Chemoimmunotherapy With Epratuzumab in Relapsed Acute Lymphoblastic Leukemia (ALL)

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.

Inclusion Criteria:

- Diagnosis of B lymphoblastic leukemia (B-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 a regulator gene that codes for a transcription
factor (MYC) translocation by molecular or cytogenetic analysis

- No Down syndrome

- Patients with CNS or other extramedullary site involvement are allowed

- Performance status - Karnofsky 50-100% (for patients > 10 years of age)

- Performance status - Lansky 50-100% (for patients ≤ 10 years of age)

- White Blood Count (WBC) ≤ 50,000/mm^3 (part A only [closed to accrual as of 10/30/06])

- Bilirubin ≤ 1.5 times upper limit of normal unless disease-related (ULN)

- Alanine aminotransferase (ALT) ≤ 5 times ULN

- Albumin ≥ 2 g/dL

- Creatinine clearance OR radioisotope glomerular filtration rate ≥ 70 mL/min

- 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)

- Shortening fraction ≥ 27% by echocardiogram

- Ejection fraction ≥ 45% by Multi Gated Acquisition Scan (MUGA)

- No dyspnea at rest

- No exercise intolerance

- Pulse oximetry > 94%

- No active or uncontrolled infection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- 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

- 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

- Recovered from prior radiotherapy

- No concurrent radiotherapy

- At least 2 days since prior hydroxyurea

- No other concurrent investigational drugs

- No other concurrent anticancer agents