Intergroup Randomized Trial for Children or Adolescents With B-Cell Non Hodgkin Lymphoma or B-Acute Leukemia: Rituximab Evaluation in High Risk Patients

Study Overview
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Brief Summary
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The aim of the trial is to test whether adding 6 injections of rituximab to standard Lymphome malin B LMB chemotherapy regimen improves the Event Free Survival (EFS) compared with LMB chemotherapy alone in children / adolescents with advanced stage B-cell Non-Hodgkin Lymphoma (NHL) / B-Acute Leukemia (B-AL)(stage III and LDH > Nx2, any stage IV or B-AL).

Official Title
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Intergroup Trial for Children or Adolescents With B-Cell Non Hodgkin Lymphoma or B-Acute Leukemia: Evaluation of Rituximab Efficacy and Safety in High Risk Patients - Phase III Trial

Conditions
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B-cell Non Hodgkin Lymphoma, Mature B-cell Leukemia Burkitt-type

Intervention / Treatment
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* Drug: Vincristine, cyclophosphamide, methotrexate, doxorubicin, cytarabine, ara-C
* Drug: Rituximab, Vincristine, cyclophosphamide, methotrexate, doxorubicin, cytarabine, ara-C


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven B-cell malignancies, either Burkitt lymphoma or B-AL (=Burkitt leukaemia = L3-AL) or diffuse large B-cell NHL or aggressive mature B-cell NHL non other specified or specifiable. Stage III with elevated LDH level (B-high), [LDH > twice the institutional upper limit of the adult normal values (> Nx2)] or any stage IV or B-AL. 6 months to less than 18 years of age at the time of consent. Males and females of reproductive potential must agree to use an effective contraceptive method during the treatment, and after the end of treatment: during twelve months for women, taking into account the characteristics of rituximab and during five months for men, taking into account the characteristics of methotrexate. Complete initial work-up within 8 days prior to treatment that allows definite staging. Able to comply with scheduled follow-up and with management of toxicity. Signed informed consent from patients and/or their parents or legal guardians Exclusion Criteria: Follicular lymphoma, MALT and nodular marginal zone are not included into this therapeutic study Patients with congenital immunodeficiency, chromosomal breakage syndrome, prior organ transplantation, previous malignancy of any type, or known positive HIV serology. Evidence of pregnancy or lactation period. There will be no exclusion criteria based on organ function. Past or current anti-cancer treatment except corticosteroids during less than one week. Tumor cell negative for CD20 Prior exposure to rituximab. Severe active viral infection, especially hepatitis B. Hepatitis B carrier status history of HBV or positive serology. Participation in another investigational drug clinical trial. Patients who, for any reason, are not able to comply with the national legislation.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 17 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: LMB chemo<br>Prephase (COP) for all groups followed by: in group B: 4 courses: 2 COPADM + 2 CYM, with MTX 3g/m² in group C: 6 courses: 2 COPADM + 2 CYVE + 2 maintenance courses, with MTX 8g/m², in 4h in C1, in 24h in C3 (except the 1st course) and CNS positive patients receive additional IT before each CYVE courses and HDMTX between CYVE courses. | Drug: Vincristine, cyclophosphamide, methotrexate, doxorubicin, cytarabine, ara-C<br>* Prephase (COP) for all groups followed by: in group B: 4 courses: 2 COPADM + 2 CYM, with MTX 3g/m² in group C: 6 courses: 2 COPADM + 2 CYVE + 2 maintenance courses, with MTX 8g/m², in 4h in C1, in 24h in C3 (except the 1st course) and CNS positive patients receive additional IT before each CYVE courses and HDMTX between CYVE courses.<br>|
| Experimental: LMB chemo + Rituximab<br>LMB chemo as in the comparator arm Rituximab 375 mg/m² i.v.: 6 injections: two doses at 48h interval are given at D-2 and D1 of the 2 first courses (COPADM) and one dose at the beginning of the 2 following courses (CYM or CYVE). | Drug: Rituximab, Vincristine, cyclophosphamide, methotrexate, doxorubicin, cytarabine, ara-C<br>* LMB chemo as in the comparator arm Rituximab 375 mg/m² i.v.: 6 injections: two doses at 48h interval are given at D-2 and D1 of the 2 first courses (COPADM) and one dose at the beginning of the 2 following courses (CYM or CYVE).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival | Minimum time to death from any cause, presence of viable cells in residue after [2nd (Rituximab-)CYVE], relapse, progressive disease, or second malignancy measured from randomization. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Overall survival | 5 years | 
| Acute toxicity | Acute toxicity during treatment according to NCI-CTC V4 | 6 months | 
| Long term toxicity | Long term toxicity, especially immune reconstitution, cardiac toxicity | 5 years |