Combination Chemotherapy and Imatinib Mesylate in Treating Children With Relapsed Acute Lymphoblastic Leukemia
Condition: L1 Childhood Acute Lymphoblastic Leukemia; L2 Childhood Acute Lymphoblastic Leukemia; Non-T, Non-B Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional

Summary: 
      Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop
      growing or die. Imatinib mesylate may stop the growth of cancer cells by blocking the enzymes
      necessary for cancer cell growth. Combining more than one chemotherapy drug with imatinib
      mesylate may kill more cancer cells. Randomized phase II trial to study the effectiveness of
      combination chemotherapy and imatinib mesylate in treating children who have relapsed acute
      lymphoblastic leukemia.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. To assess the feasibility and safety of using an intensified sequential induction regimen
      to treat children with acute lymphoblastic leukemia (ALL), who experience an isolated, or
      combined bone marrow relapse.

      II. To determine the potential of this regimen to serve, as a backbone, for the future
      testing of novel therapeutic agents.

      SECONDARY OBJECTIVES:

      I. To estimate the remission re-induction rates and four-month event-free survival (EFS) for
      children, stratified by the duration of first remission.

      II. To determine the feasibility of measuring minimal residual disease (MRD) quantitatively
      in all patients at time points throughout re-induction, and to correlate post-remission
      events with disease burden during induction.

      III. To use deoxyribonucleic acid (DNA) arrays to characterize patterns of gene expression
      that predict treatment failure, and to compare gene expression profiles at the time of
      relapse with those at the time of initial diagnosis to gain an understanding of the pathways
      that may be involved in disease recurrence.

      IV. To determine the feasibility of combining intensive re-induction therapy with imatinib
      mesylate (STI571) for children with a relapse of Philadelphia chromosome positive (Ph+) ALL.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I:

      Treatment Block 1: Patients receive cytarabine intrathecally (IT) on day 1 and methotrexate
      IT on days 15 and 29. Patients also receive vincristine intravenously (IV) on days 1, 8, 15,
      and 22; prednisone orally (PO) twice or thrice daily (BID or TID) on days 1-29; pegaspargase
      intramuscularly (IM) on days 2, 8, 15, and 22; and doxorubicin IV over 15 minutes on day 1.
      Ph-positive patients also receive imatinib mesylate PO on days 1-14.

      Treatment Block 2: Patients receive methotrexate IT on days 1 and 22, cyclophosphamide IV
      over 30 minutes and etoposide IV over 2 hours on days 1-5, and filgrastim (G-CSF)
      subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. Patients
      also receive methotrexate IV over 24 hours on day 22 followed by leucovorin calcium IV every
      6 hours on days 24 and 25. Ph-positive patients receive imatinib mesylate PO on days 1-14.

      Treatment Block 3a (Ph-negative patients): Patients receive cytarabine IV over 3 hours every
      12 hours on days 1, 2, 8, and 9, asparaginase IM on days 2 and 9, and G-CSF SC beginning on
      day 10 and continuing until blood counts recover.

      Treatment Block 3b (Ph-positive patients): Patients receive cytarabine IV over 3 hours every
      12 hours on days 1 and 2, asparaginase IM on day 2, and G-CSF SC beginning on day 3 and
      continuing until blood counts recover. Patients also receive imatinib mesylate PO on days
      1-14.

      ARM II:

      Treatment Block 1: Patients receive cytarabine IT on day 1 and then methotrexate, cytarabine
      and hydrocortisone IT (triple intrathecal therapy; TIT) on days 8, 15, 22, and 29.
      Vincristine, prednisone, pegaspargase, doxorubicin, and imatinib mesylate are administered as
      in arm I.

      Treatment Block 3: Patients receive cytarabine, asparaginase, G-CSF, and imatinib mesylate as
      in arm I.

      Treatment Block 2: Patients receive TIT on days 1 and 22. Patients then receive
      cyclophosphamide, etoposide, G-CSF, methotrexate IV, leucovorin calcium, and imatinib
      mesylate as in arm I. After each block is completed, disease is assessed. The next block is
      started on day 36 if blood counts have recovered and marrow during block 1 is at least M2/M3.
      Patients are removed from protocol therapy if disease progresses, unacceptable toxicity
      occurs, marrow is M2/M3 at day 15 of the second administered block of treatment, or
      cerebrospinal fluid blasts persist after 6 weekly doses of TIT.

      After completion of study treatment, patients are followed up for 4 months.

      PROJECTED ACCRUAL: A total of 63-126 patients will be accrued for this study within 14
      months.
    

Intervention name(s): cytarabine; methotrexate; vincristine sulfate; prednisone; pegaspargase; doxorubicin hydrochloride; imatinib mesylate; cyclophosphamide; etoposide; filgrastim; leucovorin calcium; asparaginase; therapeutic hydrocortisone
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Biological; Drug; Drug; Drug
Intervention description(s): Given IT; Given IT; Given IV; Given PO; Given IM; Given IV; Given PO; Given IV; Given IV; Given SC; Given IV; Given IM; Given IT
Intervention MeSH terms: Leucovorin; Cytarabine; Prednisone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Imatinib Mesylate; Asparaginase; Pegaspargase; Levoleucovorin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment