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

Primary Purpose

Diffuse, Large B-Cell, Lymphoma

Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
Bortezomib
Rituximab
Cyclophosphamide
Doxorubicin
Prednisone
Vincristine
Sponsored by
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse, Large B-Cell, Lymphoma focused on measuring Lymphoma, Large B-Cell

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Hospital Clínico Universitario Lozano Blesa
  • Hospital Universitario Central de Asturias
  • Institut Català d'Oncologia, Hospital Germans Trias i Pujol
  • Institut Català d'Oncologia, Hospital Duran i Reynals
  • Hospital Universitario Marqués de Valdecilla
  • Hospital de Jerez
  • Hospital Son Llàtzer
  • Hospital Universitario Fundación Alcorcón
  • Complejo Hospitalario Universitario de Vigo
  • Hospital Clinic i Provincial de Barcelona
  • Hospital Universitari de Girona Doctor Josep Trueta
  • Hospital Universitario Infanta Leonor
  • Hospital Universitario Ramón y Cajal
  • Hospital Universitario 12 de Octubre
  • Hospital Universitario La Paz
  • Centro Integral Oncológico Clara Campal
  • Hospital Universitario de Salamanca
  • Hospital Universitario de Canarias
  • Hospital Universitario Virgen del Rocío
  • Hospital Universitario Doctor Peset
  • Hospital Universitari i Politècnic La Fe

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

R-CHOP

B-R-CAP

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

Full Information

First Posted
May 3, 2013
Last Updated
September 18, 2018
Sponsor
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Collaborators
Janssen-Cilag, S.A.
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1. Study Identification

Unique Protocol Identification Number
NCT01848132
Brief Title
Efficacy/Safety Study of R-CHOP vs Bortezomib-R-CAP for Young Patients With Diffuse Large B-cell Lymphoma With Poor IPI.
Official Title
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.
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
October 3, 2013 (Actual)
Primary Completion Date
January 2018 (Actual)
Study Completion Date
August 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Collaborators
Janssen-Cilag, S.A.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse, Large B-Cell, Lymphoma
Keywords
Lymphoma, Large B-Cell

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
121 (Actual)

8. Arms, Groups, and Interventions

Arm Title
R-CHOP
Arm Type
Active Comparator
Arm Description
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
Arm Title
B-R-CAP
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
Velcade
Intervention Description
Bortezomib: subcutaneous, 1,3 mg/m2, day 1, 8, 15.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Description
Rituximab: intravenous, 375 mg/m2, day 1
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
Cyclophosphamide: intravenous, 750 mg/m2, day 1
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Adriamycin
Intervention Description
Adriamycin:intravenous, 50 mg/m2, day 1
Intervention Type
Drug
Intervention Name(s)
Prednisone
Intervention Description
Prednisone: oral, 100 mg, days 1-5
Intervention Type
Drug
Intervention Name(s)
Vincristine
Intervention Description
Vincristine: intravenous, 1,4 mg/m2, day 1
Primary Outcome Measure Information:
Title
Proportion of patients with Event-Free Survival at 2 years.
Description
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 Outcome Measure Information:
Title
Event-Free survival at 2 years in the different subtypes of DLBCL
Description
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
Title
Overall survival at 2 years
Description
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)
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.
Title
Overall response rate and complete remissions
Description
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).
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.
Title
Toxicity according to the CTC criteria
Description
Toxicity according to the Common Toxicity Criteria (CTC) (version 3.0) of the National Cancer Institute (NCI).
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.
Title
To evaluate the predictive value for EFS of interim PET/CT evaluation
Description
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.
Title
To identify clinical and biological prognostic factors for response and survival.
Description
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.
Other Pre-specified Outcome Measures:
Title
Biological project
Description
To explore the mutational profile in a selection of these cases by massive sequencing. To analyze the impact of the molecular classification of DLBCL based on immunohistochemistry (IHC) (as Hans algorithms, Choi and Meyer) in the prospective series of the patients of this clinical trial. To explore the effect of the expression of genes, Micro-Ribonucleic Acid (miRNAs) and proteins of interest. Refine the IHC analysis with automatic quantification methods of protein expression. To explore the effect of frequent cytogenetic alterations in DLBCL.
Time Frame
During recruitment period, after patient randomization.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eva González, MD
Organizational Affiliation
Institut Catalá d'Oncología, Hospital Duran i Reynals
Official's Role
Study Chair
Facility Information:
Facility Name
Hospital Clínico Universitario Lozano Blesa
City
Zaragoza
State/Province
Aragón
ZIP/Postal Code
50009
Country
Spain
Facility Name
Hospital Universitario Central de Asturias
City
Oviedo
State/Province
Asturias
ZIP/Postal Code
33006
Country
Spain
Facility Name
Institut Català d'Oncologia, Hospital Germans Trias i Pujol
City
Badalona
State/Province
Barcelona
ZIP/Postal Code
08916
Country
Spain
Facility Name
Institut Català d'Oncologia, Hospital Duran i Reynals
City
L'Hospitalet de Llobregat
State/Province
Barcelona
ZIP/Postal Code
08908
Country
Spain
Facility Name
Hospital Universitario Marqués de Valdecilla
City
Santander
State/Province
Cantabria
ZIP/Postal Code
39008
Country
Spain
Facility Name
Hospital de Jerez
City
Jerez de la Frontera
State/Province
Cádiz
ZIP/Postal Code
11407
Country
Spain
Facility Name
Hospital Son Llàtzer
City
Palma
State/Province
Islas Baleares
ZIP/Postal Code
07198
Country
Spain
Facility Name
Hospital Universitario Fundación Alcorcón
City
Alcorcón
State/Province
Madrid
ZIP/Postal Code
28922
Country
Spain
Facility Name
Complejo Hospitalario Universitario de Vigo
City
Vigo
State/Province
Pontevedra
ZIP/Postal Code
36036
Country
Spain
Facility Name
Hospital Clinic i Provincial de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital Universitari de Girona Doctor Josep Trueta
City
Girona
ZIP/Postal Code
17007
Country
Spain
Facility Name
Hospital Universitario Infanta Leonor
City
Madrid
ZIP/Postal Code
28031
Country
Spain
Facility Name
Hospital Universitario Ramón y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Hospital Universitario 12 de Octubre
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
Hospital Universitario La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Centro Integral Oncológico Clara Campal
City
Madrid
ZIP/Postal Code
28050
Country
Spain
Facility Name
Hospital Universitario de Salamanca
City
Salamanca
ZIP/Postal Code
37007
Country
Spain
Facility Name
Hospital Universitario de Canarias
City
Santa Cruz de Tenerife
ZIP/Postal Code
38320
Country
Spain
Facility Name
Hospital Universitario Virgen del Rocío
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Facility Name
Hospital Universitario Doctor Peset
City
Valencia
ZIP/Postal Code
46017
Country
Spain
Facility Name
Hospital Universitari i Politècnic La Fe
City
Valencia
ZIP/Postal Code
46026
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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