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SNCTP000003449 | EUCTR2013-003253-21 | BASEC2019-01283

B-NHL 2013, Klinische Studie zur Behandlung von B-NHL und B-AL bei Kindern und Jugendlichen

Datenbasis: BASEC (Import vom 29.11.2021), WHO (Import vom 18.04.2021)
Geändert: 10.11.2021
Krankheitskategorie: Leukämie, Non-Hodgkin-Lymphom

Zusammenfassende Beschreibung der Studie (Datenquelle: BASEC)

Die Studie B-NHL 2013 ist eine internationale Therapieoptimierungsstudie, in welcher Zentren der NHL-BFM Studiengruppe (Deutschland, Österreich, Schweiz, Tschechien) sowie der NOPHO Studiengruppe (Schweden, Norwegen, Dänemark und Finnland) teilnehmen. Das Konzept der Studie B-NHL 2013 wurde aus den eigenen Ergebnissen der vorangegangenen Studien sowie den international neuesten Erkenntnissen erarbeitet. Das Ziel der Studie ist es, die Verabreichung des Medikaments Rituximab bei der Behandlung von reifen aggressiven B-Zell-Non-Hodgkin-Lymphom und Leukämie (B-NHL und B-AL) bei Kindern und Jugendlichen in Kombination mit herkömmlichen Chemotherapeutika zu untersuchen.

Untersuchte Krankheiten (Datenquelle: BASEC)

Reife B-Zell Non-Hodgkin-Lymphome (B-NHL) und B-Zell Leukämien (B-AL)

Health conditions (Datenquelle: WHO)

mature aggressive B-cell lymphoma and leukemia in children and adolescents
MedDRA version: 20.0 Level: HLGT Classification code 10025320 Term: Lymphomas non-Hodgkin's B-cell System Organ Class: 10005329 - Blood and lymphatic system disorders ;Therapeutic area: Diseases [C] - Cancer [C04]

Seltene Krankheit (Datenquelle: BASEC)

Ja

Untersuchte Intervention (z.B. Medikament, Therapie, Kampagne) (Datenquelle: BASEC)

Die Behandlung erfolgt nach dem jeweiligen Risiko des Patienten in so genannten Risikogruppen. Bei diesen Risikogruppen bestehen Unterschiede in der Stärke und Dauer der Behandlung, woraus sich unterschiedliche Studienziele ergeben:
• Für Patienten mit sehr wenig fortgeschrittener Erkrankung möchte man die Nebenwirkungen und Langzeitfolgen der Therapie verbessern. Dies soll erreicht werden, indem aus der bisherigen Standardtherapie ein Medikament herausgenommen und stattdessen das neuere Medikament Rituximab eingesetzt wird.
• Für Patienten mit etwas weiter fortgeschrittener, aber immer noch begrenzter Erkrankung soll überprüft werden, ob durch die Hinzunahme von Rituximab zur bisherigen Therapie die Heilungsraten verbessert werden können.
• Für Patienten mit fortgeschrittenen Ausbreitungsstadien sollen die Heilungschancen durch die Erweiterung der Therapie mit Rituximab verbessert werden. Es wird untersucht, ob durch die Intensivierung mit einer bzw. sieben Gaben Rituximab das Therapieergebnis (ereignisfreies Überleben) verbessert werden kann.
• Ein weiteres Ziel der Studie ist die Analyse der Auswirkungen der Therapie mit Rituximab auf das Immunsystem. Es wird erstmalig systematisch untersucht, ob und wie lange es durch die Therapie zu einer Verminderung bestimmter Abwehrzellen bzw. deren Produkte im Blut kommt (Immunrekonstitution). Das Ziel der wissenschaftlichen Begleitforschung ist ein besseres Verständnis für die Biologie der Erkrankung und die Mechanismen der Krankheitsentstehung, um neue Medikamente, Therapieansätze oder diagnostische Methoden zu entwickeln.

Interventions (Datenquelle: WHO)


Trade Name: MabThera
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Pharmaceutical Form:
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50-18-0

Pharmaceutical Form:
INN or Proposed INN: DEXAMETHASONE
CAS Number: 50-02-2

Pharmaceutical Form:
INN or Proposed INN: Cytarabine
CAS Number: 147-94-4
Other descriptive name: CYTARABINE

Pharmaceutical Form:
INN or Proposed INN: Cytarabine
CAS Number: 147-94-4
Other descriptive name: CYTARABINE

Pharmaceutical Form:
INN or Proposed INN: Doxorubicin hydrochloride
CAS Number: 25316-40-9
Other descriptive name: DOXORUBICIN HYDROCHLORIDE

Pharmaceutical Form:
INN or Proposed INN: Etoposide
CAS Number: 33419-42-0
Other descriptive name: ETOPOSIDE

Pharmaceutical Form:
INN or Proposed INN: IFOSFAMIDE
CAS Number: 3778-73-2

Pharmaceutical Form:
INN or Proposed INN: Methotrexate
CAS Number: 59-05-2
Other descriptive name: METHOTREXATE

Pharmaceutical Form:
INN or Proposed INN: Methotrexate
CAS Number: 59-05-2
Other descriptive name: METH

Kriterien zur Teilnahme an der Studie (Datenquelle: BASEC)

- Neu diagnostiziertes reifes aggressives B-Zell-Non-Hodgkin-Lymphom (B-NHL) oder B-Zellleukämie (B-AL)
- CD20-Expression der Lymphomzellen
- Diagnosestellung vor dem 18. Geburtstag

Ausschlusskriterien (Datenquelle: BASEC)

- Hepatitis B oder durchgemachte Hepatitis B
- medizinische, psychiatrische oder soziale Bedingungen, die mit der Studie nicht vereinbar sind
- Überempfindlichkeit gegen Rituximab oder gegen einen Bestandteil der Prüfmedikation

Inclusion/Exclusion Criteria (Datenquelle: WHO)

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
• 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

Are the trial subjects under 18? yes
Number of subjects for this age range: 650
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 (MabThera) or to ingredients of other IMPs
• lack of CD20 expression of the lymphoma cells
• pregnancy and lactation


Weitere Angaben zur Studie im WHO-Primärregister

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-003253-21

Weitere Angaben zur Studie aus der Datenbank der WHO (ICTRP)

https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2013-003253-21-NO

Weitere Informationen zur Studie

Registrationsdatum der Studie

09.11.2017

Einschluss der ersten teilnehmenden Person

03.01.2017

Rekrutierungsstatus

Authorised-recruitment may be ongoing or finished

Wissenschaftlicher Titel (Datenquelle: WHO)

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 - B-NHL 2013

Studientyp (Datenquelle: WHO)

Interventional clinical trial of medicinal product

Design der Studie (Datenquelle: WHO)


Controlled: yes
Randomised: yes
Open: yes
Single blind: no
Double blind: no
Parallel group: yes
Cross over: no
Other: no
If controlled, specify comparator, Other Medicinial Product: no
Placebo: no
Other: yes
Other specify the comparator: historical control group; different dosing schedule of the same product; standard therapy alone
Number of treatment arms in the trial: 6

Phase (Datenquelle: WHO)

Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Primäre Endpunkte (Datenquelle: WHO)


Main Objective: Analyzing in pediatric patients (pts)
•the event-free survival (EFS) in pts with very limited B-NHL (R1 and R2 stage I and II) substituting anthracyclines by the rituximab window (R) without compromising survival rates.
•the EFS in pts with limited B-NHL (R2 stage III) randomly assigned to receive R plus standard chemotherapy (S-CTX) or S-CTX without R.
•the EFS and the immune reconstitution (recovery of CD19+ B-cells, IR) in pts with advanced B-NHL/B-AL (R3 and R4 incl. R4 CNS+) treated with BFM-type CTX and randomly assigned schedules of one versus seven doses rituximab. One dose rituximab = R plus S-CTX. Seven doses rituximab = R plus S-CTX with additional six doses of rituximab added to the first four courses of CTX. It will be tested whether EFS can be improved by adding rituximab and whether one dose rituximab is sufficient to achieve the intended improvement of EFS. In addition, the IR will be analyzed comparing the effect of the two regimens of rituximab added to S-CTX.
;
Secondary Objective: Analyzing
•Event-free survival, overall survival and immune reconstitution for subgroups: histology; CNS status; gender; age: <10 years (y), 10-14 y, >14 y; risk group: R3 versus R4; CD19+ count and/or immunoglobulin (Ig) level prior treatment; Ig substitution; initial performance; response after rituximab window R, after prephase V, after 2nd course; study groups/national groups: BFM versus NOPHO; national groups; and others
•additional parameters for immune reconstitution (IR): lymphocyte subpopulations, Ig levels and grade III/V infections at 6, 12, 18 and 24 months after start of treatment continued 6-monthly until normalization comparing the randomized arms in R3/R4 patients (pts) and evaluating IR in R1/R2 pts. The rate of pts who achieve sufficient titers after vaccination one year after start of treatment will be analyzed
•the effect of one versus seven doses of rituximab on the rate of AE and SAE profile of the randomized arms in R3/R4 pts
;
Timepoint(s) of evaluation of this end point: • Interim analysis (intended to be performed 4 years after the first patient in)
• Final analysis (2 years after the end of recruitment period, approximately 2023)
;
Primary end point(s): For R1/R2- patients with stage I+II the primary endpoint is event-free survival (EFS_T) defined as time from start of treatment 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.

For R2 patients with stage III disease (the 1st randomized study question) the primary endpoint is event-free survival (EFS_R) defined as time from 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.

For R3/R4 patients (the 2nd randomized study question) the primary endpoints are:
1. Event-free survival (EFS_T/EFS_R) 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.
2. Immune reconstitution (IR) rate defined as percentage of patients achieving age adjusted normal B-cell counts 12 months after start of treatment. Achievement of normal B-cell count defined as CD19 positive subpopulations within normal age adjusted range measured in the reference laboratories of the trial.

Sekundäre Endpunkte (Datenquelle: WHO)


Secondary end point(s): For R1/R2 and R3/R4 patients, the secondary endpoints of the trial are
• Overall survival (OS_T/OS_R) 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_T/RFS_R) 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) after rituximab window, after prephase and after 2nd course.
• Adverse event rate (AE): 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 and the 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 and the 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 and 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.

For R1/R2 patients, an additional secondary endpoint is
• Immune reconstitution (IR) rate as defined above in for R3/R4 patients.
;Timepoint(s) of evaluation of this end point: • Final analysis (2 years after the end of recruitment period, approximately 2023)

Kontakt für Auskünfte (Datenquelle: WHO)

Deutsche Krebshilfe

Ergebnisse der Studie (Datenquelle: WHO)

Zusammenfassung der Ergebnisse

noch keine Angaben verfügbar

Link zu den Ergebnissen im Primärregister

noch keine Angaben verfügbar

Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten

noch keine Angaben verfügbar

Studiendurchführungsorte

Durchführungsorte in der Schweiz (Datenquelle: BASEC)

Aarau, Basel, Bellinzona, Bern, Genf, Lausanne, Luzern, St Gallen, Zürich

Durchführungsländer (Datenquelle: WHO)

Austria, Czech Republic, Denmark, Finland, Germany, Norway, Sweden, Switzerland

Kontakt für weitere Auskünfte zur Studie

Angaben zur Kontaktperson in der Schweiz (Datenquelle: BASEC)

Dr Francesco Ceppi
+41 21 314 34 89
francesco.ceppi@chuv.ch

Kontakt für allgemeine Auskünfte (Datenquelle: WHO)

NHL-BFM study center
Domagkstr. 24
Universitätsklinikum Münster
+492518355696
birgit.burkhardt@ukmuenster.de

Kontakt für wissenschaftliche Auskünfte (Datenquelle: WHO)

NHL-BFM study center
Domagkstr. 24
Universitätsklinikum Münster
+492518355696
birgit.burkhardt@ukmuenster.de

Studienverantwortliche

Hauptsponsor (Datenquelle: WHO)

Universitätsklinikum Münster

Bewilligung durch Ethikkommission (Datenquelle: BASEC)

Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)

Kantonale Ethikkommission Zürich

Datum der Bewilligung durch die Ethikkommission

30.10.2019

Weitere Studienidentifikationsnummern

Studienidentifikationsnummer der Ethikkommission (BASEC-ID) (Datenquelle: BASEC)

2019-01283

Secondary ID (Datenquelle: WHO)

2013-99
2013-003253-21-CZ