Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents

Study Overview
=================
Brief Summary
-----------------
The trial B-NHL 2013 is a collaborative prospective, multi-national, multi-center, randomized trial with participating centers of the NHL-BFM group (Austria, Switzerland, Czech Republic, Germany) and the Scandinavian NOPHO group (Denmark, Finland, Norway, Sweden). The aim of the trial is to evaluate the role of rituximab in the treatment of mature aggressive B-cell Non-Hodgkin lymphoma and leukemia (B-NHL and B-AL) in children and adolescents. The following primary study questions are going to be analyzed: the effectiveness (event-free survival) in pediatric patients with very limited mature B-NHL (R1 and R2 stage I and II) of substituting anthracyclines by the rituximab window without compromising survival rates. the effectiveness (event-free survival) in pediatric patients with limited mature B-NHL (R2 stage III) randomly assigned to receive the rituximab window plus standard chemotherapy or standard chemotherapy without the rituximab window. the effectiveness (event-free survival) and the immune reconstitution (recovery of CD19+ B-cells, IR) in pediatric patients with advanced mature B-NHL/B-AL (R3 and R4 incl. R4 CNS+) treated with BFM-type chemotherapy and randomly assigned schedules of one versus seven doses rituximab. Secondary study questions will address additional parameters for immune reconstitution, lymphocyte subpopulations, immunoglobulin levels, vaccination titers and infection rates kinetics of immune reconstitution after treatment adverse event and severe adverse event profile inter-individual variability of rituximab response role of different mechanisms of action of rituximab in advanced B-NHL/B-AL

Detailed Description
-----------------
Risk group stratification: R1/R2 stage I+II: R1: resection status: complete R2: resection status: incomplete, stage I and II R2 III: - R 2: resection status: incomplete, stage III and LDH < 2 x ULN (according to local reference value for adults) R3/R4: R3: resection status: incomplete, stage III and LDH ≥ 2 x ULN but < 4 x ULN or stage IV/B-AL and LDH < 4 x ULN and CNS negative R4: resection status: incomplete, Stage III and LDH ≥ 4 x ULN or stage IV/B-AL and LDH ≥ 4 x ULN and CNS negative R4 CNS +: stage IV/B-AL and CNS positive For patients with very limited disease (R1/R2 stage I/II), the addition of rituximab might allow the omission of anthracyclines without jeopardizing survival rates but reducing acute and long term toxicities. In this treatment arm, it is tested whether the event-free survival is similar to that of the historical control when all patients receive one dose of rituximab as monotherapeutic agent in the rituximab window R five days prior to the start of standard chemotherapy as a substitute for anthracyclines. For patients with limited disease (R2 stage III) it is tested whether the event-free survival can be improved by adding rituximab to the standard chemotherapy. Two different treatment regimens will be evaluated in a randomized design: Patients in the standard arm will receive the standard chemotherapy. Patients of the rituximab plus arm will receive one dose of rituximab as monotherapeutic agent in the rituximab window R five days prior to the start of standard chemotherapy. For patients with advanced disease (R3/R4) it is tested whether the event-free survival can be improved by adding rituximab to the standard chemotherapy. Two different rituximab regimens will be evaluated in a randomized design: Patients in the standard arm will receive one dose of rituximab as monotherapeutic agent in the rituximab window R five days prior to the start of standard chemotherapy. Patients of the rituximab plus arm will receive the rituximab window and additional six doses of rituximab added to the first four courses of chemotherapy. In addition the immune reconstitution will be analyzed comparing the effect of the two regimens of rituximab added to standard chemotherapy.

Official Title
-----------------
B-NHL 2013 - Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents

Conditions
-----------------
Mature B-cell Non-Hodgkin Lymphoma

Intervention / Treatment
-----------------
* Drug: Rituximab window
* Drug: Additional doses of Rituximab
* Drug: Cyclophosphamide
* Drug: Cytarabine
* Drug: Dexamethasone
* Drug: Doxorubicin hydrochloride
* Drug: Vindesine Sulfate
* Drug: Etoposide
* Drug: Ifosfamide
* Drug: Methotrexate
* Drug: Prednisolone
* Drug: Vincristine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Newly diagnosed, histological or cytological and immunological proven aggressive mature B-cell Non-Hodgkin lymphoma including Burkitt lymphoma (BL), Burkitt leukemia (B-AL), diffuse large B-cell lymphoma (DLBCL), or mature B-cell NHL not further classified according to current WHO classification124. For rare subtypes (e.g. primary mediastinal large B-NHL, PMLBL, double hit lymphoma or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements), consultation of the study center is recommended. availability of slides/blocks for reference pathology and international pathology panel (except in cases with immunological and cytomorphological assurance of diagnosis) age at diagnosis < 18 years diagnostics and treatment in one of the participating centers of the trial no previous chemotherapy, no previous lymphoma-directed treatment. No application of steroids for more than two days during the last month adequate hepatic, renal and cardiac function, except if alteration is due to lymphoma infiltration. Please contact the study center in case of unclear cases. signed informed consent of patient and/or parents/guardians for treatment according to the protocol, participation and transfer of data follow-up of at least two years after initial diagnosis is expected Certificate of vaccination against hepatitis B or negative serology, defined as evidence of immunization with HBs-antigen negative, anti-HBs positive and anti-HBc negative or negative hepatitis B serology with HBs-antigen negative, anti-HBs and anti- HBc negative Exclusion Criteria: patients with insufficient work up not allowing a correct stratification into the risk groups B-cell neoplasia as second malignancy any other medical, psychiatric or social condition prohibiting treatment according to the protocol (e.g. previous malignancy, prior organ transplant, HIV infection or AIDS or severe immunodeficiency, etc.) participation within a different trial for treatment of B-cell malignancies and/or concurrent treatment within any other clinical trial. Exceptions to this are the NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment which can run parallel to B-NHL 2013 without influencing the outcome of this trial e.g. trials on antiemetics, antibiotics, strategies for psychosocial support etc. overt hepatitis B or history of hepatitis B hypersensitivity to rituximab or to murine proteins or to any of the other excipients of the Investigational Medicinal Product rituximab (MabThera®) or to ingredients of other IMPs. lack of CD20 expression of the lymphoma cells pregnancy and lactation

Ages Eligible for Study
-----------------
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R1/R2 stage I+II<br>Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1) | Drug: Rituximab window<br>* Rituximab window (375 mg/m²)<br>Drug: Cyclophosphamide<br>* see detailed protocol description<br>Drug: Cytarabine<br>* see detailed protocol description<br>Drug: Dexamethasone<br>* see detailed protocol description<br>Drug: Etoposide<br>* see detailed protocol description<br>Drug: Ifosfamide<br>* see detailed protocol description<br>Drug: Methotrexate<br>* see detailed protocol description<br>Drug: Prednisolone<br>* see detailed protocol description<br>Drug: Vincristine<br>* see detailed protocol description<br>|
| Experimental: R2 stage III experimental arm<br>Rituximab window + Standard chemotherapy | Drug: Rituximab window<br>* Rituximab window (375 mg/m²)<br>Drug: Cyclophosphamide<br>* see detailed protocol description<br>Drug: Cytarabine<br>* see detailed protocol description<br>Drug: Dexamethasone<br>* see detailed protocol description<br>Drug: Doxorubicin hydrochloride<br>* see detailed protocol description<br>Drug: Etoposide<br>* see detailed protocol description<br>Drug: Ifosfamide<br>* see detailed protocol description<br>Drug: Methotrexate<br>* see detailed protocol description<br>Drug: Prednisolone<br>* see detailed protocol description<br>Drug: Vincristine<br>* see detailed protocol description<br>|
| Other: R2 stage III standard arm<br>Standard chemotherapy | Drug: Cyclophosphamide<br>* see detailed protocol description<br>Drug: Cytarabine<br>* see detailed protocol description<br>Drug: Dexamethasone<br>* see detailed protocol description<br>Drug: Doxorubicin hydrochloride<br>* see detailed protocol description<br>Drug: Etoposide<br>* see detailed protocol description<br>Drug: Ifosfamide<br>* see detailed protocol description<br>Drug: Methotrexate<br>* see detailed protocol description<br>Drug: Prednisolone<br>* see detailed protocol description<br>Drug: Vincristine<br>* see detailed protocol description<br>|
| Experimental: R3/R4 rituximab plus arm<br>Rituximab window + standard chemotherapy plus six additional doses of rituximab | Drug: Rituximab window<br>* Rituximab window (375 mg/m²)<br>Drug: Additional doses of Rituximab<br>* 2 doses of Rituximab (375 mg/m²) before the start of the first chemotherapy cycle, 2 doses of Rituximab before the start of the second chemotherapy cycle, 1 dose of rituximab before the start of the third chemotherapy cycle, 1 dose of Rituximab before the start of the forth chemotherapy cycle<br>Drug: Cyclophosphamide<br>* see detailed protocol description<br>Drug: Cytarabine<br>* see detailed protocol description<br>Drug: Dexamethasone<br>* see detailed protocol description<br>Drug: Doxorubicin hydrochloride<br>* see detailed protocol description<br>Drug: Vindesine Sulfate<br>* see detailed protocol description<br>Drug: Etoposide<br>* see detailed protocol description<br>Drug: Ifosfamide<br>* see detailed protocol description<br>Drug: Methotrexate<br>* see detailed protocol description<br>Drug: Prednisolone<br>* see detailed protocol description<br>Drug: Vincristine<br>* see detailed protocol description<br>|
| Experimental: R3/R4 standard arm<br>Rituximab window + standard chemotherapy | Drug: Rituximab window<br>* Rituximab window (375 mg/m²)<br>Drug: Cyclophosphamide<br>* see detailed protocol description<br>Drug: Cytarabine<br>* see detailed protocol description<br>Drug: Dexamethasone<br>* see detailed protocol description<br>Drug: Doxorubicin hydrochloride<br>* see detailed protocol description<br>Drug: Vindesine Sulfate<br>* see detailed protocol description<br>Drug: Etoposide<br>* see detailed protocol description<br>Drug: Ifosfamide<br>* see detailed protocol description<br>Drug: Methotrexate<br>* see detailed protocol description<br>Drug: Prednisolone<br>* see detailed protocol description<br>Drug: Vincristine<br>* see detailed protocol description<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | EFS is defined as time from start of treatment/randomization up to event or to date of last contact for patients without event. The following occurrences are defined as an event: non-response, progressive disease or relapse, treatment related death, death of any other cause or diagnosis of secondary malignancies. | through study completion, maximal seven years | 
| Immune reconstitution rate (only in R3/R4 patients) | Immune reconstitution rate is defined as percentage of patients achieving age adjusted normal B-cell counts (CD19 positive subpopulations) 12 months after start of treatment. | 12 months after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS is defined as time from start of treatment/randomization up to death of any cause or to date of last contact for patients alive. | through study completion, maximal seven years | 
| Relapse-free survival (RFS) | RFS is defined as time from start of treatment/randomization up to event or to date of last contact for patients without event. The following occurrences are defined as an event: non-response, progressive disease, or relapse. | through study completion, maximal seven years | 
| Response rate (RR) | Complete response, partial remission, objective effect, stable disease or progressive disease | after rituximab window on day 5, after prephase (patients with rituximab window on day 10, patients without rituximab window on day 6) and after second course (on an average 5 to 6 weeks after start of treatment) | 
| Adverse event rate | Rate of patients with acute toxicity defined as grade III/IV/V AE | from the first day of protocol defined treatment until two years after start of protocol defined treatment | 
| Rate of patients achieving normal immunoglobulin level 12 months after start of treatment |  | 12 months after start of treatment | 
| Time interval to normal immunoglobulin level |  | through study completion, maximal seven years | 
| Time interval from start of treatment to normal CD19 positive B-cells in the peripheral blood. |  | through study completion, maximal seven years | 
| Rate of patients with normal lymphocyte subpopulations in the peripheral blood 12 months after start of treatment |  | 12 months after start of treatment | 
| Interval to normal lymphocyte subpopulations in the peripheral blood. |  | through study completion, maximal seven years | 
| Rate of infections (defined by CTCAE V4) in the time interval from start of treatment until 24 months after start of treatment |  | 24 months after start of treatment | 
| Rate of infections (defined by CTCAE V4) in the time interval from start of treatment until immune reconstitution (achievement of age adjusted normal B-cell counts) |  | through study completion, maximal seven years | 
| Rate of patients with sufficient titers after vaccination one year after start of treatment |  | 1 year after start of treatment | 
| Immune reconstitution rate (only in R1/R2 patients) | Immune reconstitution rate is defined as percentage of patients achieving age adjusted normal B-cell counts (CD19 positive subpopulations) 12 months after start of treatment. | 12 months after start of treatment |