Clinical Trials /

Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia

NCT01824693

Description:

This randomized phase II trial studies how well giving busulfan, cyclophosphamide, and melphalan or busulfan and fludarabine phosphate before donor hematopoietic cell transplant works in treating younger patients with juvenile myelomonocytic leukemia. Giving chemotherapy before a donor hematopoietic transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not yet known whether giving busulfan, cyclophosphamide, and melphalan or busulfan and fludarabine phosphate before a donor stem cell transplant is more effective in treating juvenile myelomonocytic leukemia.

Related Conditions:
  • Juvenile Myelomonocytic Leukemia
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Busulfan</span>, <span class="go-doc-concept go-doc-intervention">Cyclophosphamide</span>, and <span class="go-doc-concept go-doc-intervention">Melphalan</span> or <span class="go-doc-concept go-doc-intervention">Busulfan and Fludarabine</span> Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia

Title

  • Brief Title: Busulfan, Cyclophosphamide, and Melphalan or Busulfan and Fludarabine Phosphate Before Donor Hematopoietic Cell Transplant in Treating Younger Patients With Juvenile Myelomonocytic Leukemia
  • Official Title: A Randomized Phase II Study Comparing Two Different Conditioning Regimens Prior to Allogeneic Hematopoietic Cell Transplantation (HCT) for Children With Juvenile Myelomonocytic Leukemia (JMML)
  • Clinical Trial IDs

    NCT ID: NCT01824693

    ORG ID: ASCT1221

    NCI ID: NCI-2013-00738

    Trial Conditions

    Juvenile Myelomonocytic Leukemia

    Trial Interventions

    Drug Synonyms Arms
    busulfan BSF, BU, Misulfan, Mitosan, Myeloleukon Arm I (busulfan, cyclophosphamide, melphalan), Arm II (busulfan, fludarabine phosphate)
    cyclophosphamide CPM, CTX, Cytoxan, Endoxan, Endoxana Arm I (busulfan, cyclophosphamide, melphalan)
    melphalan Alkeran, CB-3025, L-PAM, L-phenylalanine mustard, L-Sarcolysin Arm I (busulfan, cyclophosphamide, melphalan)
    fludarabine phosphate 2-F-ara-AMP, Beneflur, Fludara Arm II (busulfan, fludarabine phosphate)
    tacrolimus FK 506, Prograf Arm I (busulfan, cyclophosphamide, melphalan), Arm II (busulfan, fludarabine phosphate)
    mycophenolate mofetil Cellcept, MMF Arm I (busulfan, cyclophosphamide, melphalan), Arm II (busulfan, fludarabine phosphate)

    Trial Purpose

    This randomized phase II trial studies how well giving busulfan, cyclophosphamide, and
    melphalan or busulfan and fludarabine phosphate before donor hematopoietic cell transplant
    works in treating younger patients with juvenile myelomonocytic leukemia. Giving
    chemotherapy before a donor hematopoietic transplant helps stop the growth of cancer cells.
    It may also stop the patient's immune system from rejecting the donor's stem cells. When the
    healthy stem cells from a donor are infused into the patient, they may help the patient's
    bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not
    yet known whether giving busulfan, cyclophosphamide, and melphalan or busulfan and
    fludarabine phosphate before a donor stem cell transplant is more effective in treating
    juvenile myelomonocytic leukemia.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To compare - in a randomized fashion - the day 100 treatment related mortality (TRM)
    incidence for two myeloablative conditioning regimens, busulfan-fludarabine (fludarabine
    phosphate) (BU-FLU) and busulfan-cyclophosphamide-melphalan (BU-CY-MEL), prior to
    hematopoietic cell transplant (HCT) for children with juvenile myelomonocytic leukemia
    (JMML), in order to determine the preferred regimen for future trials.

    II. To compare - in a randomized fashion - the 18-month event-free survival (EFS) following
    two different myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for
    children with JMML, in order to determine the preferred regimen for future trials.

    SECONDARY OBJECTIVES:

    I. To determine the 18-month relapse incidence (RI) following two different myeloablative
    conditioning regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML.

    II. To determine the graft failure rates following two different myeloablative conditioning
    regimens (BU-FLU vs. BU-CY-MEL) prior to HCT for children with JMML.

    TERTIARY OBJECTIVES:

    I. To determine the rates of severe toxicities (grade 3/4) at day 100 post-HCT between the
    two myeloablative conditioning regimens (BU-FLU vs. BU-CY-MEL).

    II. To determine the rates of acute and chronic (at 18 months post-HCT) graft-versus-host
    disease (GVHD) following HCT using two different conditioning regimens (BU-FLU vs.
    BU-CY-MEL) in children with JMML.

    III. To create a JMML-specific pre-HCT index to allow better risk-stratification of future
    patients.

    IV. To determine the feasibility of assessing post-transplant disease burden by donor
    chimerism measurements and allele-specific polymerase chain reaction (PCR) in mononuclear
    and sorted cell subsets.

    V. To validate gene expression and methylation classifiers predictive of relapse in patients
    with JMML.

    VI. To comprehensively assess genetic and biochemical alterations amongst patients with JMML
    who are treated on this transplant protocol.

    OUTLINE: Patients are randomized to 1 of 2 treatment arms.

    ARM I:

    CONDITIONING REGIMEN: Patients receive busulfan intravenously (IV) over 2-3 hours once daily
    (QD), every 12 hours, or every 6 hours on days -8 to -5, cyclophosphamide IV over 60 minutes
    QD on days -4 and -3, and melphalan IV over 15-30 minutes on day -1.

    TRANSPLANT: Patients undergo allogeneic HCT on day 0.

    Patients receive tacrolimus IV or orally (PO) on days -1 to 98 (related donor) or 180
    (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30
    (related donor) or 45 (unrelated donor).

    ARM II:

    CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV
    over 30-60 minutes on days -5 to -2.

    TRANSPLANT: Patients undergo allogeneic HCT as in Arm I.

    Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated
    donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related
    donor) or 45 (unrelated donor).

    After completion of study treatment, patients are followed up for 5 years.

    Trial Arms

    Name Type Description Interventions
    Arm I (busulfan, cyclophosphamide, melphalan) Experimental CONDITIONING REGIMEN: Patients receive busulfan IV QD, every 12 hours, or every 6 hours over 2-3 hours on days -8 to -5, cyclophosphamide IV QD over 60 minutes on days -4 and -3, and melphalan IV over 15-30 minutes on day -1. TRANSPLANT: Patients undergo allogeneic HCT no sooner than 24 hours after the last dose of chemotherapy. Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor). busulfan, cyclophosphamide, melphalan, tacrolimus, mycophenolate mofetil
    Arm II (busulfan, fludarabine phosphate) Experimental CONDITIONING REGIMEN: Patients receive busulfan as in Arm I and fludarabine phosphate IV over 1 hour on days -5 to -2. TRANSPLANT: Patients undergo allogeneic HCT as in Arm I. Patients receive tacrolimus IV or PO on days -1 to 98 (related donor) or 180 (unrelated donor) and mycophenolate mofetil IV over 2 hours or PO every 8 hours on days 1-30 (related donor) or 45 (unrelated donor). busulfan, fludarabine phosphate, tacrolimus, mycophenolate mofetil

    Eligibility Criteria

    Inclusion Criteria:

    - Patients must have a strong clinical suspicion of JMML, based on a modified category
    1 of the revised diagnostic criteria; specifically, eligible patients must have all
    of the following:

    - Splenomegaly

    - Absolute monocyte count (AMC) > 1000/uL

    - Blasts in peripheral blood (PB)/bone marrow (BM) < 20%

    - For the 7-10% of patients without splenomegaly, the diagnostic entry criteria must
    include all other features described above and at least 2 of the following criteria:

    - Circulating myeloid precursors

    - White blood cell (WBC) > 10,000/uL

    - Increased fetal hemoglobin (HgbF) for age

    - Sargramostim (GM-CSF) hypersensitivity OR, patients must have been previously
    diagnosed with JMML

    - Patients must be previously untreated with HCT

    - All patients and/or their parents or legal guardians must sign a written informed
    consent

    - All institutional, Food and Drug Administration (FDA), and National Cancer Institute
    (NCI) requirements for human studies must be met

    Exclusion Criteria:

    - Patients with a known germline mutation of PTPN11 (Noonan's Syndrome) are not
    eligible

    - Patients with a known history of NF1 (Neurofibromatosis Type 1) and either

    - A history of a tumor of the central nervous system (astrocytoma or optic
    glioma), or

    - A malignant peripheral nerve sheath tumor with a complete remission of < 1 year
    are not eligible

    - Human immunodeficiency virus (HIV) positive patients are not eligible

    Minimum Eligible Age: 3 Months

    Maximum Eligible Age: 18 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Treatment-related mortality (TRM)

    EFS

    Secondary Outcome Measures

    Relapse/non-response rates

    Graft failure rates

    Trial Keywords