OBJECTIVES:
Primary
- 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.
- Determine the toxic effects of this regimen in these patients.
- Determine the antitumor activity of this regimen in these patients.
Secondary
- Determine the pharmacokinetics of epratuzumab in these patients.
- Determine the biologic activity of epratuzumab using measurements of minimal residual disease in these patients.
- 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. Patients enrolled in part B are stratified according to relapse (first early marrow relapse occurring < 36 months from initial diagnosis vs first late marrow relapse occurring ≥ 36 months from initial diagnosis vs in second or subsequent relapse).
- Part A (closed to accrual as of 10/30/06):
- Reduction therapy: Patients receive epratuzumab IV over 1 hour 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) will not receive this first dose of IT cytarabine.
- Re-induction therapy (block 1): Patients receive 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 receive 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 receive etoposide IV over 2 hours and cyclophosphamide IV over 30 minutes on days 1-5. Patients also receive high-dose methotrexate IV continuously over 24 hours on day 22. Beginning 42 hours after the start of the methotrexate infusion (day 24), patients receive 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 receive 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 receive cytarabine IV over 3 hours twice daily on days 1, 2, 8, and 9 and asparaginase IM on days 2 and 9. Patients receive G-CSF SC once daily beginning on day 10 and continuing until blood counts recover.
- Part B:
- Re-induction therapy (block 1): Patients receive vincristine, prednisone, pegaspargase, doxorubicin, cytarabine, methotrexate, and epratuzumab as in phase I re-induction therapy (block 1). Patients with CNS-negative disease receive methotrexate IT on days 1 and 22. Patients with CNS-positive disease receive triple IT therapy comprising methotrexate, cytarabine, and hydrocortisone on days 8, 15, 22, and 29.
- Re-induction therapy (blocks 2 and 3): Patients receive 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.
PROJECTED ACCRUAL: A total of 116 patients will be accrued for this study.
DISEASE CHARACTERISTICS:
- Diagnosis of B-cell precursor acute lymphoblastic leukemia (ALL)
- At least 25% expression of CD22 by immunophenotyping
- In marrow relapse (M3 bone marrow) with or without associated extramedullary disease as defined by 1 of the following:
- In first or later marrow relapse occurring any time after initial diagnosis (part A [closed to accrual as of 10/30/06] or B)
- In first, early marrow relapse with or without associated extramedullary disease occurring < 36 months from the time of initial diagnosis (part B only)
- No B-cell L3 morphology OR evidence of MYC translocation by molecular or cytogenetic analysis
- No Down syndrome
- Patients with CNS or other extramedullary site involvement are allowed
PATIENT CHARACTERISTICS:
Age
- 2 to 31 years old
Performance status
- Karnofsky 50-100% (for patients > 10 years of age)
- Lansky 50-100% (for patients ≤ 10 years of age)
Life expectancy
- Not specified
Hematopoietic
- WBC ≤ 50,000/mm^3 (part A only [closed to accrual as of 10/30/06])
Hepatic
- Bilirubin ≤ 1.5 times upper limit of normal (ULN)
- ALT ≤ 5 times ULN ( unless disease-related)
- Albumin ≥ 2 g/dL
Renal
- Creatinine clearance OR radioisotope glomerular filtration rate ≥ 70 mL/min OR
- Creatinine as defined by age as follows:
- ≤ 0.5 mg/dL (for patients < 1 year old)
- ≤ 0.8 mg/dL (for patients 1 to 5 years old)
- ≤ 1.0 mg/dL (for patients 6 to 10 years old)
- ≤ 1.2 mg/dL (for patients 11 to 15 years old)
- ≤ 1.5 mg/dL (for patients > 15 years old)
Cardiovascular
- Shortening fraction ≥ 27% by echocardiogram OR
- Ejection fraction ≥ 45% by MUGA
Pulmonary
- No dyspnea at rest
- No exercise intolerance
- Pulse oximetry > 94%
Other
- No active or uncontrolled infection
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
PRIOR CONCURRENT THERAPY:
Biologic therapy
- Recovered from prior immunotherapy
- At least 4 months since prior stem cell transplantation or rescue AND no evidence of active graft-vs-host disease
- At least 7 days since prior hematopoietic growth factors
- At least 7 days since prior biologic therapy*
- No other concurrent immunotherapy
- No other concurrent biologic therapy NOTE: *A longer washout period may be required for agents with known adverse events that occur beyond 7 days after administration
Chemotherapy
- Recovered from prior chemotherapy
- No waiting period for children who relapse while receiving standard ALL maintenance therapy
- No prior cumulative anthracycline exposure > 400 mg/m^2*
- No concurrent chemotherapy NOTE: *Each 10 mg/m2 of idarubicin should be calculated as the isotoxic equivalent of 30 mg/m2 of daunorubicin or doxorubicin
Endocrine therapy
- Not specified
Radiotherapy
- Recovered from prior radiotherapy
- No concurrent radiotherapy
Surgery
- Not specified
Other
- At least 2 days since prior hydroxyurea
- No other concurrent investigational drugs
- No other concurrent anticancer agents
Last updated: 08/03/2012
NCT ID: NCT00098839
IRB Number:08-007058
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