Clinical trial NCT01861002
Conditions: Lymphoblastic Leukemia, Acute, Childhood Myelogenous Leukemia, Acute, Childhood
Keywords: Relapse Lymphoblastic Leukemia Azacytidine Refractory Myelogenous Acute Childhood Pediatric ALL AML Methylation Epigenetic therapy
Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
Start date: 2013-05-22; Completion date: 2014-07-28
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief 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.

Arms: arm 1: Participants with Acute Myeloid Leukemia (AML)

Intervention:

* Azacytidine (Dose Level 1 @ 75 mg/m2/day)
* Fludarabine 30 mg/m2/dose
* Cytarabine 2000 mg/m2/dose
* Intrathecal (IT) Cytarabine arm 2: Patients with Acute Lymphocytic Leukemia

Intervention:

* Azacytidine (Dose Level 1 @ 75 mg/m2/day)
* Fludarabine 30 mg/m2/dose
* Cytarabine 2000 mg/m2/dose
* Intrathecal Methotrexate (IT MTX)
Interventions: intervention 1: Azacytidine intervention 2: Fludarabine intervention 3: Cytarabine intervention 4: Intrathecal (IT) Cytarabine intervention 5: Intrathecal Methotrexate (IT MTX)
Intervention descriptions: intervention 1: Dose assigned at study entry (75 mg/m2/day). Given subcutaneously, once daily on days 1 to 5, for a total of 5 doses. intervention 2: 30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses intervention 3: 2000 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. intervention 4: Intrathecally 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 intervention 5: * 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

Protocol documents: