Rituximab and Combination Chemotherapy 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, can block cancer growth in different ways. Some find cancer cells and kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab together with combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy works in treating older patients with previously untreated B-cell lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine a pharmacokinetic profile for pharmacokinetics-based or rituximab within a CHOP-14 regimen comprising cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone in elderly patients with previously untreated aggressive B-cell lymphoma. To determine whether increased single-doses of rituximab for males can compensate their lower serum levels. Evaluate the safety and toxicity profile of this regimen in male patients. Secondary Determine the rate of complete responses, primary progressions under therapy, event-free survival, progression-free survival, and overall survival in patients treated with this regimen. Determine the rate of primary progression in patients treated with this regimen. OUTLINE: This is a multicenter study. All patients undergo the following treatment. Prephase treatment: Patients receive vincristine subcutaneously on day -6 and oral prednisone on days -6 to 0. Immunochemotherapy and radiotherapy: Patients receive CHOP chemotherapy comprising cyclophosphamide IV over 15 minutes, doxorubicin hydrochloride IV, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Patients also receive pegfilgrastim subcutaneously on days 4, 18, 32, 46, 60, and 74. Treatment with CHOP chemotherapy repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who show no response after course 4 of CHOP chemotherapy proceed to salvage chemotherapy off study. Patients are evaluated 2-4 weeks after completion of CHOP. Patients with initial bulky disease (i.e., diameter ≥ 7.5 cm) or extranodal involvement AND achieving complete remission (CR), unconfirmed CR (CRu), or partial remission undergo radiotherapy 5 days a week for 4 weeks. Patients who do not achieve CR or CRu 2 months after completion of radiotherapy proceed to salvage chemotherapy off study. Patients are then stratified according to center, International Prognostic Index (1-2 vs 3-5), disease involvement (bulky vs extranodal vs bulky and/or extranodal), age (61-70 years old vs 71-80 years old), and gender. Patients are randomized to 1 of 2 treatment arms. Arm I (2-weekly rituximab): Patients receive rituximab IV 375 mg/m^2 (females) and 500 mg/m^2 (males) over 4 hours on days 0, 14, 28, 42, 56, 70, 84, and 98. Patients also receive pegfilgrastim subcutaneously on day 4 of each course. Arm II (pharmacokinetic-based dose-dense rituximab): Patients receive rituximab IV 375 mg/m^2 (females) and 500 mg/m^2 (males) over 4 hours on days -1, 0, 3, 7, 14, 21, 28, and 42. Patients also receive pegfilgrastim subcutaneously on day 4 of each course. Some patients undergo blood sample collection periodically during and after treatment for pharmacokinetic studies. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then once a year therafter.

Official Title
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2-Weekly CHOP Chemotherapy With Dose-Dense Rituximab for the Treatment of Patients Aged 61 to 80 Years With Aggressive CD-20 Positive B-Cell Lymphomas: A Phase-II/Pharmacokinetic Study (CHOP-R-ESC)

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: pegfilgrastim
* Biological: rituximab
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: prednisone
* Drug: vincristine sulfate
* Other: pharmacological study
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histological diagnosis of aggressive B-cell lymphoma Previously untreated disease Stage I-IV disease CD20-positive disease Any International Prognostic Index (IPI) score No secondary lymphoma after prior chemotherapy or radiotherapy No primary CNS lymphoma No primary gastrointestinal (MALT) lymphoma PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 3 months AST and ALT ≤ 3 times normal unless related to lymphoma Bilirubin ≤ 2 mg/dL unless related to lymphoma Creatinine ≤ 2 times normal unless related to lymphoma Fertile patients must use effective contraception No known allergic reactions against foreign proteins No active infections requiring systemically administered antibiotics or antiviral medications No noncompensated heart failure No dilatative cardiomyopathy No coronary heart disease with ST-segment depression in ECG No myocardial infarction during the past 6 months No chronic lung disease with hypoxemia No severe noncompensated hypertension No severe noncompensated diabetes mellitus No clinical signs of cerebral dysfunction No severe psychiatric disease No known HIV infection No active chronic hepatitis B or C infection No other concurrent diseases that exclude the administration of therapy as outlined by the study protocol PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 12 weeks since prior clinical trial participation No prior participation in this study No prior therapy, including murine antibody, for this cancer No prior organ transplantation No concurrent response-adapted radiotherapy (iceberg radiotherapy) No other concurrent anticancer chemotherapy or other study medication

Ages Eligible for Study
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Minimum Age: 61 Years
Maximum Age: 80 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Interventional: CHOP-14 + 8 x 2-weekly rituximab<br>Arm I (2-weekly rituximab): Patients receive rituximab IV 375 mg/m^2 (females) and 500 mg/m^2 (males) over 4 hours on days 0, 14, 28, 42, 56, 70, 84, and 98. Patients also receive pegfilgrastim subcutaneously on day 4 of each course. | Biological: pegfilgrastim<br> <br> Biological: rituximab<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: prednisone<br> <br> Drug: vincristine sulfate<br> <br> Other: pharmacological study<br> <br> Radiation: radiation therapy<br> <br> |
| Active Comparator: Interventional: CHOP-14 + 8 x dose-dense rituximab<br>Arm II (pharmacokinetic-based dose-dense rituximab): Patients receive rituximab IV 375 mg/m^2 (females) and 500 mg/m^2 (males) over 4 hours on days -1, 0, 3, 7, 14, 21, 28, and 42. Patients also receive pegfilgrastim subcutaneously on day 4 of each course. | Biological: pegfilgrastim<br> <br> Biological: rituximab<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: prednisone<br> <br> Drug: vincristine sulfate<br> <br> Other: pharmacological study<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (in first 20 patients of each cohort with a distinct variation of the rituximab schedule) assessed on days -4, -1, 10, 29, 57, 99, 155, 239, 267, 295, 407, and 491 of treatment |  | -4 to 491 days of treatment | 
| Safety and treatment related deaths at 3 months after study completion |  | 3 months after study completion | 
| Toxicity assessed by NCI criteria, adverse events, serious adverse events, protocol adherence, and treatment-related deaths at 3 months after study completion |  | 3 months after study completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure assessed at 2 years within the study and periodically thereafter |  | at 2 years within the study and periodically thereafterlif | 
| Complete response rate assessed at 2 years within the study and periodically thereafter |  | at 2 years within the study and periodically thereafter | 
| Progression rate |  | life-long | 
| Survival time |  | life-long | 
| Progression-free survival |  | life-long | 

 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 I adult diffuse large cell lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma, contiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, stage I adult immunoblastic large cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, contiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult Burkitt lymphoma, stage I adult Burkitt lymphoma, stage III adult Burkitt lymphoma, stage IV adult Burkitt lymphoma, contiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, stage I adult diffuse mixed cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage IV adult diffuse mixed cell lymphoma, contiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, stage I adult diffuse small cleaved cell lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, contiguous stage II grade 1 follicular lymphoma, contiguous stage II grade 2 follicular lymphoma, contiguous stage II grade 3 follicular lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, stage I grade 1 follicular lymphoma, stage I grade 2 follicular lymphoma, stage I grade 3 follicular lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma