Rituximab and CVP Plus Interferon for Follicular Non Hodgkins Lymphoma (NHL) (LNH-Pro-05)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Fundación Leucemia y Linfoma, Spain
ClinicalTrials.gov Identifier:
NCT00842114
First received: February 10, 2009
Last updated: November 20, 2013
Last verified: November 2013
  Purpose

Rituximab plus CVP and Interferon chemoimmunotherapy for newly diagnosed Follicular Lymphoma with FLIPI index >2


Condition Intervention Phase
Non-Hodgkin's Lymphoma
Drug: Rituximab
Biological: Immunochemotherapy With CVP + Interferon
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Association of Rituximab to Immunochemotherapy With CVP + Interferon in Newly Diagnosed Follicular Lymphoma Patients With Intermediate-high FLIPI Score. Phase II Study.

Resource links provided by NLM:


Further study details as provided by Fundación Leucemia y Linfoma, Spain:

Primary Outcome Measures:
  • Progression-free survival (PFS) with the CVP + IFNalfa + Rituximab treatment [ Time Frame: August 2012 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall response (ORR) and complete response (CR) rates. Overall Survival MRD by RT-PCR assay Toxicity [ Time Frame: August 2012 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 50
Study Start Date: February 2006
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: R+CVP+IFN
8 cycles of Rituximab plus CVP chemotherapy (as Bagley et al) associated with Interferón for 12 weeks
Drug: Rituximab
Rituximab 375mg/sm, day 1 of each cycle, for 8 cycles
Other Name: Mabthera
Biological: Immunochemotherapy With CVP + Interferon
Other Names:
  • Cyclophosphamide (400 mg/m2 days 1-5)
  • Prednisone (100 mg/m2 days 1-5)
  • Vincristine (1.4 mg/m2, max 2 mg, day 1)
  • Interferón (3MU/m2, three times/week, for 12 weeks)

Detailed Description:

This study is a multicentric trial evaluating the efficacy of the CVP + 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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00842114

Locations
Spain
Hospital Universitario de La Princesa
Madrid, Spain, 28006
Sponsors and Collaborators
Fundación Leucemia y Linfoma, Spain
Roche Pharma AG
Investigators
Principal Investigator: Reyes Arranz-Saez, MD Fundación Leucemia y Linfoma, Spain
  More Information

No publications provided

Responsible Party: Fundación Leucemia y Linfoma, Spain
ClinicalTrials.gov Identifier: NCT00842114     History of Changes
Other Study ID Numbers: LNH-Pro-05, EudraCT Number:2005-004761-42
Study First Received: February 10, 2009
Last Updated: November 20, 2013
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Fundación Leucemia y Linfoma, Spain:
Intermediate-high FLIPI score
Follicular Lymphoma
Progression free survival

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Interferons
Rituximab
Anti-Infective Agents
Antineoplastic Agents
Antirheumatic Agents
Antiviral Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014