Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Temporarily closed	1 to 29	NCI	COG-ANHL01P1 ANHL01P1, NCT00057811

Objectives

1. 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.
2. 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.
3. 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.
4. Determine the response rate of patients treated with COMRAP incorporated into LMB/FAB therapy.
5. Assess minimal residual disease in patients before and during COMRAP therapy incorporated into LMB/FAB therapy.

Entry Criteria

Disease Characteristics:

• 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)

   [Note: Patients with FAB Group A disease (completely resected stage I and abdominal stage II lesions) are not eligible]

 [Note: *A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.]

Prior/Concurrent Therapy:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• At least 1 week since prior steroids except emergency steroids initiated within 72 hours of study entry

Radiotherapy

• No prior radiotherapy except emergency radiotherapy initiated within 72 hours of study entry
• No concurrent radiotherapy

Surgery

• No prior solid organ transplantation

Patient Characteristics:

Age

• 1 to 29

Performance status

• Not specified

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Hepatitis B status known

Renal

• Not specified

Other

• 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

Expected Enrollment

A total of 90 patients (50 for group B and 40 for group C) will be accrued for this study within 2.5 years.

Outcomes

Toxicity
Incidence of tumor lysis syndrome
Response rate
Minimal residual disease

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 thereafter.

Cairo MS, Lynch J, Harrison L, et al.: Safety, efficacy and rituximab levels following chemoimmunotherapy (rituximab + FAB chemotherapy) in children and adolescents with mature B-cell Non-Hodgkin lymphoma (B-NHL): a Children’s Oncology Group report. [Abstract] Blood 112 (11): A-838, 2008.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Mitchell Cairo, MD, Protocol chair		Ph: 212-305-8316 Email: mc1310@columbia.edu

Registry Information
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
Trial Start Date		2004-06-28
Trial Completion Date		2008-09-20 (estimated)
Registered in ClinicalTrials.gov		NCT00057811
Date Submitted to PDQ		2003-01-29
Information Last Verified		2009-05-13
NCI Grant/Contract Number		CA37400