R-ACVBP and DA-EPOCH-R in Patients With Non-GCB DLBCL

Study Overview
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Brief Summary
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This is a randomized, open-label, multi-center, phase 3 study evaluating the efficacy of R-ACVBP and DA-EPOCH-R in patients with newly diagnosed non-germinal b-cell-like diffuse large B-cell lymphoma

Detailed Description
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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. According to Hans' algorithms, DLBCL can be identified as 2 subtypes: germinal b-cell-like(GCB) and non-germinal b-cell-like(non-GCB). Approximately 50 to 60% of diffuse large-B cell lymphoma(DLBCL) was non-GCB subtype DLBCL. Although the introduction of rituximab in immunochemotherapy has dramatically improved the outcome of patients with DLBCL, The survival was still poor in non-GCB DLBCL patients treated with R-CHOP. The LNH03-2B study has shown that R-ACVBP regimen gave a longer PFS (93% vs. 74% at 3 years, p=0.0074) and a longer OS (97% vs. 83% at 3 years, p=0.0067) than R-CHOP in young patients with non-GCB DLBCL. It also showed that R-ACVBP regimen gave a longer PFS (87% vs. 73% at 3 years, p=0.0074) and a longer OS (92% vs. 84% at 3 years, p=0.0067) than R-CHOP in young low-intermediate risk DLBCL patients. The LNH2003-3 study has shown that in high-risk (2/3 IPI factors) DLBCL patients treated with R-ACVBP followed by auto-ASCT results in a 74% PFS and 76% OS. Hematological toxic effects of the intensive regimen were raised but manageable. The CALGB study showed that in DLBCL patients at least 18 years of age and at least stage II, DA-EPOCH-R regimen is effective in both GCB and non-GCB subtypes, with a 5-years TTP 67%, EFS 58% and OS 68% in non-GCB subtype DLBCL. It is encouraging that PETHEMA Group study showed that in the long-term follow-up of untreated DLBCL patients with poor prognosis, DA-EPOCH-R achieved a 70.8% EFS and 76.4% OS at 10 years in non-GCB subtype DLBCL. However the efficacy of R-ACVBP compared to DA-EPOCH-R in patients with newly diagnosed non-germinal b-cell-like diffuse large B-cell lymphoma remains unknown. All the above-mentioned results led us to propose a randomized trial comparing R-ACVBP to DA-EPOCH-R in previously untreated patients with non-GCB DLBCL.

Official Title
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Study of R-ACVBP and DA-EPOCH-R in Patients With Newly Diagnosed Non-germinal Center B-cell-like Diffuse Large B-cell Lymphoma

Conditions
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Lymphoma, Large B-Cell, Diffuse

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with histologically proven CD20+ diffuse large B cell lymphoma (WHO Classification), aaIPI>1, Age >18 and < 61 years, Negative HIV serologies 4 weeks Ability to understand and willingness to sign a written informed consent Exclusion Criteria: Any other histological type of lymphoma. Any history of treated or non-treated indolent lymphoma. Central nervous system or meningeal involvement by lymphoma. Contraindication to any drug contained in the chemotherapy regimens. Any serious active disease (according to the investigator's decision). Poor renal function (creatinin level>150µmol/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 <1.5 G/l or platelets <100 G/l, unless related to bone marrow infiltration. Treatment with any investigational drug within 30 days before planned first cycle of chemotherapy and during the study. Pregnant or lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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 |
| --- | --- |
| Active Comparator: DA-EPOCH-R<br>DA-EPOCH-R regimen: rituximab (375 mg/m2) given intravenously (IV) on day 0, etoposide(50 mg/m2), doxorubicin(10 mg/m2) and vincristine(0.4 mg/m2) given continuous intravenously (CIV) from day 1-4(96 hours), cyclophosphamide(750 mg/m2)/dayg IV on days 5, prednisone (60 mg/m2) given orally bid on days 1 through to 5.All patients received granulocyte colony-stimulating factor (G-CSF) beginning on day 6 and continued until the ANC was more than 5 × 109/L above the nadir level. The adjustment paradigm was based on the ANC nadir in the previous cycle as previously described(Wilson, Grossbard et al. 2002) | Drug: Rituximab<br>* rituximab (375 mg/m2) given intravenously (IV) on day 0<br>Drug: Etoposide<br>* Etoposide(50 mg/m2) given continuous intravenously (CIV) from day 1-4(96 hours)<br>Drug: Doxorubicin<br>* Doxorubicin(10 mg/m2) given continuous intravenously (CIV) from day 1-4(96 hours)<br>Drug: Vincristine<br>* Vincristine(0.4 mg/m2) given continuous intravenously (CIV) from day 1-4(96 hours)<br>Drug: Cyclophosphamide<br>* Cyclophosphamide(750 mg/m2)/dayg IV on days 5<br>Drug: Prednisone<br>* prednisone (100 mg) given orally bid on days 1 through to 5.<br>|
| Experimental: Modified R-ACVBP<br>R-ACVBP regimen: rituximab (375 mg/m2) given intravenously (IV) on day 0, doxorubicin (75 mg/m2) and cyclophosphamide (1,200 mg/m2) given intravenously (IV) on day 1, vindesine (2 mg/m2) given on days 1 and 5, bleomycin (10 mg) given IV on days 1 and 5, prednisone (60 mg/m2) given orally on days 1 through to 5. | Drug: Rituximab<br>* rituximab (375 mg/m2) given intravenously (IV) on day 0<br>Drug: Prednisone<br>* prednisone (100 mg) given orally bid on days 1 through to 5.<br>Drug: Doxorubicin<br>* Doxorubicin (75 mg/m2) given intravenously (IV) on day 1,<br>Drug: Cyclophosphamide<br>* Cyclophosphamide (1,200 mg/m2) given intravenously (IV) on day 1,<br>Drug: Vindesine<br>* Vindesine (2 mg/m2) given on days 1 and 5<br>Drug: Bleomycin<br>* Bleomycin (10 mg) given IV on days 1 and 5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | 3 years | 
| Complete remission rate | 4 cycles after chemotherapy | about 13 weeks after initial chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-germinal b-cell-like, R-ACVBP, DA-EPOCH-R