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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

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)

Dose assigned at study entry (75 mg/m2/day). Given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.

Azacytidine

30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses

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.

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

Intrathecal (IT) Cytarabine

* 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

Intrathecal Methotrexate (IT MTX)

Weili Sun, MD, PhD

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.

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.

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

To evaluate the side effects of giving Azacytidine before and during chemotherapy using the standard drugs Fludarabine, Cytarabine, IT Cytarabine (AML patients) and IT methotrexate (ALL patients)

CR is defined as a bone marrow with \< 5% blast by morphology, no evidence of extramedullary disease, and recovery of peripheral counts (ANC ≥ 1000/μl and platelet counts ≥ 100,000/μl). CR with incomplete count recovery (CRi) was defined as CR without recovery of ANC and/or platelets. Partial response (PR) was defined as complete disappearance of circulating blasts and a decrease of at least 50% of blasts in the bone marrow. Progressive disease (PD) was defined as an increase of at least 25% in the absolute number of bone marrow or circulating blasts, development of new sites of extramedullary disease, or other laboratory or clinical evidence of progression of disease. Stable disease (SD) referred to patient who did not satisfy the criteria for either CR, CRi, PR or PD.

Gateway for Cancer Research

Therapeutic Advances in Childhood Leukemia Consortium

The definitions of AE and SAE do not differ from the clinicaltrials.gov definitions.

Any patients in the AML arm who are evaluable for toxicity. Any patient who experiences a DLT after receiving at least one dose of AZA on study will be considered evaluable for toxicity of AZA. Patients who do not experience a DLT must receive at least 80% of the prescribed course of AZA in the first cycle (i.e., must receive at least 4 of the planned 5 doses of AZA between days 1 to 5) to be evaluable for toxicity of AZA. Patients not evaluable for toxicity of AZA will be replaced.

AML Cohort: 75 mg/m2/Day

Any patients in the ALL arm who are evaluable for toxicity. Any patient who experiences a DLT after receiving at least one dose of AZA on study will be considered evaluable for toxicity of AZA. Patients who do not experience a DLT must receive at least 80% of the prescribed course of AZA in the first cycle (i.e., must receive at least 4 of the planned 5 doses of AZA between days 1 to 5) to be evaluable for toxicity of AZA. Patients not evaluable for toxicity of AZA will be replaced.

ALL Cohort: 75 mg/m2/Day

This arm is comprised of the AML and ALL participants that completed Dose Level 1 75 mg/m2/day

Dose Level 1 75 mg/m2/Day

Age, Continuous

Sex: Female, Male

CNS Negative (better outcome): absence of blasts on a cytospin preparation in cerebral spinal fluid (CSF) or clinical signs of CNS leukemia

CNS Positive (worse outcome): presence of any number of blasts on a cytospin preparation in CSF or clinical signs of CNS leukemia

Central Nervous System (CNS) Status

Measurement of bone marrow response

M2 (better outcome): Marrow has between 5% and 25% leukemic blasts M3 (worse outcome): Marrow has more than 25% leukemic blasts

Bone Marrow Status (at study entry)

# Prior treatment regimens

Prior Hematopoetic Stem Cell Transplantation (HSCT)

White blood cell (WBC) Count

Peripheral blasts

Bone marrow blasts

Number that completed therapy and were analyzed

Roy Leong, BA, CCRP

# of patients with DLT

# of patients without DLT

# of patients not evaluable

Evaluable Participants who received azacytidine @ 75 mg/m2/day (Dose Level 1)

Dose 75 mg/m2/Day Azacytidine Diagnosed With AML

Evaluable ALL participants who received azacytidine @ 75 mg/m2/day (Dose Level 1)

Dose 75 mg/m2/Day Azacytidine Diagnosed With ALL

Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)

Participants with Acute Myeloid Leukemia (AML) who are evaluable for response.

A patient will be considered evaluable for response if: (1) the patient is eligible; (2) the patient receives all or part of protocol therapy; and (3) the patient is under follow-up for a sufficient period to evaluate the disease at the end of the course 2 or meets the definition of progressive disease. A patient who dies as a result of toxicity after receiving all or part of protocol therapy will be considered a non-responder.

Intervention:

* Azacytidine (Dose Level 1 @ 75 mg/m\^2/day)
* Fludarabine 30 mg/m\^2/dose
* Cytarabine 2000 mg/m\^2/dose
* Intrathecal (IT) Cytarabine

Dose 75 mg/m2/Day for AML Patients

Participants with Acute Lymphoblastic Leukemia (ALL) who are evaluable for response.

A patient will be considered evaluable for response if: (1) the patient is eligible; (2) the patient receives all or part of protocol therapy; and (3) the patient is under follow-up for a sufficient period to evaluate the disease at the end of the course 2 or meets the definition of progressive disease. A patient who dies as a result of toxicity after receiving all or part of protocol therapy will be considered a non-responder.

Intervention:

* Azacytidine (Dose Level 1 @ 75 mg/m\^2/day)
* Fludarabine 30 mg/m\^2/dose
* Cytarabine 2000 mg/m\^2/dose
* Intrathecal (IT) Methotrexate

Dose 75 mg/m2/Dose Azacytidine for ALL Patients

Disease Response Rate After Treatment

* Azacytidine (Dose Level @ 75 mg/m2/day),all patients will start at Dose Level 1. If 2 DLTs are observed within the first 6 patients enrolled, dose will be reduced to Dose Level 0 @ 50 mg/m2/day
* Fludarabine 30 mg/m2/dose
* Cytarabine 2000 mg/m2/dose
* Intrathecal (IT) Cytarabine

Spots Global Cancer Trial Database for intrathecal methotrexate (it mtx)