Clinical trial NCT03206671: Treatment Protocol of the NHL-BFM and the NOPHO Study Groups for Mature Aggressive B-cell Lymphoma and Leukemia in Children and Adolescents
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Mature B-cell Non-Hodgkin Lymphoma
Lead sponsor: University Hospital Muenster
Sponsor class: OTHER
Collaborators: name: Deutsche Krebshilfe e.V., Bonn (Germany)
First posted: 2017-07-02
Enrollment: 650
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Event-free survival (EFS)
timeFrame: through study completion, maximal seven years
measure: Immune reconstitution rate (only in R3/R4 patients)
timeFrame: 12 months after start of treatment
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: through study completion, maximal seven years
measure: Relapse-free survival (RFS)
timeFrame: through study completion, maximal seven years
measure: Response rate (RR)
timeFrame: 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)
measure: Adverse event rate
timeFrame: from the first day of protocol defined treatment until two years after start of protocol defined treatment
measure: Rate of patients achieving normal immunoglobulin level 12 months after start of treatment
timeFrame: 12 months after start of treatment
measure: Time interval to normal immunoglobulin level
timeFrame: through study completion, maximal seven years
measure: Time interval from start of treatment to normal CD19 positive B-cells in the peripheral blood.
timeFrame: through study completion, maximal seven years
measure: Rate of patients with normal lymphocyte subpopulations in the peripheral blood 12 months after start of treatment
timeFrame: 12 months after start of treatment
measure: Interval to normal lymphocyte subpopulations in the peripheral blood.
timeFrame: through study completion, maximal seven years
measure: Rate of infections (defined by CTCAE V4) in the time interval from start of treatment until 24 months after start of treatment
timeFrame: 24 months after start of treatment
measure: 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)
timeFrame: through study completion, maximal seven years
measure: Rate of patients with sufficient titers after vaccination one year after start of treatment
timeFrame: 1 year after start of treatment
measure: Immune reconstitution rate (only in R1/R2 patients)
timeFrame: 12 months after start of treatment
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Univ.Klinik für Kinder- und Jugendheilkunde Graz, Klin. Abteilung für pädiatrische Hämato-Onkologie
city: Innsbruck
country: Austria
facility: Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck, Universitätsklinik für Pädiatrie I
city: Klagenfurt
country: Austria
facility: Klinikum Klagenfurt am Wörthersee, Abteilung für Kinder- und Jugendheilkunde
city: Linz
country: Austria
facility: Kepler Universitätsklinikum, Med Campus IV / Onkologie
city: Salzburg
country: Austria
facility: LKH Salzburg, Universitätsklinik für Kinder- und Jugendheilkunde, Kinderonkologie
city: Wien
country: Austria
facility: St. Anna Kinderspital
city: Prague
country: Czechia
facility: Department of Pediatric Hematology and Oncology, University Hospital Motol
city: Aalborg
country: Denmark
facility: Børneonkologisk afsnit 303B, Børneafdelingen, Aalborg Universitetshospital Nord
city: Aarhus
country: Denmark
facility: Børn og Unge afsnit 4, Børneafdelingen, Aarhus Universitetshospital Skejby
city: Kobenhavn
country: Denmark
facility: Børneonkologisk afsnit 5054, BørneUngeKlinikken, Juliane Marie Centret, Rigshospitalet
city: Odense
country: Denmark
facility: Børneonkologisk afsnit H2, H. C. Andersen Børnehospital, Odense Universitetshospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital, Children´s Hospital, Dept of Pediatric Hematology and Oncology
city: Kuopio
country: Finland
facility: Kuopio University Hospital, Paediatric Haematology and Oncology
city: Oulu
country: Finland
facility: University Hospital of Oulu, Paediatric Haematology and Oncology
city: Tampere
country: Finland
facility: Tampere University Hospital, Paediatric Haematology and Oncology
city: Turku
country: Finland
facility: Turku University Hospital, Paediatric and Adolescent Haematology and Oncology
city: Aachen
country: Germany
facility: Universitätsklinikum Aachen, Klinik für Kinder - und Jugendmedizin, Hämatologie / Onkologie
city: Augsburg
country: Germany
facility: Klinikum Augsburg, Schwäbisches Kinderkrebszentrum, I. Klinik für Kinder und Jugendliche, Hämatologie / Onkologie
city: Berg
country: Germany
facility: Charité Campus Virchow-Klinikum, Zentrum für Kinder- und Jugendmedizin, Abt. Hämatologie / Onkologie
city: Berlin
country: Germany
facility: HELIOS Klinikum Berlin-Buch, Kinderklinik, Pädiatrische Hämatologie und Onkologie
city: Bielefeld
country: Germany
facility: Evangelisches Krankenhaus Bielefeld GmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie und Onkologie
city: Bonn
country: Germany
facility: Zentrum für Kinderheilkunde der Universität Bonn, Abt. Päd. Hämatologie / Onkologie
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig gGmbH, Klinik für Kinder- und Jugendmedizin, Station K5 / Päd. Hämato- und Onkologie
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte gGmbH, Prof.-Hess-Kinderklinik,Pädiatrische Onkologie und Hämatologie
city: Cottbus
country: Germany
facility: Carl-Thieme-Klinikum Cottbus gGmbH, Klinik für Kinder- und Jugendmedizin
city: Datteln
country: Germany
facility: Vestische Kinderklinik, Universität Witten / Herdecke
city: Dortmund
country: Germany
facility: Klinikum Dortmund gGmbH, Klinik für Kinder- und Jugendmedizin, Station K1, Abt. Päd. Onkologie / Hämatologie
city: Dresden
country: Germany
facility: Universitätsklinik Carl Gustav Carus der TU Dresden, Klinik für Kinder- und Jugendmedizin
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf, Zentrum für Kinder- und Jugendmedizin, Klinik für Päd. Hämatologie und Onkologie
city: Erfurt
country: Germany
facility: HELIOS Klinikum Erfurt GmbH, Klinik für Kinder- und Jugendmedizin, Päd. Onkologie / Hämatologie
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Klinik für Kinder- und Jugendmedizin, Pädiatrische Onkologie / Hämatologie
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Zentrum für Kinder- und Jugendmedizin, Hämatologie / Onkologie
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin, Klinik IV: Päd. Hämatologie und Onkologie
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen und Marburg, Standort Gießen, Zentrum für Kinderhämatologie und -onkologie
city: Greifswald
country: Germany
facility: Universitätsklinikum Greifswald KdöR, Klinik und Poliklinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Onkologie und Hämatologie
city: Göttingen
country: Germany
facility: Georg-August-Universität Universitäts-Kinderklinik, Pädiatrie I
city: Halle (Saale)
country: Germany
facility: Universitätsklinikum Halle (Saale), Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / Onkologie
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg Eppendorf, Zentrum für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und Onkologie
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover, Kinderheilkunde, Päd. Hämatologie / Onkologie
city: Heidelberg
country: Germany
facility: Universitäts-Kinderklinik Heidelberg, Abt. Hämatologie / Onkologie
city: Herdecke
country: Germany
facility: Gemeinschaftskrankenhaus Herdecke, Kinder- und Jugendmedizin, Päd. Hämatologie / Onkologie
city: Homburg
country: Germany
facility: Universitätskliniken für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie, Geb. 9
city: Jena
country: Germany
facility: Universitätsklinikum Jena, Klinik für Kinder- und Jugendmedizin
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe gGmbH, Kinderklinik, Station S 24
city: Kassel
country: Germany
facility: Klinikum Kassel Gesundheit Nordhessen Holding AG, Klinik für pädiatrische Hämatologie und Onkologie
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig Holstein Campus Kiel, Klinik für Allgemeine Pädiatrie, Päd. Onkologie / Hämatologie
city: Koblenz
country: Germany
facility: Gemeinschaftsklinikum Mittelrhein Kemperhof, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und Onkologie
city: Krefeld
country: Germany
facility: HELIOS Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin, Päd. Hämatologie/Onkologie
city: Köln
country: Germany
facility: Klinikum der Universität zu Köln, Klinik für Kinder- und Jugendmedizin, Abt. Kinderonkologie und -hämatologie
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig, Klinik für Kinder und Jugendliche, Abt. Päd. Hämatologie / Onkologie
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig Holstein Campus Lübeck, Klinik für Kinder- und Jugendmedizin, Hämatologie und Onkologie
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg A. ö. R., Kinderklinik, Päd. Hämatologie / Onkologie
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Zentrum für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / Onkologie
city: Mannheim
country: Germany
facility: Klinikum Mannheim gGmbH, Universitäts-Kinderklinik, Päd. Onkologie /Hämatologie
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie / Onkologie, Station E 22
city: München
country: Germany
facility: Klinikum der LMU, Dr. von Haunersches Kinderspital, Pädiatrische Hämatologie / Onkologie
city: München
country: Germany
facility: Klinikum Schwabing, Kinderklinik der TU Päd. Hämatologie / Onkologie, Station 24d
city: Münster
country: Germany
facility: Universitätsklinikum Münster, Klinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und Onkologie
city: Nürnberg
country: Germany
facility: Diakonie Neuendettelsau, Kliniken Hallerwiese / Cnopf'sche Kinderklinik, Pädiatrische Hämatologie /Onkologie
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg AöR, Zentrum für Kinder- und Jugendmedizin, Abt. Hämatologie / Onkologie
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg, Klinik für Kinder- und Jugendmedizin, Abt. Päd. Hämatologie, Onkologie, SZT
city: Rostock
country: Germany
facility: Universitätsklinikum Rostock, Kinder- und Jugendklinik, Päd. Hämatologie und Onkologie
city: Sankt Augustin
country: Germany
facility: Asklepios Klinik St. Augustin GmbH, Kinder- und Jugendmedizin, Kinder-Hämatologie und Onkologie
city: Schwerin
country: Germany
facility: HELIOS Kliniken Schwerin GmbH, Klinik für Kinder- und Jugendmedizin, Station A1
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart, Olgahospital Zentrum für Kinder- und Jugendmedizin Pädiatrie 5 (Onkologie, Hämatologie, Immunologie)
city: Tübingen
country: Germany
facility: Universitätsklinik Tübingen Klinik für Kinderheilkunde und Jugendmedizin, Päd. Hämatologie / Onkologie
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie
city: Würzburg
country: Germany
facility: Universitätskinderklinik Würzburg, Päd. Onkologie und Hämatologie
city: Bergen
country: Norway
facility: Haukeland University Hospital, National Study Center Norway
city: Oslo
country: Norway
facility: Oslo University Hospital, Rikshospitalet
city: Tromsø
country: Norway
facility: University Hospital Northern Norway
city: Trondheim
country: Norway
facility: St Olavs Hospital
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset, Drottning Silvias Barn och Ungdomssjukhus, Barncancercentrum
city: Linköping
country: Sweden
facility: Universitetssjukhuset i Linköping, Barn och Ungdomsmedicinska kliniken, Barnonkologiska enheten
city: Lund
country: Sweden
facility: Skåne Universitetssjukhus, Barnonkologi
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset, Astrid Lindgrens Barnsjukhus, Barnonkologen
city: Umeå
country: Sweden
facility: Universitetssjukhus Umeå, Barnonkologiska avdelningen, Barn 3 Norrlands
city: Uppsala
country: Sweden
facility: Akademiska sjukhuset, Barnavdelningen för blod- och tumörsjukdomar
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau, Kinderklinik
city: Basel
country: Switzerland
facility: Universitäts - Kinderspital beider Basel
city: Bellinzona
country: Switzerland
facility: Ospedale San Giovanni, Reparto die Pediatria
city: Bern
country: Switzerland
facility: Universitätsklinik für Kinderheilkunde, Pädiatrische Hämatologie/ Onkologie, Inselspital
city: Geneva
country: Switzerland
facility: Hôpital des Enfants, Unité d'Oncologie Hématologie
city: Lausanne
country: Switzerland
facility: Centre hospitalier universitaire vaudois, Unité d'hémato-oncologie pédiatrique
city: Luzern
country: Switzerland
facility: Kinderspital Pädiatrische Hämatologie/ Onkologie
city: Saint Gallen
country: Switzerland
facility: Ostschweizer Kinderspital, Hämatologie/ Onkologie
city: Zürich
country: Switzerland
facility: Universitäts-Kinderspital, Pädiatrische Onkologie
Study officials:
affiliation: University Hospital Muenster, Klinik für Kinder- und Jugendmedizin - Pädiatrische Hämatologie und Onkologie
name: Birgit Burkhardt, Prof. Dr. Dr.
role: PRINCIPAL_INVESTIGATOR
References: