Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents
NCT ID: NCT03206671
Last Updated: 2025-03-24
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ACTIVE_NOT_RECRUITING
PHASE3
650 participants
INTERVENTIONAL
2017-08-03
2027-06-30
Brief Summary
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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
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
Rituximab window
Rituximab window (375 mg/m²)
Cyclophosphamide
see detailed protocol description
Cytarabine
see detailed protocol description
Dexamethasone
see detailed protocol description
Etoposide
see detailed protocol description
Ifosfamide
see detailed protocol description
Methotrexate
see detailed protocol description
Prednisolone
see detailed protocol description
Vincristine
see detailed protocol description
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
Rituximab window
Rituximab window (375 mg/m²)
Cyclophosphamide
see detailed protocol description
Cytarabine
see detailed protocol description
Dexamethasone
see detailed protocol description
Doxorubicin hydrochloride
see detailed protocol description
Etoposide
see detailed protocol description
Ifosfamide
see detailed protocol description
Methotrexate
see detailed protocol description
Prednisolone
see detailed protocol description
Vincristine
see detailed protocol description
R2 stage III standard arm
Standard chemotherapy
Cyclophosphamide
see detailed protocol description
Cytarabine
see detailed protocol description
Dexamethasone
see detailed protocol description
Doxorubicin hydrochloride
see detailed protocol description
Etoposide
see detailed protocol description
Ifosfamide
see detailed protocol description
Methotrexate
see detailed protocol description
Prednisolone
see detailed protocol description
Vincristine
see detailed protocol description
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
Rituximab window
Rituximab window (375 mg/m²)
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
Cyclophosphamide
see detailed protocol description
Cytarabine
see detailed protocol description
Dexamethasone
see detailed protocol description
Doxorubicin hydrochloride
see detailed protocol description
Vindesine Sulfate
see detailed protocol description
Etoposide
see detailed protocol description
Ifosfamide
see detailed protocol description
Methotrexate
see detailed protocol description
Prednisolone
see detailed protocol description
Vincristine
see detailed protocol description
R3/R4 standard arm
Rituximab window + standard chemotherapy
Rituximab window
Rituximab window (375 mg/m²)
Cyclophosphamide
see detailed protocol description
Cytarabine
see detailed protocol description
Dexamethasone
see detailed protocol description
Doxorubicin hydrochloride
see detailed protocol description
Vindesine Sulfate
see detailed protocol description
Etoposide
see detailed protocol description
Ifosfamide
see detailed protocol description
Methotrexate
see detailed protocol description
Prednisolone
see detailed protocol description
Vincristine
see detailed protocol description
Interventions
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Rituximab window
Rituximab window (375 mg/m²)
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
Cyclophosphamide
see detailed protocol description
Cytarabine
see detailed protocol description
Dexamethasone
see detailed protocol description
Doxorubicin hydrochloride
see detailed protocol description
Vindesine Sulfate
see detailed protocol description
Etoposide
see detailed protocol description
Ifosfamide
see detailed protocol description
Methotrexate
see detailed protocol description
Prednisolone
see detailed protocol description
Vincristine
see detailed protocol description
Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
ALL
No
Sponsors
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Deutsche Krebshilfe e.V., Bonn (Germany)
OTHER
University Hospital Muenster
OTHER
Responsible Party
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Principal Investigators
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Birgit Burkhardt, Prof. Dr. Dr.
Role: PRINCIPAL_INVESTIGATOR
University Hospital Muenster, Klinik für Kinder- und Jugendmedizin - Pädiatrische Hämatologie und Onkologie
Locations
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Univ.Klinik für Kinder- und Jugendheilkunde Graz, Klin. Abteilung für pädiatrische Hämato-Onkologie
Graz, , Austria
Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck, Universitätsklinik für Pädiatrie I
Innsbruck, , Austria
Klinikum Klagenfurt am Wörthersee, Abteilung für Kinder- und Jugendheilkunde
Klagenfurt, , Austria
Kepler Universitätsklinikum, Med Campus IV / Onkologie
Linz, , Austria
LKH Salzburg, Universitätsklinik für Kinder- und Jugendheilkunde, Kinderonkologie
Salzburg, , Austria
St. Anna Kinderspital
Vienna, , Austria
Department of Pediatric Hematology and Oncology, University Hospital Motol
Prague, , Czechia
Børneonkologisk afsnit 303B, Børneafdelingen, Aalborg Universitetshospital Nord
Aalborg, , Denmark
Børn og Unge afsnit 4, Børneafdelingen, Aarhus Universitetshospital Skejby
Aarhus, , Denmark
Børneonkologisk afsnit 5054, BørneUngeKlinikken, Juliane Marie Centret, Rigshospitalet
Copenhagen, , Denmark
Børneonkologisk afsnit H2, H. C. Andersen Børnehospital, Odense Universitetshospital
Odense, , Denmark
Helsinki University Hospital, Children´s Hospital, Dept of Pediatric Hematology and Oncology
Helsinki, , Finland
Kuopio University Hospital, Paediatric Haematology and Oncology
Kuopio, , Finland
University Hospital of Oulu, Paediatric Haematology and Oncology
Oulu, , Finland
Tampere University Hospital, Paediatric Haematology and Oncology
Tampere, , Finland
Turku University Hospital, Paediatric and Adolescent Haematology and Oncology
Turku, , Finland
Universitätsklinikum Aachen, Klinik für Kinder - und Jugendmedizin, Hämatologie / Onkologie
Aachen, , Germany
Klinikum Augsburg, Schwäbisches Kinderkrebszentrum, I. Klinik für Kinder und Jugendliche, Hämatologie / Onkologie
Augsburg, , Germany
Charité Campus Virchow-Klinikum, Zentrum für Kinder- und Jugendmedizin, Abt. Hämatologie / Onkologie
Berg, , Germany
HELIOS Klinikum Berlin-Buch, Kinderklinik, Pädiatrische Hämatologie und Onkologie
Berlin, , Germany
Evangelisches Krankenhaus Bielefeld GmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie und Onkologie
Bielefeld, , Germany
Zentrum für Kinderheilkunde der Universität Bonn, Abt. Päd. Hämatologie / Onkologie
Bonn, , Germany
Städtisches Klinikum Braunschweig gGmbH, Klinik für Kinder- und Jugendmedizin, Station K5 / Päd. Hämato- und Onkologie
Braunschweig, , Germany
Klinikum Bremen-Mitte gGmbH, Prof.-Hess-Kinderklinik,Pädiatrische Onkologie und Hämatologie
Bremen, , Germany
Klinikum der Universität zu Köln, Klinik für Kinder- und Jugendmedizin, Abt. Kinderonkologie und -hämatologie
Cologne, , Germany
Carl-Thieme-Klinikum Cottbus gGmbH, Klinik für Kinder- und Jugendmedizin
Cottbus, , Germany
Vestische Kinderklinik, Universität Witten / Herdecke
Datteln, , Germany
Klinikum Dortmund gGmbH, Klinik für Kinder- und Jugendmedizin, Station K1, Abt. Päd. Onkologie / Hämatologie
Dortmund, , Germany
Universitätsklinik Carl Gustav Carus der TU Dresden, Klinik für Kinder- und Jugendmedizin
Dresden, , Germany
Universitätsklinikum Düsseldorf, Zentrum für Kinder- und Jugendmedizin, Klinik für Päd. Hämatologie und Onkologie
Düsseldorf, , Germany
HELIOS Klinikum Erfurt GmbH, Klinik für Kinder- und Jugendmedizin, Päd. Onkologie / Hämatologie
Erfurt, , Germany
Universitätsklinikum Erlangen, Klinik für Kinder- und Jugendmedizin, Pädiatrische Onkologie / Hämatologie
Erlangen, , Germany
Universitätsklinikum Essen, Zentrum für Kinder- und Jugendmedizin, Hämatologie / Onkologie
Essen, , Germany
Universitätsklinikum Frankfurt, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie
Frankfurt am Main, , Germany
Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin, Klinik IV: Päd. Hämatologie und Onkologie
Freiburg im Breisgau, , Germany
Universitätsklinikum Gießen und Marburg, Standort Gießen, Zentrum für Kinderhämatologie und -onkologie
Giessen, , Germany
Georg-August-Universität Universitäts-Kinderklinik, Pädiatrie I
Göttingen, , Germany
Universitätsklinikum Greifswald KdöR, Klinik und Poliklinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Onkologie und Hämatologie
Greifswald, , Germany
Universitätsklinikum Halle (Saale), Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / Onkologie
Halle, , Germany
Universitätsklinikum Hamburg Eppendorf, Zentrum für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und Onkologie
Hamburg, , Germany
Medizinische Hochschule Hannover, Kinderheilkunde, Päd. Hämatologie / Onkologie
Hanover, , Germany
Universitäts-Kinderklinik Heidelberg, Abt. Hämatologie / Onkologie
Heidelberg, , Germany
Gemeinschaftskrankenhaus Herdecke, Kinder- und Jugendmedizin, Päd. Hämatologie / Onkologie
Herdecke, , Germany
Universitätskliniken für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie, Geb. 9
Homburg, , Germany
Universitätsklinikum Jena, Klinik für Kinder- und Jugendmedizin
Jena, , Germany
Städtisches Klinikum Karlsruhe gGmbH, Kinderklinik, Station S 24
Karlsruhe, , Germany
Klinikum Kassel Gesundheit Nordhessen Holding AG, Klinik für pädiatrische Hämatologie und Onkologie
Kassel, , Germany
Universitätsklinikum Schleswig Holstein Campus Kiel, Klinik für Allgemeine Pädiatrie, Päd. Onkologie / Hämatologie
Kiel, , Germany
Gemeinschaftsklinikum Mittelrhein Kemperhof, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie
Koblenz, , Germany
HELIOS Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin, Päd. Hämatologie/Onkologie
Krefeld, , Germany
Universitätsklinikum Leipzig, Klinik für Kinder und Jugendliche, Abt. Päd. Hämatologie / Onkologie
Leipzig, , Germany
Universitätsklinikum Schleswig Holstein Campus Lübeck, Klinik für Kinder- und Jugendmedizin, Hämatologie und Onkologie
Lübeck, , Germany
Universitätsklinikum Magdeburg A. ö. R., Kinderklinik, Päd. Hämatologie / Onkologie
Magdeburg, , Germany
Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Zentrum für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / Onkologie
Mainz, , Germany
Klinikum Mannheim gGmbH, Universitäts-Kinderklinik, Päd. Onkologie /Hämatologie
Mannheim, , Germany
Johannes Wesling Klinikum Minden, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie / Onkologie, Station E 22
Minden, , Germany
Klinikum der LMU, Dr. von Haunersches Kinderspital, Pädiatrische Hämatologie / Onkologie
München, , Germany
Klinikum Schwabing, Kinderklinik der TU Päd. Hämatologie / Onkologie, Station 24d
München, , Germany
Universitätsklinikum Münster, Klinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und Onkologie
Münster, , Germany
Diakonie Neuendettelsau, Kliniken Hallerwiese / Cnopf'sche Kinderklinik, Pädiatrische Hämatologie /Onkologie
Nuremberg, , Germany
Klinikum Oldenburg AöR, Zentrum für Kinder- und Jugendmedizin, Abt. Hämatologie / Onkologie
Oldenburg, , Germany
Universitätsklinikum Regensburg, Klinik für Kinder- und Jugendmedizin, Abt. Päd. Hämatologie, Onkologie, SZT
Regensburg, , Germany
Universitätsklinikum Rostock, Kinder- und Jugendklinik, Päd. Hämatologie und Onkologie
Rostock, , Germany
Asklepios Klinik St. Augustin GmbH, Kinder- und Jugendmedizin, Kinder-Hämatologie und Onkologie
Sankt Augustin, , Germany
HELIOS Kliniken Schwerin GmbH, Klinik für Kinder- und Jugendmedizin, Station A1
Schwerin, , Germany
Klinikum Stuttgart, Olgahospital Zentrum für Kinder- und Jugendmedizin Pädiatrie 5 (Onkologie, Hämatologie, Immunologie)
Stuttgart, , Germany
Universitätsklinik Tübingen Klinik für Kinderheilkunde und Jugendmedizin, Päd. Hämatologie / Onkologie
Tübingen, , Germany
Universitätsklinikum Ulm, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie
Ulm, , Germany
Universitätskinderklinik Würzburg, Päd. Onkologie und Hämatologie
Würzburg, , Germany
Haukeland University Hospital, National Study Center Norway
Bergen, , Norway
Oslo University Hospital, Rikshospitalet
Oslo, , Norway
University Hospital Northern Norway
Tromsø, , Norway
St Olavs Hospital
Trondheim, , Norway
Sahlgrenska Universitetssjukhuset, Drottning Silvias Barn och Ungdomssjukhus, Barncancercentrum
Gothenburg, , Sweden
Universitetssjukhuset i Linköping, Barn och Ungdomsmedicinska kliniken, Barnonkologiska enheten
Linköping, , Sweden
Skåne Universitetssjukhus, Barnonkologi
Lund, , Sweden
Karolinska Universitetssjukhuset, Astrid Lindgrens Barnsjukhus, Barnonkologen
Stockholm, , Sweden
Universitetssjukhus Umeå, Barnonkologiska avdelningen, Barn 3 Norrlands
Umeå, , Sweden
Akademiska sjukhuset, Barnavdelningen för blod- och tumörsjukdomar
Uppsala, , Sweden
Kantonsspital Aarau, Kinderklinik
Aarau, , Switzerland
Universitäts - Kinderspital beider Basel
Basel, , Switzerland
Ospedale San Giovanni, Reparto die Pediatria
Bellinzona, , Switzerland
Universitätsklinik für Kinderheilkunde, Pädiatrische Hämatologie/ Onkologie, Inselspital
Bern, , Switzerland
Hôpital des Enfants, Unité d'Oncologie Hématologie
Geneva, , Switzerland
Centre hospitalier universitaire vaudois, Unité d'hémato-oncologie pédiatrique
Lausanne, , Switzerland
Kinderspital Pädiatrische Hämatologie/ Onkologie
Lucerne, , Switzerland
Ostschweizer Kinderspital, Hämatologie/ Onkologie
Sankt Gallen, , Switzerland
Universitäts-Kinderspital, Pädiatrische Onkologie
Zurich, , Switzerland
Countries
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Other Identifiers
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2013-003253-21
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
UKM12_0020
Identifier Type: -
Identifier Source: org_study_id
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