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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoblastic Leukemia, Acute, Childhood; Myelogenous Leukemia, Acute, Childhood
• Intervention / Treatment: Drug: Azacytidine; Drug: Fludarabine; Drug: Cytarabine; Drug: Intrathecal (IT) Cytarabine; Drug: Intrathecal Methotrexate (IT MTX)

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Sydney Children's Hospital
    • Westmead, New South Wales, Australia, 2145
      • Children's Hospital at Westmead
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • British Columbia Children's Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T-1C5
      • Sainte-Justine University Hospital Center
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
    • San Francisco, California, United States, 94143-0106
      • UCSF School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta, Emory University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0914
      • C.S. Mott Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404-4597
      • Childrens Hospital & Clinics of Minnesota
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospitals and Clinics
  • New York
    • New York, New York, United States, 10032
      • Children's Hospital New York-Presbyterian
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Levine Children's Hospital at Carolinas Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies & Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Childrens Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Children's Hospital
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas at Southwestern
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Patients must be ≥ 1 and ≤ 21 years of age.

Diagnosis

1. Patients with AML must have ≥5% blasts (by morphology) in the bone marrow.
2. Patients with ALL must have an M2 or M3 marrow (≥5% blasts by morphology).
3. Patients may have disease in the central nervous system (CNS) or other sites of extramedullary disease. No cranial irradiation is allowed during the protocol therapy.
4. Patients with secondary AML are eligible.
5. Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.

Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age.

Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

Myelosuppressive chemotherapy - the eligibility criteria is different between phase I and expansion phase

1. Phase I

   • Any patient with AML in 1st or greater relapse, OR
   • Any patient with ALL in 2nd or greater relapse, OR
   • Patients with AML or ALL failed to go into remission after first or greater relapse, OR
   • Patients with AML or ALL failed to go into remission from original diagnosis after two or more courses of induction attempts.
2. Expansion phase - will be restricted to AML patients only
3. Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of azacytidine. It is recommended to use hydroxyurea in patients with significant leukocytosis (WBC > 50,000/L) to control blast count before initiation of systemic protocol therapy.
4. Patients who relapsed while they are receiving cytotoxic therapy (including AZA , decitabine, or vorinostat) At least 14 days must have elapsed since the completion of the cytotoxic therapy.

Hematopoietic stem cell transplant: Patients who have experienced their relapse after a stem cell transplant are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are at least 90 days post-transplant at the time of enrollment.

Hematopoietic growth factors: It must have been at least 7 days since the completion of therapy with filgrastim or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).

Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair

Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days)

Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines.

Radiation Therapy (XRT): Craniospinal XRT is prohibited during protocol therapy. No washout period is necessary for radiation given to non-CNS chloromas; ≥ 90 days must have elapsed if prior total body radiation or craniospinal radiation.

Renal and hepatic function

Patients must have adequate renal and hepatic functions as indicated by the following laboratory values:

• Patient must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) greater than or equal to 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender.
• Direct bilirubin < 1.5 x upper limit of normal (ULN) for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age.

Adequate Cardiac Function Defined as: Shortening fraction greater than or equal to 27% by echocardiogram, OR ejection fraction greater than or equal to 50% by radionuclide angiogram (MUGA).

Reproductive Function

• Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while on this study.
• Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.

Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study. All patients and/or their parents or legal guardians must sign a written informed consent.

Exclusion Criteria:

Patients will be excluded if they have a known allergy to any of the drugs used in the study.

Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours.

Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.

Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results.

Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: AML Arm; 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	Drug: Azacytidine; Dose assigned at study entry (75 mg/m2/day). Given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.; Other Names: Vidaza; 5 Azacytidine; Drug: Fludarabine; 30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses; Other Names: Fludara; Oforta; fludarabine phosphate; 2-fluoro-ara-AMP; Drug: Cytarabine; 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.; Other Names: Ara-C; Arabinosylcytosine; Cytosar-U; cytosine arabinoside; Drug: Intrathecal (IT) Cytarabine; 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 mg3 - MTX: 12 mg, HC: 35 mg, ARAC: 70 mg; Other Names: (See Cytarabine)
EXPERIMENTAL: ALL Arm; 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)	Drug: Azacytidine; Dose assigned at study entry (75 mg/m2/day). Given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.; Other Names: Vidaza; 5 Azacytidine; Drug: Fludarabine; 30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses; Other Names: Fludara; Oforta; fludarabine phosphate; 2-fluoro-ara-AMP; Drug: Cytarabine; 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.; Other Names: Ara-C; Arabinosylcytosine; Cytosar-U; cytosine arabinoside; Drug: Intrathecal 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): - 1.99 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 mg9 MTX: 15 mg, HC: 15 mg, ARAC: 30 mg; Other Names: Amethopterin; Rheumatrex; Trexall; Otrexup; Rasuvo; Methotrexate Sodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)	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)	From Day 1 to Day 42 (Cycle 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Response Rate After Treatment	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.	Between Days 36-42 of Courses 1 and 2

Collaborators and Investigators

• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
• Collaborators: Gateway for Cancer Research
• Investigators: Study Chair: Weili Sun, MD, PhD, Children's Hospital Los Angeles

Publications and helpful links

General Publications

• Sun W, Triche T Jr, Malvar J, Gaynon P, Sposto R, Yang X, Bittencourt H, Place AE, Messinger Y, Fraser C, Dalla-Pozza L, Salhia B, Jones P, Wayne AS, Gore L, Cooper TM, Liang G. A phase 1 study of azacitidine combined with chemotherapy in childhood leukemia: a report from the TACL consortium. Blood. 2018 Mar 8;131(10):1145-1148. doi: 10.1182/blood-2017-09-803809. Epub 2018 Jan 16. No abstract available.

Helpful Links

• Therapeutic Advances in Childhood Leukemia & Lymphoma Consortium web site

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 22, 2013
• Primary Completion (ACTUAL): July 28, 2014
• Study Completion (ACTUAL): July 28, 2014

Study Registration Dates

• First Submitted: May 21, 2013
• First Submitted That Met QC Criteria: May 22, 2013
• First Posted (ESTIMATE): May 23, 2013

Study Record Updates

• Last Update Posted (ACTUAL): June 9, 2021
• Last Update Submitted That Met QC Criteria: May 14, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Pediatric; Lymphoblastic; Refractory; AML; ALL; Leukemia; Childhood; Relapse; Acute; Methylation; Epigenetic therapy; Azacytidine; Myelogenous
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, Lymphoid; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Acute Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Azacitidine; Fludarabine; Fludarabine phosphate; Cytarabine; Methotrexate
• Other Study ID Numbers: T2011-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No