A Phase I Study of 5-Azacytidine in Combination With Chemotherapy for Children With Relapsed or Refractory ALL or AML
Condition: Lymphoblastic Leukemia, Acute, Childhood; Myelogenous Leukemia, Acute, Childhood
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Acute Disease
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Azacytidine; Fludarabine; Cytarabine; Intrathecal (IT) Cytarabine; Intrathecal Methotrexate (IT MTX)
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Dose assigned at study entry (75 mg/m2/day). Given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.; 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):
- 1.99 MTX: 8 mg, HC: 15 mg, ARAC: 30 mg
- 2.99 MTX: 10 mg, HC: 25 mg, ARAC: 50 mg
3 - MTX: 12 mg, HC: 35 mg, ARAC: 70 mg; 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):
- 1.99 MTX: 8 mg, HC: 8 mg, ARAC: 16 mg
- 2.99 MTX: 10 mg, HC: 10 mg, ARAC: 20 mg
- 8.99 MTX: 12 mg, HC: 12 mg, ARAC: 24 mg
9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg
Other intervention name(s): 5 Azacytidine; Vidaza; fludarabine phosphate; Fludara; 2-fluoro-ara-AMP; Oforta; Cytosar-U; Ara-C; Arabinosylcytosine; cytosine arabinoside; (See Cytarabine); Otrexup; Rasuvo; Rheumatrex; Trexall; Amethopterin; Methotrexate Sodium
Intervention MeSH terms: Cytarabine; Methotrexate; Fludarabine phosphate; Azacitidine; Fludarabine
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Relapse; Lymphoblastic; Leukemia; Azacytidine; Refractory; Myelogenous; Acute; Childhood; Pediatric; ALL; AML; Methylation; Epigenetic therapy