Rituximab and Combination Chemotherapy Combined With Yttrium Y 90 Ibritumomab Tiuxetan in Treating Older Patients With Previously Untreated B-Cell Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies such as rituximab and yttrium Y 90 ibritumomab tiuxetan can locate cancer cells and either kill them or deliver radioactive cancer-killing substances to them without harming normal cells. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining rituximab and combination chemotherapy with yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells. PURPOSE: Phase II trial to study the effectiveness of combining rituximab and combination chemotherapy with yttrium Y 90 ibritumomab tiuxetan in treating older patients who have B-cell lymphoma that has not been previously treated.

Detailed Description
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OBJECTIVES: Determine the progression-free and overall survival of patients age 60 and over with previously untreated diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) combined with yttrium Y 90 ibritumomab tiuxetan. Determine the incidence of adverse experiences, hematologic toxicity (WBC, hemoglobin, and platelet nadirs; and transfusion requirements), cardiac toxicity (incidence of left ventricular dysfunction and cardiomyopathy by echocardiography), and the development of human antimouse antibody/human anti-chimeric antibody in patients treated with this regimen. Determine the predictive value of detecting minimal residual disease by molecular techniques for future relapse/recurrence in patients treated with this regimen. Determine the response rate of patients treated with this regimen. Determine the red blood cell transfusion requirements, change in hemoglobin from baseline, and incidence of anemia with prophylactic darbepoetin alfa support in patients treated with this regimen. Determine the conversion rate to complete remission in patients treated with ibritumomab tiuxetan who achieve a partial remission post-R-CHOP. Determine the effect of darbepoetin alfa on the quality of life of these patients. OUTLINE: This is an open-label, nonrandomized study. Chemotherapy: Patients receive rituximab IV over 2-5 hours, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1; oral prednisone on days 1-5 or 2-6; and filgrastim (G-CSF) subcutaneously (SC) on days 7-15. Patients also receive darbepoetin alfa SC on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Radioimmunotherapy: Patients receive rituximab IV over 3-5 hours and indium In 111 ibritumomab tiuxetan (IDEC-In2B8) IV over 10 minutes on day 0. Patients undergo gamma camera imaging at 2-24 hours and 48-72 hours after the injection of IDEC-In2B8 to observe the flow of ibritumomab tiuxetan. If the flow is deemed safe, then patients receive yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 7. Quality of life is assessed at baseline, before course 5 of chemotherapy, before radioimmunotherapy, and at 3 months. Patients are followed every 3 months for 1 year and then every 6 months for 4 years. PROJECTED ACCRUAL: A total of 65 patients will be accrued for this study.

Official Title
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A Phase II Study of R-CHOP and Ibritumomab Tiuxetan (Zevalin) for Elderly Patients With Previously Untreated Diffuse Large B-Cell Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: darbepoetin alfa
* Biological: filgrastim
* Biological: rituximab
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: prednisone
* Drug: vincristine sulfate
* Radiation: indium In 111 ibritumomab tiuxetan
* Radiation: yttrium Y 90 ibritumomab tiuxetan


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diffuse large B-cell lymphoma, including any of the following subtypes: Centroblastic Immunoblastic T-cell/histiocyte-rich Lymphomatoid granulomatosis type Anaplastic large B-cell Plasmablastic Mediastinal Intravascular large B-cell lymphoma Previously untreated High-intermediate or high-risk disease, defined by an age-adjusted international prognostic index score of 2 or 3 (with 1 point each assigned for a ECOG greater than 1/Karnofsky less than 80%, lactate dehydrogenase greater than normal, and stage III or IV) Lymphomas with discordant histology and a diffuse large B-cell component are eligible Must have an initial diagnostic specimen that is CD20+ At least Ann Arbor stage II disease No confinement of disease to an involved-field radiotherapy port (stage I or limited stage II disease) Bidimensionally measurable disease with at least 1 lymph node at least 2.0 cm by 2.0 cm by physical examination, CT scan, or positron-emission tomography Bone marrow cellularity greater than 15% No known brain or leptomeningeal metastases No primary effusion lymphomas PATIENT CHARACTERISTICS: Age 60 and over* NOTE: *Patients 60 to 65 years of age must be deemed ineligible for autologous stem cell transplantation Performance status Karnofsky 50-100% Life expectancy Not specified Hematopoietic Not specified Hepatic Bilirubin no greater than 2.0 mg/dL (except for Gilbert's disease) Renal Creatinine no greater than 1.5 mg/dL* OR Creatinine clearance greater than 50 mL/min* NOTE: *Patients not meeting either criterion but who have renal insufficiency directly related to lymphomatous involvement of the kidneys or renal collecting system are allowed Cardiovascular Cardiac ejection fraction at least 50% by echocardiogram No acute myocardial infarction within the past 3 months No uncontrolled hypertension No New York Heart Association class III or IV congestive heart failure No unstable angina pectoris Other Not pregnant or nursing Fertile patients must use effective contraception HIV negative B12 and folate greater than the lower limit of normal Transferrin saturation at least 15% Ferritin greater than 10 µg/L At least 6 weeks since prior RBC donation No active seizure disorder Prior seizure disorder allowed if free of antiseizure medication and evidence of seizure activity for the past 5 years No concurrent uncontrolled medical problems that would preclude administration of chemotherapy or radioimmunotherapy No other concurrent malignancy treated with chemotherapy or radiotherapy except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy At least 4 weeks since prior RBC transfusion No prior biologic therapy No other concurrent biologic therapy Chemotherapy No prior chemotherapy (one course of R-CHOP allowed) No other concurrent standard or investigational chemotherapy Endocrine therapy No more than 7 consecutive days of prior steroids (premedication allowed for prior intravenous contrast allergy) No other concurrent corticosteroids Radiotherapy No prior radiotherapy Surgery Not specified

Ages Eligible for Study
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Minimum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R-CHOP and Ibritumomab Tiuxetan (Zevalin)<br>Chemotherapy: Patients receive rituximab IV over 2-5 hours, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1; oral prednisone on days 1-5 or 2-6; and filgrastim (G-CSF) subcutaneously (SC) on days 7-15. Patients also receive darbepoetin alfa SC on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Radioimmunotherapy: Patients receive rituximab IV over 3-5 hours and indium In 111 ibritumomab tiuxetan (IDEC-In2B8) IV over 10 minutes on day 0. Patients undergo gamma camera imaging at 2-24 hours and 48-72 hours after the injection of IDEC-In2B8 to observe the flow of ibritumomab tiuxetan. If the flow is deemed safe, then patients receive yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 7. Quality of life is assessed at baseline, before course 5 of chemotherapy, before radioimmunotherapy, and at 3 months. Patients are followed every 3 months for 1 year and then every 6 months for 4 years. | Biological: darbepoetin alfa<br> <br> Biological: filgrastim<br> <br> Biological: rituximab<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: prednisone<br> <br> Drug: vincristine sulfate<br> <br> Radiation: indium In 111 ibritumomab tiuxetan<br> <br> Radiation: yttrium Y 90 ibritumomab tiuxetan<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | 2 years | 
| Progression-free Survival |  | 2 years | 
| Event-free Survival |  | 2 years | 
| Incidence of Adverse Experiences | Determine the incidence of adverse experiences, hematologic toxicity (WBC, hemoglobin, and platelet nadirs; and transfusion requirements), cardiac toxicity (incidence of left ventricular dysfunction and cardiomyopathy by echocardiography), and the development of human antimouse antibody/human anti-chimeric antibody in patients treated with this regimen. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Conversion Rate to Complete Remission |  | 2 years | 

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