Mature B-Cell Lymphoma And Leukemia Study III

Official Title: “Mature B-Cell Lymphoma And Leukemia Study III”

This is a phase II/III clinical trial using risk-adapted therapy. Treatment outcomes for children with B-cell NHL are excellent. Further improvements in outcome will likely be achieved through more focused study of the biology of the tumors and prospective studies of the late effects of treatment. Toward this end, this study features a spectrum of prospective biologic and late effect studies performed in patients treated with a modified regimen derived from the very successful LMB-96 regimen.

1. This study will perform transcriptional profiling and genome-wide analysis of DNA copy number abnormalities and loss-of-heterozygosity using DNA microarrays in children with newly diagnosed diffuse large B-cell lymphomas(DLBCL) and small non-cleaved lymphomas from different parts of the world.

2. This study will describe the types and frequency of mutations in the ARF-HDM2-TP53 pathway, in "non-endemic" B-cell lymphomas (United States) and those found in selected geographic regions of the world (Brazil, Chile, Guatemala, Honduras, El-Salvador, Singapore and others).

3. This study will describe the expression of ARF-HDM2-TP53 and PUMA-associated pathways in non-endemic B-cell lymphomas (United States) and that found in B-cell lymphomas of other selected geographic regions of the world (see above).

4. This study will describe the pattern and frequency of XLP gene mutations in boys presenting with B-cell lymphomas in the United States and selected geographic regions.

5. This study will describe the frequency of EBV-positive B-cell lymphomas in the United States and selected geographic regions of the world: and will describe the pattern of EBV protein expression (e.g., EBNA 3) in EBV-positive lymphomas and the study will compare patterns of EBV protein expression with clinical, laboratory and outcome data.

6. This study will establish a tumor bank of mature B-cell lymphoma samples for future molecular studies aimed to clarify the role of c-MYC oncogene and its associated pathways, and other pathways found to harbor genetic alterations from the genomic profiling studies described above.

Intervention(s) in this Clinical Trial

• Drug: COPAD
  • Vincristine Prednis(ol)one, Cyclophosphamide, Doxorubicin, G-CSF
• Drug: COP, COPD M3, CYM
  • GROUP B Treatment Details Intravenous fluids should be given at a rate of 3000 mL/m2/day. Use of rasburicase may preclude the need for HCO3 Pre-Phase: Cyclophosphamide, Vincristine, Prednis(ol)one, IT medications Induction (2 cycles): Vincristine, Prednis(ol)one, Methotrexate, Leucovorin, Cyclophosphamide, Doxorubicin, IT medications, G-CSF, Rituximab Consolidation (2 cycles): Methotrexate, Leucovorin, Cytarabine, IT medications, G-CSF, Rituximab
• Drug: COP, COPADM8, CYVE
  • Treatment: Intravenous fluids should be given at a rate of 3000 mL/m2/day. Use of rasburicase may preclude the need for HCO3. COP Pre-Phase: Cyclophosphamide, Vincristine, Prednis(ol)one, IT medications, Leucovorin. COPADM8 Induction (2 cycles): Vincristine, Prednis(ol)one, Methotrexate, Leucovorin, Cyclophosphamide, Doxorubicin, IT medications, G-CSF CYVE Consolidation (2 cycles): Cytarabine, High-Dose Ara-C, Etoposide, G-CSF. Maintenance No.1: Vincristine, Prednis(ol)one, Cyclophosphamide, Methotrexate, Leucovorin, Doxorubicin, IT medications, G-CSF. Maintenance No.2: Cytarabine, Etoposide, G-CSF, IT Medications. Maintenance No.3: Vincristine, Prednis(ol)one, Cyclophosphamide, Doxorubicin, G-CSF, IT Medications. Maintenance No. 4: Cytarabine, Etoposide, G-CSF, IT Medications.

Arms, Groups and Cohorts in this Clinical Trial

• Other: Group A
  • Completely resected stage I or completely resected abdominal stage II lesions. Group A will include: COPAD x 2 cycles.
• Other: Group B
  • All cases not eligible for Group A or Group C. (Murphy Stage III and non-CNS Stage IV) Group B will include: Pre-Phase: COP; Induction: COPAD M3 x 2 cycles; Consolidation: CYM x 2 cycles.
• Other: Group C
  • Any CNS involvement and/or bone marrow involvement ≥ 25% blasts. For CNS involvement one or more of the following applies: Any L3 blasts in CSF Cranial nerve palsy (if not explained by extracranial tumor) Clinical spinal cord compression Isolated intracerebral mass Parameningeal extension: cranial and/or spinal Group C will include: Pre-Phase: COP; Induction: COPADM8 cycle 1; Induction: COPADM8 Cycle 2; Consolidation: CYVE x 2 cycles and Maintenance

Primary Measures

• To perform transcriptional profiling and genome-wide analysis of DNA copy number abnormalities and loss-of-heterozygosity using DNA microarrays in children with newly diagnosed mature B cell lymphomas
  • Time Frame: 5 years
    Safety Issue?: No
• To describe the types and frequency of mutations in the ARF-HDM2-TP53 pathway, in B-cell lymphomas in the United States and those found in selected geographic regions of the world.
  • Time Frame: 5 years
    Safety Issue?: No
• To describe the expression of ARF-HDM2-TP53 and PUMA-associated pathways in B-cell lymphomas in the United States and that found in B-cell lymphomas of other selected geographic regions of the world
  • Time Frame: 5 years
    Safety Issue?: No
• To describe the pattern and frequency of XLP gene mutations presenting with B-cell lymphomas in the United States and selected geographic regions.
  • Time Frame: 5 years
    Safety Issue?: No
• To describe the pattern of EBV protein expression (e.g., EBNA 3) in EBV-positive lymphomas and to compare patterns of EBV protein expression with clinical, laboratory and outcome data.
  • Time Frame: 5 years
    Safety Issue?: No
• To establish a tumor bank of mature B-cell lymphoma samples for future molecular studies aimed to clarify the role of c-MYC oncogene and its associated pathways,and other pathways found to harbor genetic alterations from the genomic profiling studies
  • Time Frame: 5 years
    Safety Issue?: No

Secondary Measures

• This study will include the study of acute and late effects of this treatment on the central nervous system, bone mineral density, fertility, and cardiac system.
  • Time Frame: 5 years
    Safety Issue?: No

Inclusion Criteria:

St. Jude Participants:

• 1. Participant must have a histologic diagnosis of a mature B cell lymphoma(e.g., Burkitt lymphoma/leukemia, atypical Burkitt lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, mature B-cell lymphoma NOS) as defined in the WHO classification.
• 2. Participant must be previously untreated, (no more than 72 hours of steroids and/or emergency radiation)
• 3. Participant must be < 21 years of age at the time of diagnosis
• 4. For Group B participants with mediastinal large B cell lymphoma (MLBCL) disease only (receiving rituxumab) - Hepatitis screening has been obtained. This screening must be done for eligibility BUT the results are not needed prior to enrollment:
• Hepatitis B immunization status (vaccination Yes or No)
• HBsAg
• Anti-HBs antibody
• Anti-HBc antibody All participants must have screening prior to enrollment.
• Participants whose results indicate that they are carrier of hepatitis B can still be treated per Group B but will NOT receive rituximab.
• 5. Informed consent must be obtained according to St. Jude guidelines before enrollment into study

Non- St. Jude Participants:

• 1. Participant must have a histologic diagnosis of a mature B cell lymphoma (e.g., Burkitt lymphoma/leukemia, atypical Burkitt lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma, mature B-cell lymphoma NOS) as defined in the WHO classification
• 2. Participant must be < or = to 21 years of age at the time of diagnosis
• 3. Informed consent must be obtained by St. Jude investigator according to St. Jude guidelines before enrollment into study

Exclusion Criteria:

St. Jude Participants:

• 1. Participants with prior therapy (except steroids or RT as described in 3.1.1)
• 2. Participants known to be HIV positive(for therapeutic part of protocol, HIV participants are eligible for biology studies).
• 3. Participants who are pregnant or lactating
• 4. Inability or unwillingness of research participant or legal guardian to consent
• 5. Participants who received emergent steroids and/or radiation prior to biopsy may be included in therapeutic part of study, but will be excluded from biology studies.

Non St. Jude Participants:

• 1. Inability or unwillingness of research participant or legal guardian to consent
• 2. Histologic diagnosis other than a mature B-cell lymphoma as defined in the WHO classification
• 3. Participants who received emergent steroids and/or radiation prior to biopsy

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 20 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: St. Jude Children's Research Hospital Other

Overall Clinical Trial Officials and Contacts

John T Sandlund, MD Principal Investigator St. Jude Children's Research Hospital  

Overall Contact: John T Sandlund, MD 1-866-278-5833 Info@stjude.org

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01046825

Study ID Number: SJBC3

ClinicalTrials.gov Identifier: NCT01046825

Health Authority: United States: Institutional Review Board