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
Intervention: Azacytidine; Fludarabine; Cytarabine; Intrathecal (IT) Cytarabine; Intrathecal Methotrexate (IT MTX)
Intervention description: 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
Intervention MeSH terms: Cytarabine; Methotrexate; Fludarabine phosphate; Azacitidine; Fludarabine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Relapse; Lymphoblastic; Leukemia; Azacytidine; Refractory; Myelogenous; Acute; Childhood; Pediatric; ALL; AML; Methylation; Epigenetic therapy

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.
    

Eligibility 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.