Efficacy/Safety Study of R-CHOP vs Bortezomib-R-CAP for Young Patients With Diffuse Large B-cell Lymphoma With Poor IPI.

Study Overview
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Brief Summary
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Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for between 30% and 50% of the patients. Although it is considered a curable disease, still at least 40 % of the patients will fail first line chemotherapy. The International Prognostic Index (IPI) score and the age adjusted IPI (aIPI) has been used since they were published to identify patients with different outcome. There is not standard therapy for young patients with DLBCL and unfavourable IPI score. The survival of these patients remains poor, with EFS around 40%. The combination of RCHOP with new drugs is an attractive approach to treat these patients. The goal is to evaluate the proportion of patients with Event-Free Survival (EFS) after 2 years, with a diagnosis of DLBCL with an aIPI > 1 or an aIPI =1 with increased levels of beta-2-microglobulin (above the Upper Limits of Normal.)

Detailed Description
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Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for between 30% and 50% of the patients. Although it is considered a curable disease, still at least 40 % of the patients will fail first line chemotherapy. The International Prognostic Index (IPI) score and the age adjusted IPI (aIPI) has been used since they were published to identify patients with different outcome. CHOP chemotherapy administered every 21 days has been for years the standard therapy for advanced DLBCL achieving a long term overall survival (OS) of about 40%. Many studies show that the addition of the monoclonal antibody Rituximab improves the patients survival achieving higher rates of event-free survival in elderly patients with both,favourable and unfavourable IPI score. R-CHOP also improved survival in young patients with favourable IPI score. There is not standard therapy for young patients with DLBCL and unfavourable IPI score. The survival of these patients remains poor, with EFS around 40%. The combination of RCHOP with new drugs is an attractive approach to treat these patients. The investigators propose a phase II randomized clinical trial for young patients with unfavourable IPI score DLBCL using 6 cycles of the combination of subcutaneous Bortezomib with R-CAP (RCHOP without vincristine, to avoid neuropathy) comparing with the standard immunochemotherapy regimen R- CHOP every 21 days. The goal is to evaluate the proportion of patients with Event-Free Survival (EFS) after 2 years, with a diagnosis of DLBCL with aIPI > 1 or aIPI =1 with increased levels of beta-2-microglobulin (above the Upper Limits of Normal).

Official Title
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Multicenter Randomized Phase II Study of Treatment With R-CHOP vs Bortezomib-R-CAP for Young Patients With Diffuse Large B-cell Lymphoma With Poor IPI.

Conditions
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Diffuse, Large B-Cell, Lymphoma

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Prednisone
* Drug: Vincristine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with primary diffuse DLBCL who have never received treatment for this condition. Age between 18 and 70 years. Age-adjusted IPI (aIPI) higher than 1, or equal 1 with high levels of beta-2-microglobulin (above UNL) Cluster of Differentiation 20 (CD20) positive b lymphocytes. Eastern Cooperative Oncology Group (ECOG) 0-3. More than 12 weeks of life expectancy. Signed Informed Consent. Nor pregnant women nor breast-feeding women without heterosexual activity during the entire study. Women with heterosexual activity only if they are willing to use two methods of contraceptive. The two contraceptive methods can be, two barrier method or a barrier method combinated with an hormonal contraceptive method to prevent pregnancy, used during the entire study and until 3 months after the study completion. Exclusion Criteria: Pregnant women or in breast-feeding period, or adults in childbearing period not using an effective contraception method. Patients with Central Nervous System (CNS) lymphoma. Severely impaired renal function (creatinine> 2.5 UNL) or hepatic function impairment (bilirubin or Alanine Amino Transaminase (ALT) / Aspartate Aminotransferase (AST) > 3 UNL), unless it is suspected to be due to the disease. Human immunodeficiency virus (HIV) positive patients Patient previously treated for the DLBCL Positive determination of chronic hepatitis B (defined as positive serology for HBsAg). It will be allowed to enroll patients with hidden or previous hepatitis B (defined as positive antibodies against the core of the hepatitis B virus [HBcAb] and HBsAg negative) if undetectable Hepatitis B Virus (HBV) DNA. Positive results for hepatitis C (antibody serology for hepatitis C virus ((HCV)). Patients with HCV positive may only participate if the Polymerase Chain Reaction (PCR) result is negative for HCV RNA. History of cardiovascular disease with ventricular ejection fraction < 50%. Patients with severe psychiatric conditions that may interfere with their ability to understand the study (including alcoholism or drug addiction). Patients with known hypersensitivity to murine proteins or any other components of the study drugs. Transformed follicular lymphoma. History of other neoplastic malignancy with < 5 year of complete response (except for Squamous Cell Carcinoma of the Skin or cervical Carcinoma in situ). Presence of uncontrolled conditions: cardiac, respiratory, neurologic, metabolic etc., not related to lymphoma. Uncontrolled hypertension (diastolic blood pressure over 110 mmHg).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: R-CHOP<br>6 cycles every 21 days. Rituximab: intravenous, 375 mg/m2, day 1 Cyclophosphamide: intravenous, 750 mg/m2, day 1 Doxorubicin: intravenous, 50 mg/m2, day 1 Vincristine: intravenous, 1,4 mg/m2, day 1 Prednisone: oral, 100 mg, days 1-5 | Drug: Rituximab<br>* Rituximab: intravenous, 375 mg/m2, day 1<br>Drug: Cyclophosphamide<br>* Cyclophosphamide: intravenous, 750 mg/m2, day 1<br>Drug: Doxorubicin<br>* Adriamycin:intravenous, 50 mg/m2, day 1<br>* Other names: Adriamycin;Drug: Prednisone<br>* Prednisone: oral, 100 mg, days 1-5<br>Drug: Vincristine<br>* Vincristine: intravenous, 1,4 mg/m2, day 1<br>|
| Experimental: B-R-CAP<br>6 cycles every 21 days Bortezomib: subcutaneous, 1,3 mg/m2, day 1, 8, 15 Rituximab: intravenous, 375 mg/m2, day 1 Cyclophosphamide: intravenous, 750 mg/m2, day 1 Doxorubicin: intravenous, 50 mg/m2, day 1 Prednisone: oral, 100 mg, days 1-5 | Drug: Bortezomib<br>* Bortezomib: subcutaneous, 1,3 mg/m2, day 1, 8, 15.<br>* Other names: Velcade;Drug: Rituximab<br>* Rituximab: intravenous, 375 mg/m2, day 1<br>Drug: Cyclophosphamide<br>* Cyclophosphamide: intravenous, 750 mg/m2, day 1<br>Drug: Doxorubicin<br>* Adriamycin:intravenous, 50 mg/m2, day 1<br>* Other names: Adriamycin;Drug: Prednisone<br>* Prednisone: oral, 100 mg, days 1-5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with Event-Free Survival at 2 years. | To evaluate the proportion of patients with event-free survival at 2 years in patients diagnosed of DLBCL with aIPI > 1 or aIPI=1 with elevated levels of beta 2-microglobulin (above UNL). UNL= Upper Normal Limit. | During treatment period, there will be assessments every 2 cycles. After end of treatment every 3 month the first year, every 6 months the second year and annually from 3rd to 5th year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free survival at 2 years in the different subtypes of DLBCL | Event-free survival at 2 years in the different subtypes of DLBCL subgroups: Germinal center B-cell-like (GCB)/non-GCB. | Once the treatment is started, there will be weekly safety visits, visits before each treatment cycle, at day 60 after the sixth cycle and then follow-up visits every three months during the first 2 years and every 6 months until the 5th year | 
| Overall survival at 2 years | Overall survival at 2 years in patients diagnosed of DLBCL with aIPI > 1 or aIPI=1 with elevated levels of beta 2-microglobulin (above UNL) | Once the treatment is started, there will be weekly safety visits, visits before each treatment cycle, at day 60 after the sixth cycle and then follow-up visits every three months during the first 2 years and every 6 months until the 5th year. | 
| Overall response rate and complete remissions | Overall response rate and complete remissions in patients diagnosed of DLBCL with aIPI > 1 or aIPI=1 with elevated levels of beta 2-microglobulin (above UNL). | Once the treatment is started, there will be weekly safety visits, visits before each treatment cycle, at day 60 after the sixth cycle and then follow-up visits every three months during the first 2 years and every 6 months until the 5th year. | 
| Toxicity according to the CTC criteria | Toxicity according to the Common Toxicity Criteria (CTC) (version 3.0) of the National Cancer Institute (NCI). | Once the treatment is started, there will be weekly safety visits, visits before each treatment cycle, at day 60 after the sixth cycle and then follow-up visits every three months during the first 2 years and every 6 months until the 5th year. | 
| To evaluate the predictive value for EFS of interim PET/CT evaluation | To evaluate the predictive value for EFS of interim PET/CT evaluation after 2 and 4 cycles of chemotherapy. The PET Network group of Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea (GELTAMO), will conduct this blind central review in real-time (qualitative and quantitative, prospective central review of the PET scans performed) | Before treatment, after second cycle, after fourth cycle and after treatment completion. | 
| To identify clinical and biological prognostic factors for response and survival. | To identify clinical and biological prognostic factors for response and survival. | Once the treatment is started, there will be weekly safety visits, a visit before each treatment cycle, a visit at day 60 after the sixth cycle and then follow-up visits every three months the first 2 years and every 6 months until the 5th year. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, Large B-Cell