Chemoimmunotherapy With Epratuzumab in Relapsed Acute Lymphoblastic Leukemia (ALL)
Condition: Recurrent Childhood Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This Phase II trial is studying how well giving epratuzumab together with an established
      chemotherapy platform works in treating young patients with relapsed acute lymphoblastic
      leukemia. Monoclonal antibodies, such as epratuzumab, can block cancer growth in different
      ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and
      help kill them or carry cancer-killing substances to them. Chemotherapy drugs work in
      different ways to stop the growth of cancer cells, either by killing them or by stopping them
      from dividing. Giving monoclonal antibody therapy in combination chemotherapy may kill cancer
      cells more effectively.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. Determine the feasibility of epratuzumab administered alone and in combination with
      re-induction combination chemotherapy in pediatric patients with relapsed CD22-positive acute
      lymphoblastic leukemia.

      II. Determine the toxic effects of this regimen in these patients.

      III. Determine the antitumor activity of this regimen in these patients.

      IV. To estimate the remission re-induction rate and four-month event-free survival (EFS) for
      patients with early first relapse ALL who receive epratuzumab in combination with cytotoxic
      thermotherapy.

      SECONDARY OBJECTIVES:

      I. Determine the pharmacokinetics of epratuzumab in these patients. II. Determine the
      biologic activity of epratuzumab using measurements of minimal residual disease in these
      patients.

      III. Determine the human anti-human antibody (HAHA) response in patients treated with this
      regimen.

      OUTLINE: This is a multicenter study comprising a feasibility part A (closed to accrual as of
      10/30/06) followed by a pilot part B study. A Simon's two stage design was initially used to
      evaluate the efficacy of the once weekly dosing schedule for part B patients (called B1
      cohort), which planned to accrue a total of 112 patients with 56 to be enrolled at the first
      stage. After completion the accrual of stage 1, i.e. after 56 patients were enrolled, the
      design of part B was revised to evaluate a modified doing schedule (twice weekly doing,
      called B2 cohort) using a stratified two-stage design by London and Chang (2005), where
      patients enrolled to B2 were stratified according to relapse (first early marrow relapsed
      occurring < 18 months from initial diagnosis vs 18-36 months from initial diagnosis).

      PART A (CLOSED TO ACCRUAL 10/30/06):

      REDUCTION THERAPY: Patients receive epratuzumab IV over several hours on days -14, -10, -6,
      and -2 and cytarabine intrathecally (IT) on day -14*.

      NOTE: *Patients who receive IT chemotherapy within 7 days of study entry as prior maintenance
      chemotherapy (e.g., before the diagnosis of relapse) did not receive this first dose of IT
      cytarabine.

      RE-INDUCTION THERAPY (BLOCK 1): Patients received vincristine IV on days 1, 8, 15, and 22;
      oral prednisone two or three times daily on days 1-29; pegaspargase intramuscularly (IM) on
      days 2, 9, 16, and 23; dexrazoxane IV followed by doxorubicin IV over 15 minutes on day 1;
      methotrexate IT on days 15 and 29 for CNS-negative disease; and epratuzumab IV over 1 hour on
      days 8, 15, 22, and 29. Patients with CNS-positive disease also received triple IT therapy
      (ITT) consisting of methotrexate, cytarabine, hydrocortisone on days -10, -6, 1 and 15.

      RE-INDUCTION THERAPY (BLOCK 2): Beginning at least 7 days after the last dose of IT
      chemotherapy, patients received etoposide IV over 2 hours and cyclophosphamide IV over 30
      minutes on days 1-5. Patients also received high-dose methotrexate IV continuously over 24
      hours on day 22. Beginning 42 hours after the start of the methotrexate infusion (day 24),
      patients received leucovorin calcium IV every 6 hours for a minimum of 3 doses. Patients with
      CNS-negative disease also receive methotrexate IT on days 1 and 22. Patients with
      CNS-positive disease will receive triple IT as in re-induction therapy (block 1) on days 1
      and 22. Patients received filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day
      6 and continuing until blood counts recover.

      RE-INDUCTION THERAPY (PART 3): Beginning at least 7 days after the last dose of IT
      chemotherapy, patients received cytarabine IV over 3 hours twice daily on days 1, 2, 8, and 9
      and native E. Coli asparaginase IM on days 2 and 9. Patients receive G-CSF SC once daily
      beginning on day 10 and continuing until blood counts recovered.

      PART B:

      RE-INDUCTION THERAPY (BLOCK 1): Patients received vincristine, prednisone, pegaspargase,
      doxorubicin, cytarabine, methotrexate, and epratuzumab as in phase I re-induction therapy
      (block 1). Epratuzumab was given on Days 1, 8, 15 and 22 before amendment 5 (B1 cohort) and
      on Days 1, 4, 8, 11, 15, 18, 22 and 25 after amendment 5 (B2 cohort) Patients with
      CNS-negative disease received methotrexate IT on days 1 and 22. Patients with CNS-positive
      disease received triple IT therapy comprising methotrexate, cytarabine, and hydrocortisone on
      days 8, 15, 22, and 29.

      RE-INDUCTION THERAPY (BLOCKS 2 AND 3): Patients received re-induction therapy blocks 2 and 3
      as in the part A re-induction therapy (blocks 2 and 3) portion of the study.

      Patients are followed annually.
    

Intervention name(s): L-asparaginase; doxorubicin hydrochloride; therapeutic hydrocortisone; vincristine sulfate; epratuzumab; cytarabine; prednisone; pegaspargase; dexrazoxane hydrochloride; methotrexate; etoposide; cyclophosphamide; leucovorin calcium; filgrastim
Intervention type(s): Drug; Drug; Drug; Drug; Biological; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Biological
Intervention description(s): Given IM; Given IV; 40 mg/m2/day PO divided BID or TID; Given IV; Given IV; Given IT; Given orally; Given IM; Given IV; Given IT; Given IV; Given IV; Given IV; Given SC
Other intervention name(s): ASNase; Colaspase; Crasnitin; Elspar; L-ASP; ADM; ADR; Adria; Adriamycin PFS; Adriamycin RDF; Aeroseb-HC; Barseb HC; Cetacort; Cort-Dome; Cortef; liposomal vincristine; Marqibo; vincristine liposomal; vincristine sulfate liposome injection; AMG 412; LL2; MOAB LL2; monoclonal antibody LL2; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Cytosar-U; cytosine arabinoside; DeCortin; Deltra; L-asparaginase with polyethylene glycol; Oncaspar; PEG-ASP; PEG-L-asparaginase; Cardioxane; Savene; Totect; Zinecard; amethopterin; Folex; methylaminopterin; Mexate; MTX; EPEG; VP-16; VP-16-213; CPM; CTX; Cytoxan; Endoxan; Endoxana; CF; CFR; LV; G-CSF; Neupogen
Intervention MeSH terms: Leucovorin; Cytarabine; Prednisone; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Etoposide phosphate; Asparaginase; Pegaspargase; Epratuzumab; Dexrazoxane; Razoxane; Levoleucovorin
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment