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

Mature B-cell Non-Hodgkin Lymphoma Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03206671
• Other study ID #: UKM12_0020
• Secondary ID: 2013-003253-21
• Status: Recruiting
• Phase: Phase 3
• Start date: August 3, 2017
• Est. completion date: August 2024

Study information

• Verified date: November 2023
• Source: University Hospital Muenster
• Contact: Birgit Burkhardt, Prof. Dr. Dr.
• Phone: +49 251 83 55696
• Email: b-nhl2013[@]ukmuenster.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 650
• Est. completion date: August 2024
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

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

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, B-Cell
• Mature B-cell Non-Hodgkin Lymphoma

Intervention

Drug:
• 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

Locations

Country	Name	City	State
Austria	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	LKH Leoben, Abteilung für Kinder- und Jugendheilkunde	Leoben
Austria	Kepler Universitätsklinikum, Med Campus IV / Onkologie	Linz
Austria	LKH Salzburg, Universitätsklinik für Kinder- und Jugendheilkunde, Kinderonkologie	Salzburg
Austria	St. Anna Kinderspital	Wien
Czechia	Department of Pediatric Oncology, University Hospital Brno	Brno
Czechia	Department of Pediatric Hematology and Oncology, University Hospital Motol	Prague
Denmark	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	Kobenhavn
Denmark	Børneonkologisk afsnit H2, H. C. Andersen Børnehospital, Odense Universitetshospital	Odense
Finland	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
Germany	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 Chemnitz gGmbH, Klinik für Kinder- und Jugendmedizin, Päd. Hämatologie und Onkologie	Chemnitz
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
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 (Saale)
Germany	Universitätsklinikum Hamburg Eppendorf, Zentrum für Kinder- und Jugendmedizin, Abt. Pädiatrische Hämatologie und Onkologie	Hamburg
Germany	Medizinische Hochschule Hannover, Kinderheilkunde, Päd. Hämatologie / Onkologie	Hannover
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	Klinikum der Universität zu Köln, Klinik für Kinder- und Jugendmedizin, Abt. Kinderonkologie und -hämatologie	Köln
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	Nürnberg
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	Klinikum Mutterhaus der Borromäerinnen gGmbH, Pädiatrische Abteilung	Trier
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
Norway	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
Sweden	Sahlgrenska Universitetssjukhuset, Drottning Silvias Barn och Ungdomssjukhus, Barncancercentrum	Göteborg
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
Switzerland	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	Luzern
Switzerland	Ostschweizer Kinderspital, Hämatologie/ Onkologie	Saint Gallen
Switzerland	Universitäts-Kinderspital, Pädiatrische Onkologie	Zürich

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Muenster	Deutsche Krebshilfe e.V., Bonn (Germany)

Countries where clinical trial is conducted

Austria,  Czechia,  Denmark,  Finland,  Germany,  Norway,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	Rate of patients achieving normal immunoglobulin level 12 months after start of treatment		12 months after start of treatment
Secondary	Time interval to normal immunoglobulin level		through study completion, maximal seven years
Secondary	Time interval from start of treatment to normal CD19 positive B-cells in the peripheral blood.		through study completion, maximal seven years
Secondary	Rate of patients with normal lymphocyte subpopulations in the peripheral blood 12 months after start of treatment		12 months after start of treatment
Secondary	Interval to normal lymphocyte subpopulations in the peripheral blood.		through study completion, maximal seven years
Secondary	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
Secondary	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
Secondary	Rate of patients with sufficient titers after vaccination one year after start of treatment		1 year after start of treatment
Secondary	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