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

Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea121 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Interventions

BortezomibDRUG

Bortezomib: subcutaneous, 1,3 mg/m2, day 1, 8, 15.

RituximabDRUG

Rituximab: intravenous, 375 mg/m2, day 1

CyclophosphamideDRUG

Cyclophosphamide: intravenous, 750 mg/m2, day 1

DoxorubicinDRUG

Adriamycin:intravenous, 50 mg/m2, day 1

PrednisoneDRUG

Prednisone: oral, 100 mg, days 1-5

VincristineDRUG

Vincristine: intravenous, 1,4 mg/m2, day 1

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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).

Locations (21)

Hospital Clínico Universitario Lozano Blesa

Zaragoza, Aragon, Spain

Hospital Son Llàtzer

Palma, Balearic Islands, Spain

Institut Català d'Oncologia, Hospital Germans Trias i Pujol

Badalona, Barcelona, Spain

Institut Català d'Oncologia, Hospital Duran i Reynals

L'Hospitalet de Llobregat, Barcelona, Spain

Hospital Universitario Marqués de Valdecilla

Santander, Cantabria, Spain

Hospital de Jerez

Jerez de la Frontera, Cádiz, Spain

Hospital Universitario Fundación Alcorcón

Alcorcón, Madrid, Spain

Complejo Hospitalario Universitario de Vigo

Vigo, Pontevedra, Spain

Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, Spain

Hospital Clinic i Provincial de Barcelona

Barcelona, Spain

...and 11 more locations

Outcomes

Primary Outcomes

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.

Time frame: 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 Outcomes

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.

Time frame: 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)

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).

Toxicity according to the CTC criteria

Toxicity according to the Common Toxicity Criteria (CTC) (version 3.0) of the National Cancer Institute (NCI).

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)

Time frame: Before treatment, after second cycle, after fourth cycle and after treatment completion.

To identify clinical and biological prognostic factors for response and survival.

Time frame: 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.