A Phase I Study of 5-Azacytidine in Combination With Chemotherapy for Children With Relapsed or Refractory ALL or AML
- Conditions
- Lymphoblastic Leukemia, Acute, ChildhoodMyelogenous Leukemia, Acute, Childhood
- Interventions
- Registration Number
- NCT01861002
- Lead Sponsor
- Therapeutic Advances in Childhood Leukemia Consortium
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 15
Patients must be ≥ 1 and ≤ 21 years of age.
Diagnosis
- Patients with AML must have ≥5% blasts (by morphology) in the bone marrow.
- Patients with ALL must have an M2 or M3 marrow (≥5% blasts by morphology).
- 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.
- Patients with secondary AML are eligible.
- 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
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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.
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Expansion phase - will be restricted to AML patients only
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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.
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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.
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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description AML Arm Intrathecal (IT) Cytarabine 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 ALL Arm Intrathecal Methotrexate (IT MTX) 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) AML Arm Fludarabine 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 ALL Arm Azacytidine 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) AML Arm Azacytidine 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 AML Arm Cytarabine 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 ALL Arm 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) ALL Arm Fludarabine 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)
- Primary Outcome Measures
Name Time Method Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) From Day 1 to Day 42 (Cycle 1) 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)
- Secondary Outcome Measures
Name Time Method Disease Response Rate After Treatment Between Days 36-42 of Courses 1 and 2 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.
Trial Locations
- Locations (23)
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Sainte-Justine University Hospital Center
🇨🇦Montreal, Quebec, Canada
Children's Mercy Hospitals and Clinics
🇺🇸Kansas City, Missouri, United States
Levine Children's Hospital at Carolinas Medical Center
🇺🇸Charlotte, North Carolina, United States
Dana Farber
🇺🇸Boston, Massachusetts, United States
C.S. Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Cook Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Childrens Hospital & Clinics of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Childrens Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Nationwide Childrens Hospital
🇺🇸Columbus, Ohio, United States
Primary Children's Medical Center
🇺🇸Salt Lake City, Utah, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
UCSF School of Medicine
🇺🇸San Francisco, California, United States
Rainbow Babies & Children's Hospital
🇺🇸Cleveland, Ohio, United States
Children's Hospital New York-Presbyterian
🇺🇸New York, New York, United States
University of Texas at Southwestern
🇺🇸Dallas, Texas, United States
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Children's Hospital at Westmead
🇦🇺Westmead, New South Wales, Australia
Vanderbilt Children's Hospital
🇺🇸Nashville, Tennessee, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Sydney Children's Hospital
🇦🇺Randwick, New South Wales, Australia
British Columbia Children's Hospital
🇨🇦Vancouver, British Columbia, Canada
Children's Healthcare of Atlanta, Emory University
🇺🇸Atlanta, Georgia, United States