the end of course 1 disease evaluation and repeated every 7 days * For patients with CNS disease, IT cytarabine can be given weekly until the CSF is clear. Two additional doses of IT cytarabine should be given weekly after the initial CSF clearing. It is permitted to change to intrathecal triple therapy (ITT) if persistent blasts are present in the CSF based on the treating physician's clinical judgment. Cytarabine dose defined by age: * 30 mg for patients age 1-1.99 * 50 mg for patients age 2-2.99 * 70 mg for patients \>3 years of age ITT Dosing: Age (yrs) - Dose Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC): 1. \- 1.99 MTX: 8 mg, HC: 15 mg, ARAC: 30 mg 2. \- 2.99 MTX: 10 mg, HC: 25 mg, ARAC: 50 mg * 3 - MTX: 12 mg, HC: 35 mg, ARAC: 70 mg
DRUGIntrathecal Methotrexate (IT MTX)* Intrathecally to patients with ALL on day 1 of course 1 and 2. * Omit IT MTX on Day 1 of course 1 if patient received IT therapy within 7 days prior to study enrollment * IT therapy may be given during the end of course 1 disease evaluation and repeated every 7 days * For patients with CNS 2 or 3 disease, IT MTX can be given weekly until the CSF is clear. Two additional doses of IT MTX should be given weekly after the initial clearing of the CSF. It is permitted to change to ITT if persistent blasts are present in the CSF. Methotrexate dose defined by age * 8 mg for patients age 1-1.99 * 10 mg for patients age 2-2.99 * 12 mg for patients 3-8.99 years of age * 15 mg for patients \>9 years of age Triple IT Therapy Dosing: Age (yrs): Dose Methotrexate (MTX), Hydrocortisone (HC), Cytarabine (ARAC): 1. \- 1.99 MTX: 8 mg, HC: 8 mg, ARAC: 16 mg 2. \- 2.99 MTX: 10 mg, HC: 10 mg, ARAC: 20 mg 3. \- 8.99 MTX: 12 mg, HC: 12 mg, ARAC: 24 mg * 9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg

Timeline

Start date
2013-05-22
Primary completion
2014-07-28
Completion
2014-07-28
First posted
2013-05-23
Last updated
2021-06-09
Results posted
2021-04-30

Locations

23 sites across 3 countries: United States, Australia, Canada

Regulatory

Source: ClinicalTrials.gov record NCT01861002. Inclusion in this directory is not an endorsement.