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Rituximab, Rasburicase, and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Advanced B-Cell Leukemia or Lymphoma

Primary Purpose

Childhood Burkitt Lymphoma, Childhood Diffuse Large Cell Lymphoma, Childhood Immunoblastic Large Cell Lymphoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
doxorubicin hydrochloride
cyclophosphamide
methotrexate
rasburicase
leucovorin calcium
prednisone
methylprednisolone
filgrastim
rituximab
cytarabine
etoposide
vincristine sulfate
hydrocortisone sodium succinate
laboratory biomarker analysis
Sponsored by
Children's Oncology Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Childhood Burkitt Lymphoma

Eligibility Criteria

1 Year - 29 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Newly diagnosed mature B-lineage (CD20-positive) leukemia or lymphoma by the REAL classification of 1 of the following subtypes: Diffuse large cell lymphoma Burkitt's lymphoma High-grade B-cell lymphoma (Burkitt-like) No B-cell anaplastic large cell Ki-1 positive lymphomas and B-lymphoblastic lymphomas One of the following FAB prognostic groups: Group B (intermediate risk) Group C (high risk) Bone marrow involvement with at least 25% blasts and/or CNS involvement meeting 1 or more of the following criteria: Any L3 blasts in cerebrospinal fluid Cranial nerve palsy (if not explained by extracranial tumor) Clinical spinal cord compression Isolated intracerebral mass Parameningeal extension (cranial and/or spinal) Hepatitis B status known Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after study participation No known history of congenital immune deficiency and/or laboratory evidence of acquired immune deficiency No known G6PD deficiency (if receiving rasburicase) No prior malignancies treated with systemic chemotherapy with alkylator or anthracycline therapy No prior chemotherapy At least 1 week since prior steroids except emergency steroids initiated within 72 hours of study entry No prior radiotherapy except emergency radiotherapy initiated within 72 hours of study entry No concurrent radiotherapy No prior solid organ transplantation

Sites / Locations

  • Children's Oncology Group

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group B (chemotherapy, protective therapy, monoclonal antib.)

Group C (Chemotherapy, monoclonal antibody therapy)

Arm Description

Therapies given IV, IT, orally, or SC. Please see treatment outline. See Detailed Description.

Therapies given IV, IT, orally, or subcutaneously (same as FAB B with the addition of etoposide and high-dose methotrexate). See Detailed Description.

Outcomes

Primary Outcome Measures

Grade ≥ 3 Stomatitis
The incidence of grade ≥ 3 stomatitis. Grade 3 stomatitis: Confluent ulcerations or pseudomembranes; bleeding with minor trauma. Grade 4 stomatitis: Tissue necrosis; Significant spontaneous bleeding; life-threatening consequences
Response Rate
Response includes both complete and partial responses. Per protocol, complete Response is defined as the complete disappearance of all clinical evidence of disease by physical examination, by imaging studies, by bone marrow biopsy (where indicated), by CNS evaluation (where indicated) and by biopsy where there is a residual abnormality on an imaging study. Bone marrow must contain <5% blasts. CSF WBC must be <5/μL with no blasts or lymphomatous cells present. Partial response is defined as: at least a 50% reduction in the size of all measurable tumor areas. Each site is to be defined by the product of the maximum length, width and depth (3 dimensions). No lesion may progress. No new lesion may appear. Bone marrow must contain <5% blasts. CSF WBC must be <5/μL with no blasts or lymphomatous cells present..
Minimal Residual Disease
The presence or absence of tumor cells at the end of induction assessed by studying tissue and/or blood/marrow. Details of methods and criteria used can be found in Shiramizu at al. BJH 153:758-763, 2011 (full citation in the citation section).
Toxic Death
Implementation of the toxic death rate stopping rule, a death must be possibly, probably or definitely attributable to Rituximab and/or chemotherapy to be considered a toxic death.

Secondary Outcome Measures

Full Information

First Posted
April 7, 2003
Last Updated
September 10, 2014
Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00057811
Brief Title
Rituximab, Rasburicase, and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Advanced B-Cell Leukemia or Lymphoma
Official Title
A Pilot Study To Determine The Toxicity Of The Addition Of Rituximab To The Induction And Consolidation Phases And The Addition Of Rasburicase To The Reduction Phase In Children With Newly Diagnosed Advanced B-Cell Leukemia/Lymphoma Treated With LMB/FAB Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
September 2014
Overall Recruitment Status
Completed
Study Start Date
June 2004 (undefined)
Primary Completion Date
October 2009 (Actual)
Study Completion Date
July 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Phase II trial to study the effectiveness of combining rituximab and rasburicase with combination chemotherapy in treating young patients who have newly diagnosed advanced B-cell leukemia or lymphoma. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug with rituximab may kill more cancer cells. Chemoprotective drugs such as rasburicase may protect kidney cells from the side effects of chemotherapy.
Detailed Description
OBJECTIVES: I. Determine the toxicity of the addition of rituximab to induction chemotherapy comprising vincristine, methylprednisolone, methotrexate, leucovorin calcium, cyclophosphamide, and doxorubicin (COPADM) [COMRAP] and to consolidation chemotherapy in children with newly diagnosed FAB prognostic group B or group C leukemia or lymphoma treated with LMB/FAB therapy. II. Determine the toxicity of the addition of rasburicase to the reduction phase comprising cyclophosphamide, vincristine, prednisone or methylprednisolone, methotrexate, and leucovorin calcium (COP-R) in these patients. III. Determine the incidence of tumor lysis syndrome, renal complications, and the use of assisted renal support (i.e., dialysis or hemofiltration) during the COP-R reduction phase and the first induction phase of COPADM or COMRAP in these patients. IV. Determine the response rate of patients treated with COMRAP incorporated into LMB/FAB therapy. V. Assess minimal residual disease in patients before and during COMRAP therapy incorporated into LMB/FAB therapy. OUTLINE: This is a multicenter study. Patients are stratified according to FAB prognostic group (B vs C) and treated by group classification. FAB GROUP B TREATMENT I (first 6 patients): REDUCTION THERAPY: Patients receive the COP-R regimen comprising cyclophosphamide IV over 15 minutes, vincristine IV, and methotrexate and hydrocortisone intrathecally (IT) on day 0; rasburicase* IV over 30 minutes every 12 hours on days 0 and 1 and then once daily on days 2-4 (patients exhibiting hyperuricemia and clinical suspicion of B-cell non-Hodgkin's lymphoma or B-cell acute lymphocytic leukemia also receive rasburicase on days -3, -2, and -1); leucovorin calcium IV or orally every 12 hours on days 1 and 3; and prednisone (PRED) or methylprednisolone (MePRDL) IV (or orally) on days 0-6. Patients too critical to proceed may receive another course of reduction therapy. NOTE: *Patients with G6PD deficiency do not receive rasburicase during reduction therapy. INDUCTION THERAPY: Patients with less than 20% tumor reduction follow the group C induction phase (described below). Patients with at least 20% tumor reduction receive 1 course of the COPADM regimen: vincristine IV and methotrexate IV over 4 hours on day 0; PRED or MePRDL IV (or orally) on days 0-7; leucovorin calcium IV or orally every 6 hours for 12 doses on days 1-3; doxorubicin IV over 30-60 minutes on day 1; cyclophosphamide IV over 15 minutes every 12 hours on days 1-3; methotrexate IT and hydrocortisone IT on days 1 and 5; and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover. Patients receive the second part of induction therapy when peripheral blood counts have recovered but no fewer than 16 days after the first part of induction therapy. Patients receive 1 course of the COMRAP regimen comprising rituximab IV on days -2 and 0 with COPADM as in the first part of induction therapy. CONSOLIDATION THERAPY: Patients receive the CYM-RM regimen comprising rituximab IV and methotrexate IV over 4 hours on day 0; leucovorin calcium IV or orally every 6 hours for 12 doses on days 1-3; cytarabine IV over 24 hours daily on days 1-5; hydrocortisone IT on days 1 and 6; methotrexate IT on day 1; and cytarabine IT on day 6. After full recovery from consolidation therapy, patients with any residual masses undergo surgical excision or biopsy. Patients with histology positive for tumor (even if completely resected) proceed to Group C consolidation therapy (described below). Patients with histology negative for tumor proceed to Group B maintenance therapy. MAINTENANCE THERAPY: Patients receive the COPADM regimen comprising vincristine IV and methotrexate IV over 4 hours on day 0; PRED or MePRDL IV (or orally) on days 0-7; doxorubicin IV over 30-60 minutes, and cyclophosphamide IV over 30 minutes on days 1 and 2; methotrexate IT and hydrocortisone IT on day 1; and leucovorin calcium IV or orally every 6 hours on days 1-3 (12 doses). TREATMENT II (44 patients): REDUCTION THERAPY: Patients receive the COP-R regimen as in treatment I. INDUCTION THERAPY: Patients receive 2 courses of the COMRAP regimen as in the second induction of treatment I. CONSOLIDATION THERAPY: Patients receive the CYM-RM regimen as in treatment I. MAINTENANCE THERAPY: Patients receive the COPADM regimen as in treatment I. FAB GROUP C: TREATMENT I (first 3 patients): REDUCTION THERAPY: Patients receive the COP-R regimen as in group B treatment I, with the addition of triple intrathecal therapy (TIT) comprising methotrexate, hydrocortisone, and cytarabine on days 0, 2, and 4. INDUCTION THERAPY: Patients receive 2 courses of the COPADM regimen as in group B treatment I, with the addition of TIT on days 1, 3, and 5. Patients in group C who have biopsy-proven disease after induction therapy are off protocol therapy and treated at the discretion of the investigator. CONSOLIDATION THERAPY: CNS-POSITIVE DISEASE: Patients receive 2 courses of the CYVE-RM regimen comprising rituximab IV and methotrexate and hydrocortisone IT on day 0; cytarabine IV over 12 hours on days 0-4; high-dose cytarabine IV over 3 hours and etoposide IV over 2 hours on days 1-4; and G-CSF SC on days 6-20. During the first course, patients also receive HD-MTX IV over 4 hours on day 17; TIT on day 18; and leucovorin calcium IV or orally every 6 hours on days 18-21 (12 doses). CNS-NEGATIVE DISEASE: Patients receive the CYVE-RM regimen without intrathecal therapy, HD-MTX, or leucovorin calcium. After full recovery from consolidation therapy, patients with any residual masses undergo surgical excision or biopsy. Patients who do not achieve complete remission after consolidation therapy are considered treatment failures. MAINTENANCE THERAPY (each course lasts 28 days): COURSE M1: Patients receive vincristine IV and high-dose methotrexate IV over 4 hours on day 0; PRED or MePRDL IV (or orally) on days 0-7; doxorubicin IV over 30-60 minutes and TIT on day 1; cyclophosphamide IV over 30 minutes on days 1 and 2; and leucovorin calcium IV or orally every 6 hours on days 1-4 (12 doses). COURSE M2: Patients receive etoposide IV over 90 minutes on days 0-2 and cytarabine SC every 12 hours on days 0-4. COURSE M3: Patients receive vincristine IV on day 0; cyclophosphamide IV over 30 minutes on days 0 and 1; PRED or MePRDL IV (or orally) twice daily on days 0-7; and doxorubicin IV over 30-60 minutes on day 0 (after first dose of cyclophosphamide). COURSE M4: Patients receive etoposide and cytarabine as in course M2. TREATMENT II (37 patients): REDUCTION THERAPY: Patients receive 2 courses of the COP-R regimen as in group C treatment I. INDUCTION THERAPY: Patients receive the COMRAP regimen comprising rituximab IV, vincristine IV, and HD-MTX IV over 4 hours on day 0; PRED or MePRDL IV (or orally) on days 0-7; leucovorin calcium IV or orally and cyclophosphamide IV over 15 minutes on days 1-3; doxorubicin IV over 30-60 minutes on day 1; TIT on days 1, 3, and 5; and G-CSF SC on days 6-20. CONSOLIDATION THERAPY: CNS-positive disease: Patients receive the CYVE-RM regimen plus HD-MTX as in group C treatment I. Patients then receive CYVE-RM for a second course. CNS-NEGATIVE DISEASE: Patients receive CYVE-RM regimen as in group C treatment I. MAINTENANCE THERAPY: Patients receive maintenance therapy as in group C treatment I. Patients are followed every 3-6 months for 1 year and then every 6 months for up to 5 years

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Childhood Burkitt Lymphoma, Childhood Diffuse Large Cell Lymphoma, Childhood Immunoblastic Large Cell Lymphoma, Stage I Childhood Large Cell Lymphoma, Stage I Childhood Small Noncleaved Cell Lymphoma, Stage II Childhood Large Cell Lymphoma, Stage II Childhood Small Noncleaved Cell Lymphoma, Stage III Childhood Large Cell Lymphoma, Stage III Childhood Small Noncleaved Cell Lymphoma, Stage IV Childhood Large Cell Lymphoma, Stage IV Childhood Small Noncleaved Cell Lymphoma, Untreated Childhood Acute Lymphoblastic Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
97 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group B (chemotherapy, protective therapy, monoclonal antib.)
Arm Type
Experimental
Arm Description
Therapies given IV, IT, orally, or SC. Please see treatment outline. See Detailed Description.
Arm Title
Group C (Chemotherapy, monoclonal antibody therapy)
Arm Type
Experimental
Arm Description
Therapies given IV, IT, orally, or subcutaneously (same as FAB B with the addition of etoposide and high-dose methotrexate). See Detailed Description.
Intervention Type
Drug
Intervention Name(s)
doxorubicin hydrochloride
Other Intervention Name(s)
ADM, ADR, Adria, Adriamycin PFS, Adriamycin RDF
Intervention Description
Given IV, IT, or orally
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
CPM, CTX, Cytoxan, Endoxan, Endoxana
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
methotrexate
Other Intervention Name(s)
amethopterin, Folex, methylaminopterin, Mexate, MTX
Intervention Description
Given IV or IT
Intervention Type
Drug
Intervention Name(s)
rasburicase
Other Intervention Name(s)
Elitek, NK-631, recombinant urate oxidase
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
leucovorin calcium
Other Intervention Name(s)
CF, CFR, LV
Intervention Description
Given IV or orally
Intervention Type
Drug
Intervention Name(s)
prednisone
Other Intervention Name(s)
DeCortin, Deltra
Intervention Description
Given IV or orally
Intervention Type
Drug
Intervention Name(s)
methylprednisolone
Other Intervention Name(s)
Depo-Medrol, Medrol, MePRDL, Solu-Medrol, Wyacort
Intervention Description
Given IV or orally
Intervention Type
Biological
Intervention Name(s)
filgrastim
Other Intervention Name(s)
G-CSF, Neupogen
Intervention Description
Given subcutaneously
Intervention Type
Biological
Intervention Name(s)
rituximab
Other Intervention Name(s)
IDEC-C2B8, IDEC-C2B8 monoclonal antibody, Mabthera, MOAB IDEC-C2B8, Rituxan
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
cytarabine
Other Intervention Name(s)
ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside
Intervention Description
Given IT
Intervention Type
Drug
Intervention Name(s)
etoposide
Other Intervention Name(s)
EPEG, VP-16, VP-16-213
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
vincristine sulfate
Other Intervention Name(s)
leurocristine sulfate, VCR, Vincasar PFS
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
hydrocortisone sodium succinate
Other Intervention Name(s)
Sodium hydrocortisone succinate, Solu-Cortef, Solu-Glyc
Intervention Description
Given IT
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Grade ≥ 3 Stomatitis
Description
The incidence of grade ≥ 3 stomatitis. Grade 3 stomatitis: Confluent ulcerations or pseudomembranes; bleeding with minor trauma. Grade 4 stomatitis: Tissue necrosis; Significant spontaneous bleeding; life-threatening consequences
Time Frame
Up to 1 year
Title
Response Rate
Description
Response includes both complete and partial responses. Per protocol, complete Response is defined as the complete disappearance of all clinical evidence of disease by physical examination, by imaging studies, by bone marrow biopsy (where indicated), by CNS evaluation (where indicated) and by biopsy where there is a residual abnormality on an imaging study. Bone marrow must contain <5% blasts. CSF WBC must be <5/μL with no blasts or lymphomatous cells present. Partial response is defined as: at least a 50% reduction in the size of all measurable tumor areas. Each site is to be defined by the product of the maximum length, width and depth (3 dimensions). No lesion may progress. No new lesion may appear. Bone marrow must contain <5% blasts. CSF WBC must be <5/μL with no blasts or lymphomatous cells present..
Time Frame
Up to 5 years
Title
Minimal Residual Disease
Description
The presence or absence of tumor cells at the end of induction assessed by studying tissue and/or blood/marrow. Details of methods and criteria used can be found in Shiramizu at al. BJH 153:758-763, 2011 (full citation in the citation section).
Time Frame
Not Provided
Title
Toxic Death
Description
Implementation of the toxic death rate stopping rule, a death must be possibly, probably or definitely attributable to Rituximab and/or chemotherapy to be considered a toxic death.
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
29 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Newly diagnosed mature B-lineage (CD20-positive) leukemia or lymphoma by the REAL classification of 1 of the following subtypes: Diffuse large cell lymphoma Burkitt's lymphoma High-grade B-cell lymphoma (Burkitt-like) No B-cell anaplastic large cell Ki-1 positive lymphomas and B-lymphoblastic lymphomas One of the following FAB prognostic groups: Group B (intermediate risk) Group C (high risk) Bone marrow involvement with at least 25% blasts and/or CNS involvement meeting 1 or more of the following criteria: Any L3 blasts in cerebrospinal fluid Cranial nerve palsy (if not explained by extracranial tumor) Clinical spinal cord compression Isolated intracerebral mass Parameningeal extension (cranial and/or spinal) Hepatitis B status known Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after study participation No known history of congenital immune deficiency and/or laboratory evidence of acquired immune deficiency No known G6PD deficiency (if receiving rasburicase) No prior malignancies treated with systemic chemotherapy with alkylator or anthracycline therapy No prior chemotherapy At least 1 week since prior steroids except emergency steroids initiated within 72 hours of study entry No prior radiotherapy except emergency radiotherapy initiated within 72 hours of study entry No concurrent radiotherapy No prior solid organ transplantation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mitchell Cairo, MD CCRP
Organizational Affiliation
Children's Oncology Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
Children's Oncology Group
City
Arcadia
State/Province
California
ZIP/Postal Code
91006-3776
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
21496005
Citation
Shiramizu B, Goldman S, Kusao I, Agsalda M, Lynch J, Smith L, Harrison L, Morris E, Gross TG, Sanger W, Perkins S, Cairo MS. Minimal disease assessment in the treatment of children and adolescents with intermediate-risk (Stage III/IV) B-cell non-Hodgkin lymphoma: a children's oncology group report. Br J Haematol. 2011 Jun;153(6):758-63. doi: 10.1111/j.1365-2141.2011.08681.x. Epub 2011 Apr 18.
Results Reference
background
PubMed Identifier
30117142
Citation
Frazer JK, Li KJ, Galardy PJ, Perkins SL, Auperin A, Anderson JR, Pinkerton R, Buxton A, Gross TG, Michon J, Leverger G, Weinstein HJ, Harrison L, Shiramizu B, Barth MJ, Goldman SC, Patte C, Cairo MS. Excellent outcomes in children and adolescents with CNS+ Burkitt lymphoma or other mature B-NHL using only intrathecal and systemic chemoimmunotherapy: results from FAB/LMB96 and COG ANHL01P1. Br J Haematol. 2019 Apr;185(2):374-377. doi: 10.1111/bjh.15520. Epub 2018 Aug 16. No abstract available.
Results Reference
derived

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Rituximab, Rasburicase, and Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Advanced B-Cell Leukemia or Lymphoma

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