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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.

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ClinicalTrials.gov Identifier: NCT01848132
Recruitment Status : Completed
First Posted : May 7, 2013
Last Update Posted : September 19, 2018
Sponsor:
Collaborator:
Janssen-Cilag, S.A.
Information provided by (Responsible Party):
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea

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.)


Condition or disease Intervention/treatment Phase
Diffuse, Large B-Cell, Lymphoma Drug: Bortezomib Drug: Rituximab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Prednisone Drug: Vincristine Phase 2

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).


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 121 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : October 3, 2013
Actual Primary Completion Date : January 2018
Actual Study Completion Date : August 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma
Drug Information available for: Bortezomib

Arm Intervention/treatment
Active Comparator: R-CHOP

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
Rituximab: intravenous, 375 mg/m2, day 1

Drug: Cyclophosphamide
Cyclophosphamide: intravenous, 750 mg/m2, day 1

Drug: Doxorubicin
Adriamycin:intravenous, 50 mg/m2, day 1
Other Name: Adriamycin

Drug: Prednisone
Prednisone: oral, 100 mg, days 1-5

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

Experimental: B-R-CAP

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

Drug: Rituximab
Rituximab: intravenous, 375 mg/m2, day 1

Drug: Cyclophosphamide
Cyclophosphamide: intravenous, 750 mg/m2, day 1

Drug: Doxorubicin
Adriamycin:intravenous, 50 mg/m2, day 1
Other Name: Adriamycin

Drug: Prednisone
Prednisone: oral, 100 mg, days 1-5




Primary Outcome Measures :
  1. Proportion of patients with Event-Free Survival at 2 years. [ 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 ]

    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 :
  1. Event-Free survival at 2 years in the different subtypes of DLBCL [ 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 ]
    Event-free survival at 2 years in the different subtypes of DLBCL subgroups: Germinal center B-cell-like (GCB)/non-GCB.

  2. Overall survival at 2 years [ 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 in patients diagnosed of DLBCL with aIPI > 1 or aIPI=1 with elevated levels of beta 2-microglobulin (above UNL)

  3. Overall response rate and complete remissions [ 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 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).

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

  5. To evaluate the predictive value for EFS of interim PET/CT evaluation [ Time Frame: Before treatment, after second cycle, after fourth cycle and after treatment completion. ]

    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)


  6. 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. ]
    To identify clinical and biological prognostic factors for response and survival.


Other Outcome Measures:
  1. Biological project [ Time Frame: During recruitment period, after patient randomization. ]
    • 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01848132


Locations
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Spain
Hospital Clínico Universitario Lozano Blesa
Zaragoza, Aragón, Spain, 50009
Hospital Universitario Central de Asturias
Oviedo, Asturias, Spain, 33006
Institut Català d'Oncologia, Hospital Germans Trias i Pujol
Badalona, Barcelona, Spain, 08916
Institut Català d'Oncologia, Hospital Duran i Reynals
L'Hospitalet de Llobregat, Barcelona, Spain, 08908
Hospital Universitario Marqués de Valdecilla
Santander, Cantabria, Spain, 39008
Hospital de Jerez
Jerez de la Frontera, Cádiz, Spain, 11407
Hospital Son Llàtzer
Palma, Islas Baleares, Spain, 07198
Hospital Universitario Fundación Alcorcón
Alcorcón, Madrid, Spain, 28922
Complejo Hospitalario Universitario de Vigo
Vigo, Pontevedra, Spain, 36036
Hospital Clinic i Provincial de Barcelona
Barcelona, Spain, 08036
Hospital Universitari de Girona Doctor Josep Trueta
Girona, Spain, 17007
Hospital Universitario Infanta Leonor
Madrid, Spain, 28031
Hospital Universitario Ramón y Cajal
Madrid, Spain, 28034
Hospital Universitario 12 de Octubre
Madrid, Spain, 28041
Hospital Universitario La Paz
Madrid, Spain, 28046
Centro Integral Oncológico Clara Campal
Madrid, Spain, 28050
Hospital Universitario de Salamanca
Salamanca, Spain, 37007
Hospital Universitario de Canarias
Santa Cruz de Tenerife, Spain, 38320
Hospital Universitario Virgen del Rocío
Sevilla, Spain, 41013
Hospital Universitario Doctor Peset
Valencia, Spain, 46017
Hospital Universitari i Politècnic La Fe
Valencia, Spain, 46026
Sponsors and Collaborators
Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
Janssen-Cilag, S.A.
Investigators
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Study Chair: Eva González, MD Institut Catalá d'Oncología, Hospital Duran i Reynals

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Responsible Party: Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea
ClinicalTrials.gov Identifier: NCT01848132     History of Changes
Other Study ID Numbers: BRCAP-GELTAMO12
2012-005138-12 ( EudraCT Number )
First Posted: May 7, 2013    Key Record Dates
Last Update Posted: September 19, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea:
Lymphoma
Large B-Cell

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Rituximab
Doxorubicin
Liposomal doxorubicin
Prednisone
Bortezomib
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors