Diffuse Large B Cell Non-Hodgkin's Lymphoma in the Vulnerable/Frail Elderly. A Multicentric Randomized Phase II Trial (FRAIL-06)

Diffuse Large B Cell Non-Hodgkin's Lymphoma in the Vulnerable/Frail Elderly. A Multicentric Randomized Phase II Trial With Emphasis on Geriatric Assessment and Quality of Life

RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, prednisone, and liposome-encapsulated doxorubicin citrate, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. It is not yet known whether rituximab and combination chemotherapy are more effective when given together with or without liposome-encapsulated doxorubicin citrate in treating older patients with diffuse large B-cell non-Hodgkin lymphoma.

PURPOSE: This randomized phase II trial is studying the side effects of giving rituximab together with cyclophosphamide, vincristine sulfate, and prednisone with or without liposome-encapsulated doxorubicin citrate and to see how well it works in treating older patients with stage II, stage III, or stage IV diffuse large B-cell non-Hodgkin lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Drug: cyclophosphamide; Biological: rituximab; Drug: vincristine sulfate; Drug: prednisone; Biological: filgrastim; Biological: pegfilgrastim; Drug: liposome-encapsulated doxorubicin citrate

Detailed Description

OBJECTIVES:

Primary

• To assess the therapeutic efficacy of rituximab, cyclophosphamide, vincristine sulfate, and prednisone with vs without liposome-encapsulated doxorubicin citrate, in terms of complete remission rate at 6 months, in vulnerable or frail elderly patients with stage II, III, or IV diffuse large B-cell non-Hodgkin lymphoma.
• To assess the safety of these regimens in these patients.

Secondary

• To evaluate the progression-free survival, event-free survival, and overall survival rates at 6 and 24 months in patients treated with these regimens.
• To evaluate the overall response rate at 6 and 24 months in patients treated with these regimens.
• To evaluate the duration of complete remission in patients treated with these regimens.
• To evaluate the acute side effects (according to the International CTC scale) of these regimens in these patients.
• To evaluate the geriatric condition and quality of life of patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I (R-COP regimen): Patients receive rituximab IV, cyclophosphamide IV, and vincristine sulfate IV on day 1. Patients also receive oral prednisone on days 1-5 and filgrastim subcutaneously (SC) on days 8-14 or pegfilgrastim SC on day 2. Treatment repeats every 21 days for at least 3 courses.
• Arm II (R-COPY regimen): Patients receive rituximab, cyclophosphamide, vincristine sulfate, prednisone, and filgrastim or pegfilgrastim as in arm I. Patients also receive liposome-encapsulated doxorubicin citrate IV on day 1. Treatment repeats every 21 days for at least 3 courses.

After 3 courses of R-COP or R-COPY, patients undergo evaluation. Patients with disease progression or a response of < 25% are removed from the study. Patients with a response of ≥ 25% receive 3 more courses of R-COP or R-COPY, followed by rituximab IV alone on day 1 of courses 7 and 8 in the absence of disease progression or unacceptable toxicity.

After the completion of chemotherapy, some patients may undergo radiotherapy.

Patients complete quality of life and geriatric assessment questionnaires at baseline and periodically during study treatment.

After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 2 years.

• Study Type: Interventional
• Enrollment (Actual): 67
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Institut Bergonie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years to 120 years (Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Diagnosis of diffuse large B-cell non-Hodgkin lymphoma

  • Stage II, III, or IV disease (according to the WHO classification), including all morphological and clinical variants

    • No Burkitt-like lymphoma (presence of small cells in the bone marrow biopsy allowed)
  • CD20+ disease
• Has ≥ 1 measurable target lesion ≥ 1.1 cm (according to the International Workshop Criteria)

• Poor physiological status, as defined by ≥ 1 of the following criteria:

  • WHO performance status 3
  • Clinical evaluation and measurement of LVEF that would preclude doxorubicin administration (i.e., LVEF < 50%)
  • Creatinine clearance < 50 mL/min
  • Serum bilirubin > 30 μmol/L
  • Severe comorbidity that would preclude the use of CHOP chemotherapy
• Ineligible for standard R-CHOP therapy
• No cerebral or meningeal involvement

PATIENT CHARACTERISTICS:

• WHO performance status 0-3
• ANC > 750/mm^3
• Platelet count > 50,000/mm^3
• LVEF > 35%
• Able to receive either R-COP or R-COPY therapy
• No congestive heart failure, serious arrhythmia, or myocardial infarction within the past 6 months
• No other malignancy within the past 5 years except for adequately treated basal cell carcinoma of the skin or curatively treated carcinoma in situ of the cervix
• No active infection
• No active viral hepatitis B or C by serology
• No known HIV positivity
• No hypersensitivity to rituximab, any of its excipients, or to murine proteins
• No documented history of allergy to eggs or egg products
• No psychological, familial, sociological, or geographical condition that would preclude compliance with study treatment or follow-up schedule

PRIOR CONCURRENT THERAPY:

• No prior therapy for this cancer
• No prior anthracycline administration with a cumulative dose > 240 mg/m² of doxorubicin hydrochloride or > 400 mg/m² of epirubicin hydrochloride
• More than 30 days since prior participation in another clinical trial involving investigational drugs
• No other concurrent antineoplastic agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (R-COP regimen); Patients receive rituximab IV, cyclophosphamide IV, and vincristine sulfate IV on day 1. Patients also receive oral prednisone on days 1-5 and filgrastim subcutaneously (SC) on days 8-14 or pegfilgrastim SC on day 2. Treatment repeats every 21 days for at least 3 courses.	Drug: cyclophosphamide; Given IV; Biological: rituximab; Given IV; Drug: vincristine sulfate; Given IV; Drug: prednisone; Given orally; Biological: filgrastim; Given subcutaneously; Biological: pegfilgrastim; Given subcutaneously
Experimental: Arm II (R-COPY regimen); Patients receive rituximab, cyclophosphamide, vincristine sulfate, prednisone, and filgrastim or pegfilgrastim as in arm I. Patients also receive liposome-encapsulated doxorubicin citrate IV on day 1. Treatment repeats every 21 days for at least 3 courses.	Drug: cyclophosphamide; Given IV; Biological: rituximab; Given IV; Drug: vincristine sulfate; Given IV; Drug: prednisone; Given orally; Biological: filgrastim; Given subcutaneously; Biological: pegfilgrastim; Given subcutaneously; Drug: liposome-encapsulated doxorubicin citrate; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants in Complete Remission 6 Months After Randomization	Complete remission [CR] is defined according to Cheson criteria. CR requires the following: Complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities.; All lymph nodes and nodal masses must have regressed to normal size. Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must have decreased to ≤1 cm in their greatest transverse diameter after treatment, or by more than 75% in the sum of the products of the greatest diameters (SPD).; The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable on physical examination.; If the bone marrow was involved by lymphoma before treatment, the infiltrate must be cleared on repeat bone marrow aspirate and biopsy of the same site.	6 months after randomization
Number of Participants With Severe Toxicity	Severe toxicity, defined as febrile neutropenia or toxic death. Febrile neutropenia is defined in the International CTC toxicity scale as "fever of unknown origin without clinically or microbiologically documented infection: neutrophils < 1.0 x 109/l and fever ≥ 38.5° C. Toxic death is defined as any death which occur during treatment (from day 1 of the first cycle of chemotherapy up to day 30 of the last cycle) and is not related to lymphoma.	6 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival Time	OS is defined as the delay between the date of randomization and the date of death	from randomization, up to 5 years
Progression-free Survival Time	Delay between the date of randomization and the date of progression or death. Progression is defined according to the Cheson criteria.	from randomization, up to 5 years

Collaborators and Investigators

• Sponsor: Institut Bergonié
• Collaborators: National Cancer Institute, France
• Investigators: Principal Investigator: Pierre Soubeyran, MD, PhD, Institut Bergonie

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2008
• Primary Completion (Actual): December 31, 2012
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: May 29, 2009
• First Submitted That Met QC Criteria: May 29, 2009
• First Posted (Estimated): June 1, 2009

Study Record Updates

• Last Update Posted (Estimated): August 29, 2025
• Last Update Submitted That Met QC Criteria: August 28, 2025
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: stage III adult diffuse large cell lymphoma; stage IV adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; contiguous stage II adult diffuse large cell lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Hemic and Lymphatic Diseases; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Biological Factors; Carbohydrates; Alkaloids; Polycyclic Compounds; Indoles; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Intercellular Signaling Peptides and Proteins; Pregnadienediols; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indolizidines; Indolizines; Glycoproteins; Glycoconjugates; Antibodies, Monoclonal, Murine-Derived; Colony-Stimulating Factors; Hematopoietic Cell Growth Factors; Cytokines; Granulocyte Colony-Stimulating Factor; Rituximab; Prednisone; Cyclophosphamide; Vincristine; Filgrastim; pegfilgrastim
• Other Study ID Numbers: IB-2008-25 (Institut Bergonié); IB-FRAIL06 (Other Identifier: Institut Bergonié); INCA-RECF0892 (Other Identifier: Institut National du Cancer); EUDRACT-2008-001506-16 (Other Identifier: EUDRACT)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No