Comparison of HD Chemotherapy Followed by Auto-transplant and R-CHOP in High Risk Patients With DLBCL.

Study Overview
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Brief Summary
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Multicentric randomized phase III study comparing high doses of chemotherapy with Rituximab followed by auto-transplant HPC versus CHOP plus Rituximab as first line therapy in high risk patients with DLBCL Non-Hodgkin's lymphomas.

Detailed Description
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Diffuse large B cells Non-Hodgkin's lymphomas represents one of the most frequent form of lymphoma. Its clinical development progresses rapidly and is characterized by a biphasic survival curve with patients in complete remission (which can be considered cured) and patients that relapse. This last group of subjects have only 25%-33% chance of long free disease survival if treated with a second line therapy with high dose chemotherapy plus autologous transplant of PBPC. Therefore in order to achieve an improvement of the overall survival in patient with DLBCL, it is necessary to increase the number of complete remission after first line therapy. The aim of R-HDS study, multicentre randomized phase III trial, is to evaluate and compare the efficacy and safety of an intensive conditioning regimen with high intensity chemo-immunotherapy (R-HDS) plus autologous transplantation versus CHOP conditioning regimen plus Rituximab in patients with unfavorable prognosis at diagnosis.

Official Title
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Multicentric Randomized Phase III Study Comparing High Doses of Chemotherapy With Rituximab Followed by Auto-transplant HPC Versus CHOP Plus Rituximab as First Line Therapy in High Risk Patients With DLBCL Non-Hodgkin's Lymphomas

Conditions
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Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: Rituximab-HDS
* Drug: Rituximab-CHOP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of DLBCL CD20+. Patients with Ann Arbor classification B-bulk >= II Patients of age between 18-65 with age-adjusted IPI 2-3 and ECOG performance status 0-3 or patients of age 61-65 with IPI 3, 4, 5 and ECOG performance status 0-2. The disease stage criteria must be documented with instrumental examinations and bone marrow biopsy. Hematology parameters one week before starting study as follows: Hb >= 9 g/dl, WBC >= 3 x 10exp9/l, neutrophils >= 1.5 x 10exp9/l, PLT >= 100 x 10exp9/l. Patients with pulmonary DLCO >= 50% and cardiac EF >= 40%. Voluntary written informed consent must be signed before recruitment, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Patients must to be informed on the risk of sterility and they must agree to use contraception for the duration of the study. Male subject have to the opportunity of freezing seminal fluid. Exclusion Criteria: Diagnosis different from that describe above. Patients with concomitant, serious and uncontrolled illnesses such as cardiopathies (i.e. congestive cardiopathy, ischemic hearth disease, cardiac arrhythmia not controlled by therapy, IMA in the last six months, hearth disease NYHA class III or IV), hepatopathy not related to the lymphoma (bilirubin >= 2 mg/dl, ALT >= 2.5 times the normal value, alkaline phosphatase >=2.5 times the upper limit), kidneys insufficiency not related to the lymphoma (creatinine >=2 mg/dl). Patients affected by opportunistic infections or with positive serology for HIV, HCV, HbsAg (cases with normal levels of hepatic enzymes and not showing active viral replication documented with HBV-DNA are not excluded from randomization; patients with HBV+ can be enrolled after receiving prophylaxis with lamivudina one week before starting chemotherapy. These patients should be monitored twice a month for HbsAg, HBCab, HBV-DNA). Patients which have or have had another type of cancer exception made for skin cancers (melanoma and in situ cervical cancer not included). Patient with a history of anaphylaxes or more generally patients which have had any serious allergic reaction after serum infusion. Patient with uncontrolled epilepsy, CNS disorders or psychiatric problems which, according to the investigator, is likely to interfere with participation in this clinical study (i.e. the signing of the informed consent, therapy compliance). Inability to attend follow-up visits.

Ages Eligible for Study
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Minimum Age: 18 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-HDS<br>R-HDS : Rituximab supplemented high-dose (Cyclophosphamide,Ara-C, Methotrexate, Etoposide, Cis-Platin) sequential chemotherapy with autografting. | Drug: Rituximab-HDS<br>* Rituximab-HDS<br>* Other names: Rituximab supplemented high-dose sequential chemotherapy.;|
| Active Comparator: R-CHOP<br>Rituximab-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone). | Drug: Rituximab-CHOP<br>* Rituximab-CHOP<br>* Other names: Rituximab/Cyclophosph/doxorubic/vincrist/prednis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival | EFS was defined from the time of the study entry to any treatment failure including disease progression or discontinuation of treatment for any reason or date of the last follow-up visit | 36 months from end of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission | Clinical response was assessed by complete restaging according to Cheson criteria. Cheson BD, Pfistner B, Juweid ME, et al: Revised response criteria for malignant lymphoma. J Clin Oncol 25:579-86, 2007 | Through therapy completion an average of 8 months | 
| Disease Free Survival | DFS was defined from the time of documentation of CR to time to relapse or death as a result of lymphoma or acute toxicity of treatment or date of the last follow-up visit | 36 months from end of therapy | 
| Overall Survival | OS was defined from the time of the study entry to death as a result of any cause or date of the last follow-up visit | 36 months from end of therapy | 
| Toxicity | Percentage of participants with at least one reported episode of CTC grade III or IV toxic events | Through therapy completion an average of 8 months | 
| Efficacy of R-HDS Conditioning as Salvage Therapy in Patients Non-responders After Four Cycles of R-CHOP 14 |  | Through completion of salvage therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL, R-HDS, R-CHOP14