Rituximab and Combination Chemotherapy in Treating Patients With Non-Hodgkin's 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. It is not yet known which schedule of rituximab and combination chemotherapy is more effective in treating non-Hodgkin's lymphoma. PURPOSE: This randomized phase III trial is studying two different schedules of rituximab and combination chemotherapy to compare how well they work in treating patients with aggressive B-cell non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Primary Compare the efficacy of 2 different schedules of immunochemotherapy comprising rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone in patients with previously untreated, low-risk, aggressive B-cell non-Hodgkin's lymphoma. Compare acute and chronic side effects in patients treated with these regimens. Compare time to treatment failure in patients treated with these regimens. Secondary Compare the time to progression in patients treated with these regimens. Compare the overall and disease-free/relapse-free survival of patients treated with these regimens. Compare the complete response rate in patients treated with these regimens. Compare the tumor control in patients treated with these regimens. Compare the safety of these regimens in these patients. Compare the pharmacoeconomics of these regimens. Compare patient adherence to these regimens. OUTLINE: This is an open-label, randomized, multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 2 treatment arms. All patients are given the option of receiving a 1-week course of pretreatment therapy comprising vincristine IV once on day -6 and oral prednisone once daily on days -6 to 0. Arm I: Patients receive R-CHOP immunochemotherapy comprising rituximab IV, cyclophosphamide IV over 15 minutes, doxorubicin hydrochloride IV, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo restaging of their disease. Patients with disease progression proceed to salvage therapy off study. All other patients receive 3 more courses of R-CHOP. Arm II: Patients receive R-CHOP as in arm I. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo restaging of their disease. Patients with disease progression proceed to salvage therapy off study. All other patients receive 1 more course of R-CHOP followed by 2 courses of rituximab alone. All patients undergo final restaging after 6 courses of rituximab. Patients with disease progression, stable disease, or partial response proceed to salvage therapy off study. After completion of study treatment, patients are followed periodically for 5 years and then annually thereafter. PROJECTED ACCRUAL: A total of 622 patients will be accrued for this study.

Official Title
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Randomized Study Comparing 4 and 6 Cycles of Chemotherapy With CHOP (Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) at 21-day Intervals, Both With 6 Cycles of Immunotherapy With the Monoclonal Anti-CD20-Positive B-Cell Lymphoma Aged 18-60 Years Having no Risk Factor (Age-Adjusted IPI=0) and No Large Tumor Mass (Diameter <7,5cm) [FLYER 6-6-6-4 Study]

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: prednisone
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed aggressive B-cell non-Hodgkin's lymphoma, including the following subtypes: Grade 3 follicular lymphoma Diffuse B-cell lymphoma, including diffuse large cell lymphoma with any of the following variants: Centroblastic Immunoblastic Plasmablastic Anaplastic large cell T-cell-rich B-cell lymphoma Primary effusion lymphoma Intravascular B-cell lymphoma Primary mediastinal B-cell lymphoma Burkitt's or Burkitt-like lymphoma Mantle cell lymphoma (blastoid) Aggressive marginal zone lymphoma (monocytoid) Previously untreated disease CD20-positive disease International Prognostic Index (IPI) score 0 No bulky disease Largest single or conglomerate tumor < 7.5 cm in diameter No mucosa-associated lymphoid tissue (MALT) lymphoma No CNS involvement of lymphoma (intracerebral, meningeal, or intraspinal) PATIENT CHARACTERISTICS: ECOG performance status 0-1 Platelet count ≥ 100,000/mm^3 WBC ≥ 2,500/mm^3 Lactate dehydrogenase normal Not pregnant or lactating Fertile patients must use effective contraception during and for 1 year after study participation Negative pregnancy test No known hypersensitivity to the study medications No known HIV-positivity No active hepatitis infection No impaired left ventricular function No severe cardiac arrhythmias No other impaired organ function No other serious disorder No other malignancy within the past 5 years except carcinoma in situ or basal cell skin cancer PRIOR CONCURRENT THERAPY: No prior chemotherapy or radiotherapy No prior immunosuppressive treatment with cytostatics No planned radiotherapy to extranodal involvement No concurrent participation in other treatment studies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: 6 R-CHOP-21<br>Arm I: Patients receive R-CHOP immunochemotherapy comprising rituximab IV, cyclophosphamide IV over 15 minutes, doxorubicin hydrochloride IV, and vincristine IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo restaging of their disease. Patients with disease progression proceed to salvage therapy off study. All other patients receive 3 more courses of R-CHOP. | Biological: rituximab<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: prednisone<br> <br> Drug: vincristine sulfate<br> <br> |
| Active Comparator: Interventional: 4 R-CHOP-21 + 2 x R<br>Arm II: Patients receive R-CHOP as in arm I. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo restaging of their disease. Patients with disease progression proceed to salvage therapy off study. All other patients receive 1 more course of R-CHOP followed by 2 courses of rituximab alone. | Biological: rituximab<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: prednisone<br> <br> Drug: vincristine sulfate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure (TTF) measured from day 1 of course 1 of Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) therapy up to 3 years on study with life-long follow-up |  | through study completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate duration until first relapse |  | through study completion | 
| Progression rate during treatment |  | through study completion | 
| Survival |  | through study completion | 
| Tumor control measured from day 1 of course 1 of CHOP therapy (non-tumor related events are censored) |  | through study completion | 
| Disease-free survival measured from day 1 of course 1 of CHOP therapy |  | through study completion | 
| Safety (adverse events, serious adverse events) assessed at 3 months after treatment |  | through study completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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contiguous stage II grade 3 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, stage I grade 3 follicular lymphoma, contiguous stage II adult diffuse large cell lymphoma, contiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, stage I adult diffuse large cell lymphoma, stage I adult diffuse mixed cell lymphoma, nodal marginal zone B-cell lymphoma, anaplastic 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, contiguous stage II adult Burkitt lymphoma, contiguous stage II mantle cell lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II mantle cell lymphoma, stage I adult Burkitt lymphoma, stage I mantle cell lymphoma, contiguous stage II marginal zone lymphoma, noncontiguous stage II marginal zone lymphoma, stage I marginal zone lymphoma, stage III marginal zone lymphoma, stage IV marginal zone lymphoma, stage III adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage IV adult Burkitt lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV grade 3 follicular lymphoma, stage IV mantle cell lymphoma