B-NHL 2013, Clinical Study on the Treatment of B-NHL and B-AL in Children and Adolescents

Austria, Czech Republic, Czechia, Denmark, Finland, Germany, Norway, Sweden, Switzerland (ICTRP)

ID di studio ICTRP
EUCTR2013-003253-21 (ICTRP)

Titolo ufficiale (approvato dal comitato etico)
Treatment protocol of the NHL-BFM and the NOPHO study groups for mature aggressive B-cell lymphoma and leukemia in children and adolescents (BASEC)

Titolo accademico
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 (ICTRP)

Titolo pubblico
no (ICTRP)

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

Intervento studiato

Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7

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: METHOTREXATE

Pharmaceutical Form:
INN or Proposed INN: Prednisolone
CAS Number: 50-24-8
Other descriptive name: PREDNISOLONE

Pharmaceutical Form:
INN or Proposed INN: Vincristine
CAS Number: 2068-78-2
Other descriptive name: VINCRISTINE SULFATE

Pharmaceutical Form:
INN or Proposed INN: VINDESINE SULFATE
CAS Number: 59917-39-4

(ICTRP)

Tipo di studio
Interventional clinical trial of medicinal product (ICTRP)

Disegno dello studio
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 (ICTRP)

Criteri di inclusione/esclusione
Gender:
Female: yes
Male: yes

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), 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

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
(ICTRP)

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




Endpoint primari e secondari
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;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.
;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 2028)
(ICTRP)

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 2028) (ICTRP)

Data di registrazione
03.01.2017 (ICTRP)

Inclusione del primo partecipante
09.01.2017 (ICTRP)

Sponsor secondari
non disponibile

Contatti aggiuntivi
NHL-BFM study center, birgit.burkhardt@ukmuenster.de, +492518355696, Universit?tsklinikum M?nster (ICTRP)

ID secondari
2013-99, 2013-003253-21-CZ (ICTRP)

Risultati-Dati individuali dei partecipanti
non disponibile

Ulteriori informazioni sullo studio
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-003253-21 (ICTRP)