Improvement of Outcome and Reduction of Toxicity in Elderly Patients with CD20+ Aggressive B-Cell Lymphoma by an Optimised Schedule of the Monoclonal Antibody Rituximab, Substitution of Conventional by Liposomal Vincristine, and FDG-PET Based Reduction of Therapy in Combination with Vitamin D Substitution
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,152
- 试验地点
- 127
- 主要终点
- Progression-free survival
研究概览
简要总结
The purpose of this study is to improve the outcome of elderly patients with CD20-Aggressive B-Cell Lymphoma and to reduce the toxicity of standard used Immuno-Chemotherapy by using an optimised schedule of the monoclonal antibody Rituximab, substituting conventional by Liposomal Vincristine and by a PET-guided reduction of therapy in Combination with Vitamin D Substitution.
详细描述
Primary objective of study:
"OPTIMAL>60 Less Favourable" Patients with less favourable prognosis: To test whether progression-free survival (PFS) can be improved by substituting conventional by liposomal vincristine; To test whether PFS can be improved by 12 optimised applications instead of 8 2-week applications of rituximab.
"OPTIMAL>60 Favourable": Patients with favourable prognosis: Comparison of neurotoxicity of conventional and liposomal vincristine; Determination of PFS for the treatment strategy of reducing treatment in patients with negative FDG-PET after 4 x R-CHOP/CHLIP-14 (PET-4) and comparison with the corresponding patient population in RICOVER-60.
Secondary objectives: "OPTIMAL>60 Favourable" and "OPTIMAL>60 Less Favourable":
Comparison of the prognostic value of a pre-treatment FDG-PET (PET-0) with conventional CT/MRT.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 61 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age: 61-80 years
- •All risk groups (IPI 1-5)
- •Diagnosis of aggressive CD20+ B-NHL, based on an excisional biopsy of a lymph node or on an appropriate sample of a lymph node or of an extranodal involvement. It will be possible to treat the following entities in this study as defined by the new WHO classification of 200870:
- •Foll. lymphoma grade IIIb
- •DLBCL, not otherwise specified (NOS)
- •common morphologic variants:
- •centroblastic
- •immunoblastic
- •anaplastic
- •rare morphologic variants
- •DLBCL subtypes/entities:
- •T-cell/histiocyte-rich large B-cell lymphoma
- •primary cutaneous DLBCL, leg type
- •EBV-pos. DLBCL of the elderly
- •DLBCL associated with chronic inflammation
- •primary mediastinal (thymic) LBCL
- •intravascular large B-cell-lymphoma
- •ALK-positive large B-cell-lymphoma
- •plasmoblastic lymphoma
- •primary effusion lymphoma
- •transformed indolent lymphoma secondary or simultaneous high grade B-cell-lymphoma
- •B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
- •B-cell lymphoma, unclassifiable, with features intermediate between DLCBL and Hodgkin lymphoma
- •Performance status ECOG 0 - 2 after prephase treatment. The performance status of each patient must be assessed before the initiation and after the end of prephase treatment which, as experience has shown, can result in a significant improvement of the patient's performance status. The pre-treatment performance status which can range from ECOG 0 to ECOG 4 must be documented in the Staging CRF (see ISF); the performance status after the prephase treatment must be documented in the respective Prephase Treatment CRF (PT form: see ISF). A definition of the performance status is provided in Appendix 28.
- •Written informed consent of the patient
- •Contract of participation signed by the study centre and sponsor
排除标准
- •Already initiated lymphoma therapy (except for the prephase treatment)
- •Serious accompanying disorder or impaired organ function (except when due to lymphoma involvement), in particular:
- •heart: angina pectoris CCS >2, cardiac failure e.g. NYHA >2 and/or EF <50% or FS<25% in nuclear medicine examination/echocardiography
- •lungs: if respiratory problems are suspected the patient is to be excluded if the resultant pulmonary function test shows FeV1<50% or a diffusion capacity <50% of the reference values
- •kidneys: creatinine >2 times the upper reference limit
- •liver: bilirubin >2 times the upper reference limit, aspartate transaminase (AST, SGOT) or alanine transaminase (ALT, SGPT) >3 x institutional upper reference limit
- •uncontrollable diabetes mellitus (prephase treatment with predniso[lo]ne!)
- •Platelets <75 000/mm3, leukocytes <2 500/mm3 (if not due to lymphoma)
- •Known hypersensitivity to the medications to be used
- •Known HIV-positivity
- •Patients with severe impairment of immune defense
- •Patients with constipation with imminent risk of ileus
- •Chronic active hepatitis
- •Poor patient compliance
- •Simultaneous participation in other treatment studies or in another clinical trial within the last 6 months
- •Prior chemo- or radiotherapy, long-term use of corticosteroids or anti-neoplastic drugs for previous disorder
- •Other concomitant tumour disease and/or tumour disease in the past 5 years (except for localised skin tumors other than melanoma and carcinomas in situ of any other origin)
- •CNS involvement of lymphoma (intracerebral, meningeal, intraspinal intradural) or primary CNS lymphoma
- •Persistent neuropathy grade ≥2 (NCI CTC-AE v4.03) (unless due to lymphoma involvement)
- •History of persistent active neurologic disorders grade >2 including demyelinating form of Charcot-Marie-Tooth syndrome, acquired demyelinating disorders, or other demyelinating condition
- •Pregnancy or breast-feeding women
- •Active serious infections not controlled by oral and/or intravenous antibiotics or anti-fungal medication
- •Any medical condition which in the opinion of the investigator places the subject at an unacceptably high risk for toxicities.
- •MALT lymphoma
- •Non-conformity to eligibility criteria
- •Persons not able to understand the impact, nature, risks and consequences of the trial (including language barrier)
- •Persons not agreeing to the transmission of their pseudonymous data
- •Persons depending on sponsor or investigator
- •Persons from highly protected groups. Pts. with CNS lymphoma should not be included in this study.
研究组 & 干预措施
Favourable Prognosis F-A - Recruitment completed
Induction therapy with 4 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2 additional cycles of R-CHOP-14 + 2xR plus additional involved-site radiotherapy, if FDG-PET negative only 4xR without radiotherapy.
干预措施: Conventional Vincristine (Drug)
Favourable F-B - Arm Closed
Induction therapy with 4 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,4 mg/sqm (max. 2mg absolute), Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2 additional cycles of R-CHLIP-14 + 2xR plus additional involved-site radiotherapy, if FDG-PET negative only 4xR without radiotherapy.
干预措施: Liposomal Vincristine (Drug)
Less Favourable LF-A - Recruitment completed
Induction therapy with 6 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHOP-14 an interim restaging will be performed.
干预措施: Conventional Vincristine (Drug)
Less Favourable LF-A - Recruitment completed
Induction therapy with 6 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHOP-14 an interim restaging will be performed.
干预措施: Ricover-scheme rituximab (Drug)
Less Favourable LF-B - Recruitment completed
Induction therapy with 6 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,67 mg/sqm [uncapped], , Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHLIP-14 an interim restaging will be performed. Recruitment completed.
干预措施: Liposomal Vincristine (Drug)
Less Favourable LF-B - Recruitment completed
Induction therapy with 6 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,67 mg/sqm [uncapped], , Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHLIP-14 an interim restaging will be performed. Recruitment completed.
干预措施: Ricover-scheme rituximab (Drug)
Less Favourable LF-C - Recruitment completed
Induction therapy with 6 cycles of CHOP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) combined with an optimized Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHOP-14 an interim restaging will be performed. Recruitment completed.
干预措施: Conventional Vincristine (Drug)
Less Favourable LF-C - Recruitment completed
Induction therapy with 6 cycles of CHOP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) combined with an optimized Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHOP-14 an interim restaging will be performed. Recruitment completed.
干预措施: optimised rituximab-schedule (Drug)
Less Favourable LF-D - Recruitment completed
Induction therapy with 6 cycles of CHLIP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, 1,67 mg/sqm [uncapped], , Predniso[lo]ne 100mg/d d1-5) combined with an optimised Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHLIP-14 an interim restaging will be performed. Recruitment completed.
干预措施: Liposomal Vincristine (Drug)
Less Favourable LF-D - Recruitment completed
Induction therapy with 6 cycles of CHLIP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, 1,67 mg/sqm [uncapped], , Predniso[lo]ne 100mg/d d1-5) combined with an optimised Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHLIP-14 an interim restaging will be performed. Recruitment completed.
干预措施: optimised rituximab-schedule (Drug)
结局指标
主要结局
Progression-free survival
时间窗: 9 years
"OPTIMAL\>60 Less Favourable": To test the effects of substitution of conventional by liposomal vincristine and of a 2-week applications of 8x rituximab by an optimised application of 12 x rituximab stratified log rank tests will be performed for each question (stratified for IPI-factors). Proportional hazard models will be used to investigate treatment interaction and to obtain estimates for the single treatment effects (HR) adjusting for the IPI-factors. "OPTIMAL\>60 Favourable" Grade of neurotoxicity will be estimated and indicated with a 95% confidence interval (CI) separated to each type of vincristine. To investigate the 3-year PFS with 95% CI the Kaplan-Meier estimator will be used.
次要结局
- for efficacy: CR-rate, PR-rate, rate of primary progressions, relapse rate, EFS and OS; rate and CTC grades of PNP. Prognostic value of the FDG-PET derived imaging biomarkers for lymphoma load: SUV, MTV, TLG.(9 years)