Rituximab and CVP Plus Interferon for Follicular Non Hodgkins Lymphoma (NHL) (LNH-Pro-05)
Primary Purpose
Non-Hodgkin's Lymphoma
Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
R+CVP+IFN
Sponsored by
About this trial
This is an interventional treatment trial for Non-Hodgkin's Lymphoma focused on measuring Intermediate-high FLIPI score, Follicular Lymphoma, Progression free survival
Eligibility Criteria
Inclusion Criteria:
- Age 18 years-75 years
- Pathologically confirmed low grade, Follicular B cell lymphoma (WHO Classification Follicular grades 1 and 2) , Marginal zone lymphoma or Lymphocytic lymphoma (excluding CLL and MCL)
- FLIPI score ≥ 2
- Chemotherapy-naïve patients. Previous radiation therapy is allowed, but should have been limited.
- Adequate hepatic (bilirubin or ALT/AST < 2,5 times UNL) and renal function, except for those directly disease-related
- Performance status grade 0 to 3
- Frozen biopsy material obtained at relapse or disease progression should be available for central pathology review and molecular biology studies
- Patient information and written informed consent
Exclusion Criteria:
- Previous evolutive malignancy within 5 years of study entry
- Prior chemotherapy treatment
- Clinically significant cardiac disease, as defined by history of symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction within 12 months of study entry
- Known positivity for HIV, VHB or VHC
- Pregnant or lactating women. Women of childbearing potential, and all men, unwilling to take appropriate contraceptive measures during and for at least 12 months after cessation of therapy
- Any uncontrolled serious non malignant condition or infection which would likely compromise the study objectives
- Non controlled thyroid disfunction
- Severe Autoimmune disease
- Patients with history of severe neuropsychiatric disease
Sites / Locations
- Hospital Universitario de La Princesa
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
R+CVP+IFN
Arm Description
8 cycles of Rituximab plus CVP chemotherapy (Bagley's et al) associated with Interferon for 12 weeks
Outcomes
Primary Outcome Measures
Progression-free survival (PFS) with the CVP + IFNalfa + Rituximab treatment
Secondary Outcome Measures
Overall response (ORR) and complete response (CR) rates. Overall Survival MRD by RT-PCR assay Toxicity
Full Information
NCT ID
NCT00842114
First Posted
February 10, 2009
Last Updated
March 31, 2016
Sponsor
Fundación Leucemia y Linfoma, Spain
Collaborators
Roche Pharma AG
1. Study Identification
Unique Protocol Identification Number
NCT00842114
Brief Title
Rituximab and CVP Plus Interferon for Follicular Non Hodgkins Lymphoma (NHL)
Acronym
LNH-Pro-05
Official Title
Association of Rituximab to Immunochemotherapy With CVP + Interferon in Newly Diagnosed Follicular Lymphoma Patients With Intermediate-high FLIPI Score. Phase II Study.
Study Type
Interventional
2. Study Status
Record Verification Date
March 2016
Overall Recruitment Status
Completed
Study Start Date
February 2006 (undefined)
Primary Completion Date
March 2016 (Actual)
Study Completion Date
March 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fundación Leucemia y Linfoma, Spain
Collaborators
Roche Pharma AG
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Rituximab plus CVP and Interferon chemoimmunotherapy for newly diagnosed Follicular Lymphoma with FLIPI index >2
Detailed Description
This study is a multicentric trial evaluating the efficacy of the CVP chemotherapy + Interferon (IFN) + Rituximab induction regimen in patients aged 18 to 75 years with newly diagnosed follicular NHL.
Follicular non Hodgkin's lymphoma's (FL), as defined by the REAL Classification, are usually characterized by a slowly progressive clinical course, a transient control by standard chemotherapeutic regimen and a pattern of repeated relapses until ultimately progressive and fatal disease.
Most standard first line treatment for advanced FL consists of alkylating-based (CVP) or anthracycline containing regimens, in association with immunomodulating agents such as interferon alpha or the unconjugated chimeric anti-CD20 antibody (rituximab) to target the CD20 antigen highly expressed on follicular lymphoma cells. This strategies have significantly increased the survival of the patients, but relapses still occur. Thus, the treatment of the patients with FL, requires improvements.
IFN alpha has antiproliferative and immunomodulatory properties. Moreover, it has been described a synergistic effect when IFN is given with chemotherapy. This association has significantly improved progression free survival (PFS) and overall survival (OS). Our prior results with 12 weeks of IFN plus CVP as induction treatment, significantly increased PFS when compared with CVP alone (60% median PFS vs. 24%, p: 0.0004).
We also performed a prospective study to analyze the correlation between the duration of remission and MRD in patients who were treated with CVP+IFN . Ninety four percent of patients had a molecular marker (60% bcl-2 translocation and 34% IgH rearrangement). Molecular response, defined as achieving a negative molecular MRD, was achieved in 76% of patients and it was associated with clinical remission. There was also a significant correlation between the duration of remission and a sustained indetectable MRD Anti-CD20 monoclonal antibody (Rituximab) mediates complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) and apoptosis. Rituximab has also shown to sensitize drug-resistant lymphoma cell lines to killing by cytotoxic drugs.
There are some "in vitro" studies that have tested the effect of Rituximab and IFN combination. It's been described that when IFN is given with Rituximab, it favours the expression of CD20 and therefore increases its cytotoxic effect - . Preliminary phase II studies show an increase in response rate with duration of response going up to 12 months. Moreover, there are two clinical studies that have tested the efficacy and tolerability of Rituximab added to IFN-alpha vi- ix. The Nordic Lymphoma Group showed a significant increase in ORR (up to 94%) by adding 5 weeks of IFN to re-treatment with 4 doses of Rituximab in patients who had achieved only a minimal or partial remission. Most of these patients, maintained their responses for more than 24 months. With a similar trial design, Sacchi et al. showed an ORR of 74% (33% of CR) and a median duration of response of 19 months. The combination was safe and most grade 3-4 adverse events (15%) were hematologic toxicity (leuko-neutropenia and thrombocytopenia).
Thus, we hypothesize that the combination of rituximab, with our standard induction regimen using IFN plus CVP might lead to synergistic / additive induction of apoptosis through different pathways in poor prognostic patients with FL, improving our previous results. We also hypothesize that this combination will be able to achieve higher molecular remissions, determined by real-time PCR of Bcl-2 translocation.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Hodgkin's Lymphoma
Keywords
Intermediate-high FLIPI score, Follicular Lymphoma, Progression free survival
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Actual)
8. Arms, Groups, and Interventions
Arm Title
R+CVP+IFN
Arm Type
Experimental
Arm Description
8 cycles of Rituximab plus CVP chemotherapy (Bagley's et al) associated with Interferon for 12 weeks
Intervention Type
Biological
Intervention Name(s)
R+CVP+IFN
Other Intervention Name(s)
Mabthera -Rituximab (375 mg/sm, D1)/cycle, Cyclophosphamide (400 mg/sm, D 1-5)/cycle, Prednisone (100 mg/sm,D 1-5)/cycle, Vincristine (1.4 mg/sm, max 2 mg, D 1)/cycle, Interferon -IFN (3 MU/sm x 3 times/week, x 12 weeks)
Intervention Description
Immunochemotherapy
Primary Outcome Measure Information:
Title
Progression-free survival (PFS) with the CVP + IFNalfa + Rituximab treatment
Time Frame
August 2012
Secondary Outcome Measure Information:
Title
Overall response (ORR) and complete response (CR) rates. Overall Survival MRD by RT-PCR assay Toxicity
Time Frame
August 2012
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age 18 years-75 years
Pathologically confirmed low grade, Follicular B cell lymphoma (WHO Classification Follicular grades 1 and 2) , Marginal zone lymphoma or Lymphocytic lymphoma (excluding CLL and MCL)
FLIPI score ≥ 2
Chemotherapy-naïve patients. Previous radiation therapy is allowed, but should have been limited.
Adequate hepatic (bilirubin or ALT/AST < 2,5 times UNL) and renal function, except for those directly disease-related
Performance status grade 0 to 3
Frozen biopsy material obtained at relapse or disease progression should be available for central pathology review and molecular biology studies
Patient information and written informed consent
Exclusion Criteria:
Previous evolutive malignancy within 5 years of study entry
Prior chemotherapy treatment
Clinically significant cardiac disease, as defined by history of symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction within 12 months of study entry
Known positivity for HIV, VHB or VHC
Pregnant or lactating women. Women of childbearing potential, and all men, unwilling to take appropriate contraceptive measures during and for at least 12 months after cessation of therapy
Any uncontrolled serious non malignant condition or infection which would likely compromise the study objectives
Non controlled thyroid disfunction
Severe Autoimmune disease
Patients with history of severe neuropsychiatric disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Reyes Arranz-Saez, MD
Organizational Affiliation
Fundación Leucemia y Linfoma, Spain
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Universitario de La Princesa
City
Madrid
ZIP/Postal Code
28006
Country
Spain
12. IPD Sharing Statement
Learn more about this trial
Rituximab and CVP Plus Interferon for Follicular Non Hodgkins Lymphoma (NHL)
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