R-ACVBP Versus R-CHOP in Patients Aged 60-65 With Diffuse Large B-cell Lymphoma

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the efficacy of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) plus rituximab in comparison to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) plus rituximab in patients aged from 60 to 65 years with non-previously treated diffuse large B-cell lymphoma as measured by the event-free survival. The goal is to obtain a 10% increase of event-free survival at 3 years.

Detailed Description
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In Europe, 50% or more of new non-Hodgkin lymphoma cases occur in patients older than 60 years. More than 30% are diffuse large B-cell lymphomas (DLCL). The CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone) was considered as the standard treatment in this population. Nevertheless, this treatment is associated with some toxic events in elderly patients and it did does not succeed to increase the 3-year survival rate above 40%. Two trials in patients above 60 years with DLCL cases were conducted by the GELA in the aim to improve the results of CHOP. Protocol LNH 93-5 : The primary objective of this study was to compare CHOP to ACVBP in patients aged from 61 to 69 years with aggressive lymphoma and at least one adverse prognostic factor according to the International Prognostic Index. Unlike the CHOP regimen, the ACVBP regimen includes a more intensive induction followed by a sequential consolidation with drugs different from those used during the induction phase, and includes a prevention of neuromeningeal relapses. Out of 708 patients included in this study, the results have shown that: Complete response rate was the same in the two arms. Event free survival was significantly better in the ACVBP arm than the CHOP arm ( 5-year survival rate : 39% versus 29%, p=0.005). Overall survival was significantly better in the ACVBP arm than in the CHOP arm (the 5-year survival rate : 46% versus 38%, p=0.036). The ACVBP regimen was more toxic than the CHOP regimen, particularly in elderly patients (> 65 years) and in patients with a low performance status. Prevention of neuromeningeal relapses was necessary for these patients. Protocol LNH 98-5, the objective of this study was to compare the association CHOP + rituximab (R-CHOP) to the CHOP regimen alone in elderly patients with non previously treated diffuse large B-cell lymphoma. Long-term results based on data from 399 patients, with a median follow-up of 5 years were as follows : Complete response rate was better in the R-CHOP arm than in the CHOP arm (76% versus 61%, p<0.005). Significant prolongation of event-free survival (p<0.0002) and overall survival (p<0.0073) in the R-CHOP arm. No significant difference between the two arms in terms of toxicity. R-CHOP is now considered worldwide as the standard combination for these patients. These conclusions invited us to propose a randomized trial comparing ACVBP + rituximab to CHOP + rituximab. The study population is limited to patients aged from 60 to 65 years.

Official Title
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Randomized Study of ACVBP Plus Rituximab Versus CHOP Plus Rituximab in Non Previously Treated Patients Aged From 60 to 65 Years With Diffuse Large B-Cell Lymphoma

Conditions
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Lymphoma, Large-Cell, Diffuse

Intervention / Treatment
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* Drug: Rituximab
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Vindesine
* Drug: Bleomycin
* Drug: Prednisone
* Drug: Prednisone
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with diffuse large B-cell lymphoma according to the WHO classification (anti CD20 labeling) Aged from 60 to 65 years. Not previously treated. Ann Arbor stage II, III, IV. ECOG performance status 0 to 2. Minimum life expectancy of 3 months. Negative HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies test 4 weeks (except after vaccination). Having previously signed a written informed consent. Exclusion Criteria: T-cell lymphoma. Any history of treated or non-treated indolent lymphoma. However, patients not previously diagnosed and having a diffuse large B-cell lymphoma with some small cell infiltration in bone marrow or lymph node may be included. Central nervous system or meningeal involvement by lymphoma. Contra-indication to any drug contained in the chemotherapy regimens. Any serious active disease (according to the investigator's decision). Poor renal function (creatinine level>150micromol/l), poor hepatic function (total bilirubin level>30mmol/l, transaminases>2.5 maximum normal level) unless these abnormalities are related to the lymphoma. Poor bone marrow reserve as defined by neutrophils<1.5G/l or platelets<100G/l, unless related to bone marrow infiltration. Any history of cancer during the last 5 years with the exception of non-melanoma skin tumors or stage 0 (in situ) cervical carcinoma. Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy and during the study. Adult patient under tutelage.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R-ACVBP<br>Rituximab, Doxorubicin, Cyclophosphamide, Vindesine, Bleomycin, Prednisone | Drug: Rituximab<br>* 375 mg/m², D1, 4 cycles<br>Drug: Doxorubicin<br>* 75 mg/m², D1, 4 cycles<br>Drug: Cyclophosphamide<br>* 1200 mg/m², D1, 4 cycles<br>Drug: Vindesine<br>* 2 mg/m², D1, D5, 4 cycles<br>Drug: Bleomycin<br>* 10 mg, D1, D5, 4 cycles<br>Drug: Prednisone<br>* 60 mg, D1-D5, 4 cycles<br>|
| Active Comparator: R-CHOP<br>Rituximab, Doxorubicin, Cyclophosphamide, Vincristine, Prednisone | Drug: Rituximab<br>* 375 mg/m², D1, 4 cycles<br>Drug: Prednisone<br>* 40 mg, D1-D5, 4 cycles<br>Drug: Doxorubicin<br>* 50 mg/m², D1, 4 cycles<br>Drug: Cyclophosphamide<br>* 750 mg/m², D1, 4 cycles<br>Drug: Vincristine<br>* 1.4 mg/m², D1, 4 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| event free survival | percentage of patients alive with no event | 8 years (end of study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete response rate | percentage of patients with complete response | 8 years (end of study) | 
| progression rate | percentage of patients with progression | 8 years (end of study) | 
| relapse rate | percentage of patients with relapse | 8 years (end of study) | 
| disease-free survival for complete responders | percentage of patients with complete response who remain disease-free | 8 years (end of study) | 
| overall survival | percentage of patients alive | 8 years (end of study) | 
| neuromeningeal relapse rate | percentage of patients with neuromeningeal relapse | 8 years (end of study) | 
| number of SAE |  | 8 years (end of study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, chemotherapy, rituximab