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

This study has been completed.
Sponsor:
Collaborators:
Gateway for Cancer Research
University of Southern California
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier:
NCT01861002
First received: May 21, 2013
Last updated: May 31, 2016
Last verified: May 2016
  Purpose
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.

Condition Intervention Phase
Lymphoblastic Leukemia, Acute, Childhood
Myelogenous Leukemia, Acute, Childhood
Drug: Azacytidine
Drug: Fludarabine
Drug: Cytarabine
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of 5-Azacytidine in Combination With Chemotherapy for Children With Relapsed or Refractory ALL or AML

Resource links provided by NLM:


Further study details as provided by Therapeutic Advances in Childhood Leukemia Consortium:

Primary Outcome Measures:
  • The dose of azacytidine that can be given safely with fludarabine and cytarabine. [ Time Frame: 7 weeks ] [ Designated as safety issue: Yes ]
    The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy.


Secondary Outcome Measures:
  • The response rate after treatment. [ Time Frame: 7 weeks ] [ Designated as safety issue: No ]
  • DNA methylation and gene expression before and after treatment with azacytidine. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

    To establish the extent of hypomethylation of peripheral blood (PB) and bone marrow (BM) pre- and post- azacytidine treatment by:

    • LINE-1 methylation assay as a surrogate marker to assess global DNA methylation, and two additional DNA methylation markers to track response to DNA demethylating agents.
    • Direct Comprehensive DNA methylation analysis.
    • Gene expression profiling to assess genetic changes.


Enrollment: 15
Study Start Date: May 2013
Study Completion Date: July 2014
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dose Level 1
  • Azacytidine 75 mg/m2/day
  • Fludarabine 30 mg/m2/dose
  • Cytarabine 2000 mg/m2/dose
Drug: Azacytidine
Dose assigned at study entry. Azacytidine will be given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.
Other Names:
  • 5 Azacytidine
  • Vidaza
Drug: Fludarabine
30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses
Other Names:
  • fludarabine phosphate
  • Fludara
  • 2-fluoro-ara-AMP
  • Oforta
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:
  • Cytosar-U
  • Ara-C
  • Arabinosylcytosine
  • cytosine arabinoside
Experimental: Dose Level 0
  • Azacytidine 50 mg/m2/day
  • Fludarabine 30 mg/m2/dose
  • Cytarabine 2000 mg/m2/dose
Drug: Azacytidine
Dose assigned at study entry. Azacytidine will be given subcutaneously, once daily on days 1 to 5, for a total of 5 doses.
Other Names:
  • 5 Azacytidine
  • Vidaza
Drug: Fludarabine
30 mg/m2/dose, intravenous infusion over 30 minutes, once daily, on days 6 to 10, total 5 doses
Other Names:
  • fludarabine phosphate
  • Fludara
  • 2-fluoro-ara-AMP
  • Oforta
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:
  • Cytosar-U
  • Ara-C
  • Arabinosylcytosine
  • cytosine arabinoside

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 decades47. 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%.47 Since the use of G-CSF in conjunction with fludarabine/cytarabine didn't improve the overall survival of patient in a randomized trial48, 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.

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01861002

  Show 32 Study Locations
Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
Gateway for Cancer Research
University of Southern California
Investigators
Study Chair: Weili Sun, MD, PhD Children's Hospital Los Angeles
  More Information

Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier: NCT01861002     History of Changes
Other Study ID Numbers: T2011-002 
Study First Received: May 21, 2013
Last Updated: May 31, 2016
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
Australia: Department of Health and Ageing Therapeutic Goods Administration
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:
Relapse
Lymphoblastic
Leukemia
Azacytidine
Refractory
Myelogenous
Acute
Childhood
Pediatric
ALL
AML
Methylation
Epigenetic therapy

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myeloid
Acute Disease
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Disease Attributes
Pathologic Processes
Azacitidine
Fludarabine phosphate
Cytarabine
Vidarabine
Fludarabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on December 09, 2016