Chemoimmunotherapy With Epratuzumab in Relapsed Acute Lymphoblastic Leukemia (ALL)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Feasibility Pilot and Phase II Study Of Chemoimmunotherapy With Epratuzumab (IND #12034) for Children With Relapsed CD22-Positive Acute Lymphoblastic Leukemia (ALL)

Conditions
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Recurrent Childhood Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: L-asparaginase
* Drug: doxorubicin hydrochloride
* Drug: therapeutic hydrocortisone
* Drug: vincristine sulfate
* Biological: epratuzumab
* Drug: cytarabine
* Drug: prednisone
* Drug: pegaspargase
* Drug: dexrazoxane hydrochloride
* Drug: methotrexate
* Drug: etoposide
* Drug: cyclophosphamide
* Drug: leucovorin calcium
* Biological: filgrastim


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 31 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reinduction Chemoimmunotherapy with Epratuzumab once weekly<br>Four weekly doses of epratuzumab (360 mg/m2/dose) IV days 1, 8, 15, 22. Also received vincristine sulfate, prednisone, pegaspargase, doxorubicin hydrochloride, dexrazoxane hydrochloride, etoposide, cyclophosphamide, filgrastim, high-dose (HD) methotrexate with Leucovorin calcium rescue, L-asparaginase, cytarabine, IT cytarabine, IT methotrexate (CNS-negative), Intrathecal triple therapy (ITT) (methotrexate, cytarabine, therapeutic hydrocortisone for CNS-positive) during the 3 blocks of reinduction therapy. | Drug: L-asparaginase<br>* Given IM<br>* Other names: L-ASP;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: therapeutic hydrocortisone<br>* 40 mg/m2/day PO divided BID or TID<br>* Other names: Cortef;Drug: vincristine sulfate<br>* Given IV<br>* Other names: vincristine sulfate liposome injection;Biological: epratuzumab<br>* Given IV<br>* Other names: monoclonal antibody LL2;Drug: cytarabine<br>* Given IT<br>* Other names: cytosine arabinoside;Drug: prednisone<br>* Given orally<br>* Other names: Deltra;Drug: pegaspargase<br>* Given IM<br>* Other names: PEG-L-asparaginase;Drug: dexrazoxane hydrochloride<br>* Given IV<br>* Other names: Zinecard;Drug: methotrexate<br>* Given IT<br>* Other names: MTX;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;|
| Experimental: Reinduction Chemoimmunotherapy with Epratuzumab twice weekly<br>Eight 8 twice-weekly doses of epratuzumab (360 mg/m2/dose) IV days 1, 4, 8, 11, 15, 18, 22 & 25. Also received vincristine sulfate, prednisone, pegaspargase, doxorubicin hydrochloride, dexrazoxane hydrochloride, etoposide, cyclophosphamide, filgrastim, high-dose (HD) methotrexate with Leucovorin calcium rescue, L-asparaginase, cytarabine, IT cytarabine, IT methotrexate (CNS-negative), Intrathecal triple therapy (ITT) (methotrexate, cytarabine, therapeutic hydrocortisone for CNS-positive) during the 3 blocks of reinduction therapy. | Drug: L-asparaginase<br>* Given IM<br>* Other names: L-ASP;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: Adriamycin RDF;Drug: therapeutic hydrocortisone<br>* 40 mg/m2/day PO divided BID or TID<br>* Other names: Cortef;Drug: vincristine sulfate<br>* Given IV<br>* Other names: vincristine sulfate liposome injection;Biological: epratuzumab<br>* Given IV<br>* Other names: monoclonal antibody LL2;Drug: cytarabine<br>* Given IT<br>* Other names: cytosine arabinoside;Drug: prednisone<br>* Given orally<br>* Other names: Deltra;Drug: pegaspargase<br>* Given IM<br>* Other names: PEG-L-asparaginase;Drug: dexrazoxane hydrochloride<br>* Given IV<br>* Other names: Zinecard;Drug: methotrexate<br>* Given IT<br>* Other names: MTX;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission Re-induction (CR2) Rate | The proportion of patients who achieved complete response at the end Block 1 of re-induction therapy. Complete Remission (CR) - Attainment of M1 bone marrow (<5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC >1000/uL and platelet count >100,000/uL). Partial Remission (PR) - Complete disappearance of circulating blasts and achievement of M2 marrow status (5% or < 25% blast cells and adequate cellularity). Partial Remission Cytolytic (PRCL) - Complete disappearance of circulating blasts and achievement of at least 50% reduction from baseline in bone marrow blast count. Minimal Response Cytolytic (MRCL) - 50% reduction in the peripheral blast count with no increase in peripheral white blood cell count. | At the end of Block 1 of re-induction therapy (day 36) | 
| Event-free Survival Rate | Proportion of patients who were event free at 4 months | At 4 months after enrollment | 
| Rate of Minimal Residual Disease (MRD) < 0.01% | Proportion of patients (evaluable and had MRD measured at the end of Block 1) who had MRD < 0.01%. | At the end of Block 1 of re-induction therapy (day 36) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics | Mean trough serum concentration measured before final dose of epratuzumab. | Up to day 36 |