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

Childhood Diffuse Large Cell Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00057811
• Other study ID #: ANHL01P1
• Secondary ID: NCI-2009-00405CO
• Status: Completed
• Phase: Phase 2
• First received: April 7, 2003
• Last updated: September 10, 2014
• Start date: June 2004
• Est. completion date: July 2014

Study information

• Verified date: September 2014
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 97
• Est. completion date: July 2014
• Est. primary completion date: October 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 29 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Burkitt Lymphoma
• Childhood Burkitt Lymphoma
• Childhood Diffuse Large Cell Lymphoma
• Childhood Immunoblastic Large Cell Lymphoma
• Leukemia
• Leukemia, B-Cell
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, Large B-Cell, Diffuse
• Lymphoma, Large-Cell, Immunoblastic
• Lymphoma, Non-Hodgkin
• Precursor Cell Lymphoblastic Leukemia-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

Intervention

Drug:
• doxorubicin hydrochloride
Given IV, IT, or orally
• cyclophosphamide
Given IV
• methotrexate
Given IV or IT
• rasburicase
Given IV
• leucovorin calcium
Given IV or orally
• prednisone
Given IV or orally
• methylprednisolone
Given IV or orally

Biological:
• filgrastim
Given subcutaneously
• rituximab
Given IV

Drug:
• cytarabine
Given IT
• etoposide
Given IV
• vincristine sulfate
Given IV
• hydrocortisone sodium succinate
Given IT

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Children's Oncology Group	Arcadia	California

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Up to 1 year	Yes
Primary	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..	Up to 5 years	No
Primary	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).	Not Provided	No
Primary	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.	Up to 1 year	Yes