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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)

Primary Purpose

Mature B-cell Non-Hodgkin Lymphoma

Status

Recruiting

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Rituximab window

Additional doses of Rituximab

Cyclophosphamide

Cytarabine

Dexamethasone

Doxorubicin hydrochloride

Vindesine Sulfate

Etoposide

Ifosfamide

Methotrexate

Prednisolone

Vincristine

About this trial

This is an interventional treatment trial for Mature B-cell Non-Hodgkin Lymphoma

Eligibility Criteria

undefined - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Univ.Klinik für Kinder- und Jugendheilkunde Graz, Klin. Abteilung für pädiatrische Hämato-OnkologieRecruiting
Univ.Klinik für Kinder- und Jugendheilkunde Innsbruck, Universitätsklinik für Pädiatrie IRecruiting
Klinikum Klagenfurt am Wörthersee, Abteilung für Kinder- und Jugendheilkunde
LKH Leoben, Abteilung für Kinder- und Jugendheilkunde
Kepler Universitätsklinikum, Med Campus IV / OnkologieRecruiting
LKH Salzburg, Universitätsklinik für Kinder- und Jugendheilkunde, KinderonkologieRecruiting
St. Anna KinderspitalRecruiting
Department of Pediatric Oncology, University Hospital BrnoRecruiting
Department of Pediatric Hematology and Oncology, University Hospital MotolRecruiting
Børneonkologisk afsnit 303B, Børneafdelingen, Aalborg Universitetshospital NordRecruiting
Børn og Unge afsnit 4, Børneafdelingen, Aarhus Universitetshospital SkejbyRecruiting
Børneonkologisk afsnit 5054, BørneUngeKlinikken, Juliane Marie Centret, RigshospitaletRecruiting
Børneonkologisk afsnit H2, H. C. Andersen Børnehospital, Odense UniversitetshospitalRecruiting
Helsinki University Hospital, Children´s Hospital, Dept of Pediatric Hematology and OncologyRecruiting
Kuopio University Hospital, Paediatric Haematology and OncologyRecruiting
University Hospital of Oulu, Paediatric Haematology and OncologyRecruiting
Tampere University Hospital, Paediatric Haematology and OncologyRecruiting
Turku University Hospital, Paediatric and Adolescent Haematology and OncologyRecruiting
Universitätsklinikum Aachen, Klinik für Kinder - und Jugendmedizin, Hämatologie / OnkologieRecruiting
Klinikum Augsburg, Schwäbisches Kinderkrebszentrum, I. Klinik für Kinder und Jugendliche, Hämatologie / OnkologieRecruiting
Charité Campus Virchow-Klinikum, Zentrum für Kinder- und Jugendmedizin, Abt. Hämatologie / OnkologieRecruiting
HELIOS Klinikum Berlin-Buch, Kinderklinik, Pädiatrische Hämatologie und OnkologieRecruiting
Evangelisches Krankenhaus Bielefeld GmbH, Klinik für Kinder- und Jugendmedizin, Hämatologie und OnkologieRecruiting
Zentrum für Kinderheilkunde der Universität Bonn, Abt. Päd. Hämatologie / OnkologieRecruiting
Städtisches Klinikum Braunschweig gGmbH, Klinik für Kinder- und Jugendmedizin, Station K5 / Päd. Hämato- und OnkologieRecruiting
Klinikum Bremen-Mitte gGmbH, Prof.-Hess-Kinderklinik,Pädiatrische Onkologie und HämatologieRecruiting
Klinikum Chemnitz gGmbH, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie
Carl-Thieme-Klinikum Cottbus gGmbH, Klinik für Kinder- und JugendmedizinRecruiting
Vestische Kinderklinik, Universität Witten / HerdeckeRecruiting
Klinikum Dortmund gGmbH, Klinik für Kinder- und Jugendmedizin, Station K1, Abt. Päd. Onkologie / HämatologieRecruiting
Universitätsklinik Carl Gustav Carus der TU Dresden, Klinik für Kinder- und JugendmedizinRecruiting
Universitätsklinikum Düsseldorf, Zentrum für Kinder- und Jugendmedizin, Klinik für Päd. Hämatologie und OnkologieRecruiting
HELIOS Klinikum Erfurt GmbH, Klinik für Kinder- und Jugendmedizin, Päd. Onkologie / HämatologieRecruiting
Universitätsklinikum Erlangen, Klinik für Kinder- und Jugendmedizin, Pädiatrische Onkologie / HämatologieRecruiting
Universitätsklinikum Essen, Zentrum für Kinder- und Jugendmedizin, Hämatologie / OnkologieRecruiting
Universitätsklinikum Frankfurt, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und OnkologieRecruiting
Universitätsklinikum Freiburg, Zentrum für Kinder- und Jugendmedizin, Klinik IV: Päd. Hämatologie und OnkologieRecruiting
Universitätsklinikum Gießen und Marburg, Standort Gießen, Zentrum für Kinderhämatologie und -onkologieRecruiting
Universitätsklinikum Greifswald KdöR, Klinik und Poliklinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Onkologie und HämatologieRecruiting
Georg-August-Universität Universitäts-Kinderklinik, Pädiatrie IRecruiting
Universitätsklinikum Halle (Saale), Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / OnkologieRecruiting
Universitätsklinikum Hamburg Eppendorf, Zentrum für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und OnkologieRecruiting
Medizinische Hochschule Hannover, Kinderheilkunde, Päd. Hämatologie / OnkologieRecruiting
Universitäts-Kinderklinik Heidelberg, Abt. Hämatologie / OnkologieRecruiting
Gemeinschaftskrankenhaus Herdecke, Kinder- und Jugendmedizin, Päd. Hämatologie / OnkologieRecruiting
Universitätskliniken für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie, Geb. 9Recruiting
Universitätsklinikum Jena, Klinik für Kinder- und JugendmedizinRecruiting
Städtisches Klinikum Karlsruhe gGmbH, Kinderklinik, Station S 24Recruiting
Klinikum Kassel Gesundheit Nordhessen Holding AG, Klinik für pädiatrische Hämatologie und OnkologieRecruiting
Universitätsklinikum Schleswig Holstein Campus Kiel, Klinik für Allgemeine Pädiatrie, Päd. Onkologie / HämatologieRecruiting
Gemeinschaftsklinikum Mittelrhein Kemperhof, Klinik für Kinder- und Jugendmedizin, Pädiatrische Hämatologie und OnkologieRecruiting
HELIOS Klinikum Krefeld, Zentrum für Kinder- und Jugendmedizin, Päd. Hämatologie/OnkologieRecruiting
Klinikum der Universität zu Köln, Klinik für Kinder- und Jugendmedizin, Abt. Kinderonkologie und -hämatologieRecruiting
Universitätsklinikum Leipzig, Klinik für Kinder und Jugendliche, Abt. Päd. Hämatologie / OnkologieRecruiting
Universitätsklinikum Schleswig Holstein Campus Lübeck, Klinik für Kinder- und Jugendmedizin, Hämatologie und OnkologieRecruiting
Universitätsklinikum Magdeburg A. ö. R., Kinderklinik, Päd. Hämatologie / OnkologieRecruiting
Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Zentrum für Kinder- und Jugendmedizin, Pädiatrische Hämatologie / OnkologieRecruiting
Klinikum Mannheim gGmbH, Universitäts-Kinderklinik, Päd. Onkologie /HämatologieRecruiting
Johannes Wesling Klinikum Minden, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie / Onkologie, Station E 22Recruiting
Klinikum der LMU, Dr. von Haunersches Kinderspital, Pädiatrische Hämatologie / OnkologieRecruiting
Klinikum Schwabing, Kinderklinik der TU Päd. Hämatologie / Onkologie, Station 24dRecruiting
Universitätsklinikum Münster, Klinik für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und OnkologieRecruiting
Diakonie Neuendettelsau, Kliniken Hallerwiese / Cnopf'sche Kinderklinik, Pädiatrische Hämatologie /OnkologieRecruiting
Klinikum Oldenburg AöR, Zentrum für Kinder- und Jugendmedizin, Abt. Hämatologie / OnkologieRecruiting
Universitätsklinikum Regensburg, Klinik für Kinder- und Jugendmedizin, Abt. Päd. Hämatologie, Onkologie, SZTRecruiting
Universitätsklinikum Rostock, Kinder- und Jugendklinik, Päd. Hämatologie und OnkologieRecruiting
Asklepios Klinik St. Augustin GmbH, Kinder- und Jugendmedizin, Kinder-Hämatologie und OnkologieRecruiting
HELIOS Kliniken Schwerin GmbH, Klinik für Kinder- und Jugendmedizin, Station A1Recruiting
Klinikum Stuttgart, Olgahospital Zentrum für Kinder- und Jugendmedizin Pädiatrie 5 (Onkologie, Hämatologie, Immunologie)Recruiting
Klinikum Mutterhaus der Borromäerinnen gGmbH, Pädiatrische Abteilung
Universitätsklinik Tübingen Klinik für Kinderheilkunde und Jugendmedizin, Päd. Hämatologie / OnkologieRecruiting
Universitätsklinikum Ulm, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie und OnkologieRecruiting
Universitätskinderklinik Würzburg, Päd. Onkologie und HämatologieRecruiting
Haukeland University Hospital, National Study Center NorwayRecruiting
Oslo University Hospital, RikshospitaletRecruiting
University Hospital Northern NorwayRecruiting
St Olavs HospitalRecruiting
Sahlgrenska Universitetssjukhuset, Drottning Silvias Barn och Ungdomssjukhus, BarncancercentrumRecruiting
Universitetssjukhuset i Linköping, Barn och Ungdomsmedicinska kliniken, Barnonkologiska enhetenRecruiting
Skåne Universitetssjukhus, BarnonkologiRecruiting
Karolinska Universitetssjukhuset, Astrid Lindgrens Barnsjukhus, BarnonkologenRecruiting
Universitetssjukhus Umeå, Barnonkologiska avdelningen, Barn 3 NorrlandsRecruiting
Akademiska sjukhuset, Barnavdelningen för blod- och tumörsjukdomarRecruiting
Kantonsspital Aarau, KinderklinikRecruiting
Universitäts - Kinderspital beider BaselRecruiting
Ospedale San Giovanni, Reparto die Pediatria
Universitätsklinik für Kinderheilkunde, Pädiatrische Hämatologie/ Onkologie, InselspitalRecruiting
Hôpital des Enfants, Unité d'Oncologie Hématologie
Centre hospitalier universitaire vaudois, Unité d'hémato-oncologie pédiatrique
Kinderspital Pädiatrische Hämatologie/ OnkologieRecruiting
Ostschweizer Kinderspital, Hämatologie/ OnkologieRecruiting
Universitäts-Kinderspital, Pädiatrische OnkologieRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Other

Experimental

Arm Label

R1/R2 stage I+II

R2 stage III experimental arm

R2 stage III standard arm

R3/R4 rituximab plus arm

R3/R4 standard arm

Arm Description

Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)

Rituximab window + Standard chemotherapy

Standard chemotherapy

Rituximab window + standard chemotherapy plus six additional doses of rituximab

Rituximab window + standard chemotherapy

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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.

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.

Response rate (RR)

Complete response, partial remission, objective effect, stable disease or progressive disease

Adverse event rate

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 interval to normal immunoglobulin level

Time interval from start of treatment to normal CD19 positive B-cells in the peripheral blood.

Rate of patients with normal lymphocyte subpopulations in the peripheral blood 12 months after start of treatment

Interval to normal lymphocyte subpopulations in the peripheral blood.

Rate of infections (defined by CTCAE V4) in the time interval from start of treatment until 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)

Rate of patients with sufficient titers after vaccination one 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.

Full Information

NCT ID

NCT03206671

First Posted

June 27, 2017

Last Updated

June 7, 2021

Sponsor

University Hospital Muenster

Collaborators

Deutsche Krebshilfe e.V., Bonn (Germany)

1. Study Identification

Unique Protocol Identification Number

NCT03206671

Brief Title

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

Acronym

B-NHL 2013

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

2. Study Status

Record Verification Date

June 2021

Overall Recruitment Status

Recruiting

Study Start Date

August 3, 2017 (Actual)

Primary Completion Date

August 2024 (Anticipated)

Study Completion Date

August 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital Muenster

Collaborators

Deutsche Krebshilfe e.V., Bonn (Germany)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Mature B-cell Non-Hodgkin Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

650 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

R1/R2 stage I+II

Arm Type

Experimental

Arm Description

Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)

Arm Title

R2 stage III experimental arm

Arm Type

Experimental

Arm Description

Rituximab window + Standard chemotherapy

Arm Title

R2 stage III standard arm

Arm Type

Other

Arm Description

Standard chemotherapy

Arm Title

R3/R4 rituximab plus arm

Arm Type

Experimental

Arm Description

Rituximab window + standard chemotherapy plus six additional doses of rituximab

Arm Title

R3/R4 standard arm

Arm Type

Experimental

Arm Description

Rituximab window + standard chemotherapy

Intervention Type

Drug

Intervention Name(s)

Rituximab window

Intervention Description

Rituximab window (375 mg/m²)

Intervention Type

Drug

Intervention Name(s)

Additional doses of Rituximab

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Intervention Description