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
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 650
- 试验地点
- 88
- 主要终点
- Event-free survival (EFS)
研究概览
简要总结
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
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Cyclophosphamide (Drug)
R2 stage III standard arm
Standard chemotherapy
干预措施: Doxorubicin hydrochloride (Drug)
R2 stage III standard arm
Standard chemotherapy
干预措施: Etoposide (Drug)
R2 stage III standard arm
Standard chemotherapy
干预措施: Ifosfamide (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Methotrexate (Drug)
R2 stage III standard arm
Standard chemotherapy
干预措施: Cytarabine (Drug)
R2 stage III standard arm
Standard chemotherapy
干预措施: Dexamethasone (Drug)
R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
干预措施: Rituximab window (Drug)
R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
干预措施: Cyclophosphamide (Drug)
R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
干预措施: Cytarabine (Drug)
R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
干预措施: Dexamethasone (Drug)
R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
干预措施: Etoposide (Drug)
R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
干预措施: Ifosfamide (Drug)
R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
干预措施: Methotrexate (Drug)
R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
干预措施: Prednisolone (Drug)
R1/R2 stage I+II
Rituximab window + standard chemotherapy without anthracyclines (Vincristine not in R1)
干预措施: Vincristine (Drug)
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Rituximab window (Drug)
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Cytarabine (Drug)
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Dexamethasone (Drug)
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Doxorubicin hydrochloride (Drug)
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Etoposide (Drug)
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Ifosfamide (Drug)
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Methotrexate (Drug)
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Prednisolone (Drug)
R2 stage III experimental arm
Rituximab window + Standard chemotherapy
干预措施: Vincristine (Drug)
R2 stage III standard arm
Standard chemotherapy
干预措施: Cyclophosphamide (Drug)
R2 stage III standard arm
Standard chemotherapy
干预措施: Methotrexate (Drug)
R2 stage III standard arm
Standard chemotherapy
干预措施: Prednisolone (Drug)
R2 stage III standard arm
Standard chemotherapy
干预措施: Vincristine (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Rituximab window (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Additional doses of Rituximab (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Cyclophosphamide (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Cytarabine (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Dexamethasone (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Doxorubicin hydrochloride (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Vindesine Sulfate (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Etoposide (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Ifosfamide (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Methotrexate (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Prednisolone (Drug)
R3/R4 rituximab plus arm
Rituximab window + standard chemotherapy plus six additional doses of rituximab
干预措施: Vincristine (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Rituximab window (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Cyclophosphamide (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Cytarabine (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Dexamethasone (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Doxorubicin hydrochloride (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Vindesine Sulfate (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Etoposide (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Ifosfamide (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Prednisolone (Drug)
R3/R4 standard arm
Rituximab window + standard chemotherapy
干预措施: Vincristine (Drug)
结局指标
主要结局
Event-free survival (EFS)
时间窗: through study completion, maximal seven years
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)
时间窗: 12 months after start of treatment
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.
次要结局
- Relapse-free survival (RFS)(through study completion, maximal seven years)
- Adverse event rate(from the first day of protocol defined treatment until two years after start of protocol defined treatment)
- Time interval from start of treatment to normal CD19 positive B-cells in the peripheral blood.(through study completion, maximal seven years)
- Overall survival (OS)(through study completion, maximal seven years)
- Rate of patients with normal lymphocyte subpopulations in the peripheral blood 12 months after start of treatment(12 months after start of treatment)
- Interval to normal lymphocyte subpopulations in the peripheral blood.(through study completion, maximal seven years)
- 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)
- 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)
- Rate of patients with sufficient titers after vaccination one year after start of treatment(1 year after start of treatment)
- Response rate (RR)(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))
- Rate of patients achieving normal immunoglobulin level 12 months after start of treatment(12 months after start of treatment)
- Time interval to normal immunoglobulin level(through study completion, maximal seven years)
- Immune reconstitution rate (only in R1/R2 patients)(12 months after start of treatment)