ADVL04P2: A Phase 1/2 Pilot Study of Chemoimmunotherapy with Epratuzumab for Children with Relapsed CD22-Positive Acute Lymphoblastic Leukemia
Date Last Modified: 05-01-2006
Date First Published: 10-05-2005
| Type | Status | Age Range (yrs.) | Sponsor | Protocol ID |
|---|
| Treatment | Active | 21 and under | COG | ADVL04P2 |
Outline
This is a multicenter study comprising a feasibility part A followed by a phase II, pilot part B study.
Part A:
- 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.
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.
Projected Accrual
A total of 52 will be accrued for this study.
Entry Criteria
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 or B)
- In first marrow relapse (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
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/m2*
- 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
Radiotherapy
- No concurrent radiotherapy
- Recovered from prior radiotherapy
Surgery
Other
- No other concurrent investigational drugs
- At least 2 days since prior hydroxyurea
- No other concurrent anticancer agents
Patient Characteristics
Age
Performance status
- Karnofsky 50-100% (for patients > 10 years of age)
- Lansky 50-100% (for patients ≤ 10 years of age)
Life expectancy
Hematopoietic
- WBC ≤ 50,000/mm3 (Part A only)
Hepatic
- Bilirubin ≤ 1.5 times upper limit of normal (ULN)
- ALT ≤ 5 times ULN
- 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 evidence of dyspnea at rest
- No exercise intolerance
- Pulse oximetry > 94%
Other
- Not pregnant or nursing
- No active or uncontrolled infection
- Negative pregnancy test
- Fertile patients must use effective contraception
Who should I contact for more information?
Rebecca Turner, CCRP
Cincinnati Children's Hospital Medical Center
Division of Hematology / Oncology
3333 Burnet Ave., Cincinnati, OH 45229-3039
Phone: 513-636-2799
cancer@cchmc.org
