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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: filgrastim
* Biological: pegfilgrastim
* Biological: rituximab
* Drug: cyclophosphamide
* Drug: liposome-encapsulated doxorubicin citrate
* Drug: prednisone
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 70 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized non-comparative phase II trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (R-COP regimen)<br>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. | Biological: filgrastim<br>* Given subcutaneously<br>Biological: pegfilgrastim<br>* Given subcutaneously<br>Biological: rituximab<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: prednisone<br>* Given orally<br>Drug: vincristine sulfate<br>* Given IV<br>|
| Experimental: Arm II (R-COPY regimen)<br>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. | Biological: filgrastim<br>* Given subcutaneously<br>Biological: pegfilgrastim<br>* Given subcutaneously<br>Biological: rituximab<br>* Given IV<br>Drug: cyclophosphamide<br>* Given IV<br>Drug: liposome-encapsulated doxorubicin citrate<br>* Given IV<br>Drug: prednisone<br>* Given orally<br>Drug: vincristine sulfate<br>* Given IV<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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contiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma