Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents (B-NHL 2013)
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| ClinicalTrials.gov Identifier: NCT03206671 |
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Recruitment Status :
Recruiting
First Posted : July 2, 2017
Last Update Posted : March 25, 2019
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Sponsor:
University Hospital Muenster
Collaborator:
Deutsche Krebshilfe e.V., Bonn (Germany)
Information provided by (Responsible Party):
University Hospital Muenster
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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
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Mature B-cell Non-Hodgkin Lymphoma | 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 | Phase 3 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 650 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | August 3, 2017 |
| Estimated Primary Completion Date : | August 2024 |
| Estimated Study Completion Date : | August 2024 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
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Drug: Rituximab window
Rituximab window (375 mg/m²) Drug: Cyclophosphamide see detailed protocol description Drug: Cytarabine see detailed protocol description Drug: Dexamethasone see detailed protocol description Drug: Etoposide see detailed protocol description Drug: Ifosfamide see detailed protocol description Drug: Methotrexate see detailed protocol description Drug: Prednisolone see detailed protocol description Drug: Vincristine see detailed protocol description |
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Experimental: R2 stage III experimental arm
Rituximab window + Standard chemotherapy
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Drug: Rituximab window
Rituximab window (375 mg/m²) Drug: Cyclophosphamide see detailed protocol description Drug: Cytarabine see detailed protocol description Drug: Dexamethasone see detailed protocol description Drug: Doxorubicin hydrochloride see detailed protocol description Drug: Etoposide see detailed protocol description Drug: Ifosfamide see detailed protocol description Drug: Methotrexate see detailed protocol description Drug: Prednisolone see detailed protocol description Drug: Vincristine see detailed protocol description |
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R2 stage III standard arm
Standard chemotherapy
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Drug: Cyclophosphamide
see detailed protocol description Drug: Cytarabine see detailed protocol description Drug: Dexamethasone see detailed protocol description Drug: Doxorubicin hydrochloride see detailed protocol description Drug: Etoposide see detailed protocol description Drug: Ifosfamide see detailed protocol description Drug: Methotrexate see detailed protocol description Drug: Prednisolone see detailed protocol description Drug: Vincristine see detailed protocol description |
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Experimental: R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
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Drug: Rituximab window
Rituximab window (375 mg/m²) Drug: Additional doses of Rituximab 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 Drug: Cyclophosphamide see detailed protocol description Drug: Cytarabine see detailed protocol description Drug: Dexamethasone see detailed protocol description Drug: Doxorubicin hydrochloride see detailed protocol description Drug: Vindesine Sulfate see detailed protocol description Drug: Etoposide see detailed protocol description Drug: Ifosfamide see detailed protocol description Drug: Methotrexate see detailed protocol description Drug: Prednisolone see detailed protocol description Drug: Vincristine see detailed protocol description |
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Experimental: R3/R4 standard arm
Rituximab window + standard chemotherapy
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Drug: Rituximab window
Rituximab window (375 mg/m²) Drug: Cyclophosphamide see detailed protocol description Drug: Cytarabine see detailed protocol description Drug: Dexamethasone see detailed protocol description Drug: Doxorubicin hydrochloride see detailed protocol description Drug: Vindesine Sulfate see detailed protocol description Drug: Etoposide see detailed protocol description Drug: Ifosfamide see detailed protocol description Drug: Methotrexate see detailed protocol description Drug: Prednisolone see detailed protocol description Drug: Vincristine see detailed protocol description |
Primary Outcome Measures :
- Event-free survival (EFS) [ Time Frame: through study completion, maximal seven years ]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.
- Immune reconstitution rate (only in R3/R4 patients) [ Time Frame: 12 months after start of treatment ]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.
Secondary Outcome Measures :
- Overall survival (OS) [ Time Frame: through study completion, maximal seven years ]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.
- Relapse-free survival (RFS) [ Time Frame: through study completion, maximal seven years ]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.
- Response rate (RR) [ Time Frame: 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) ]Complete response, partial remission, objective effect, stable disease or progressive disease
- Adverse event rate [ Time Frame: from the first day of protocol defined treatment until two years after start of protocol defined treatment ]Rate of patients with acute toxicity defined as grade III/IV/V AE
- Rate of patients achieving normal immunoglobulin level 12 months after start of treatment [ Time Frame: 12 months after start of treatment ]
- Time interval to normal immunoglobulin level [ Time Frame: through study completion, maximal seven years ]
- Time interval from start of treatment to normal CD19 positive B-cells in the peripheral blood. [ Time Frame: through study completion, maximal seven years ]
- Rate of patients with normal lymphocyte subpopulations in the peripheral blood 12 months after start of treatment [ Time Frame: 12 months after start of treatment ]
- Interval to normal lymphocyte subpopulations in the peripheral blood. [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: through study completion, maximal seven years ]
- Rate of patients with sufficient titers after vaccination one year after start of treatment [ Time Frame: 1 year after start of treatment ]
- Immune reconstitution rate (only in R1/R2 patients) [ Time Frame: 12 months after start of treatment ]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.
Information from the National Library of Medicine
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| Ages Eligible for Study: | up to 18 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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 classification. For rare subtypes (e.g. primary mediastinal large B-NHL, PMLBL), 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
- signed informed consent of patient and/or parents/guardians for participation and transfer of data
- follow-up of at least two years after initial diagnosis is expected
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03206671
Contacts
| Contact: Birgit Burkhardt, Prof. Dr. Dr. | +49 251 83 55696 | b-nhl2013@ukmuenster.de |
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Sponsors and Collaborators
University Hospital Muenster
Deutsche Krebshilfe e.V., Bonn (Germany)
Investigators
| Principal Investigator: | Birgit Burkhardt, Prof. Dr. Dr. | University Hospital Muenster, Klinik für Kinder- und Jugendmedizin - Pädiatrische Hämatologie und Onkologie |
| Responsible Party: | University Hospital Muenster |
| ClinicalTrials.gov Identifier: | NCT03206671 History of Changes |
| Other Study ID Numbers: |
UKM12_0020 2013-003253-21 ( EudraCT Number ) |
| First Posted: | July 2, 2017 Key Record Dates |
| Last Update Posted: | March 25, 2019 |
| Last Verified: | January 2019 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | No | |
| Studies a U.S. FDA-regulated Device Product: | No | |
Additional relevant MeSH terms:
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Lymphoma Lymphoma, Non-Hodgkin Lymphoma, B-Cell Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Dexamethasone Prednisolone Cyclophosphamide Rituximab Doxorubicin Methotrexate |
Etoposide Cytarabine Vincristine Ifosfamide Liposomal doxorubicin Vindesine Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Physiological Effects of Drugs Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists |