Rituximab and Combination Chemotherapy in Treating Patients With Stage II, Stage III, or Stage IV Diffuse Large B-Cell 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 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 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 patients with stage II, stage III, or stage IV diffuse large B-cell non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the 2-year progression-free survival (PFS) rate after treatment with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in patients with bulky stage II or stage III or IV diffuse large B-cell non-Hodgkin's lymphoma who remain positron emission tomography (PET)-positive after 3 courses of rituximab, cyclophosphamide, vincristine, doxorubicin hydrochloride, and prednisone. Secondary Determine the proportion of mid-treatment PET-positive patients who become PET-negative after 4 courses of R-ICE. Determine the PFS of mid-treatment PET-negative patients treated with these regimens. Determine the overall survival of patients treated with these regimens. Determine the toxicity of these regimens in these patients. OUTLINE: Rituximab and Combination Chemotherapy (R-CHOP: R= Rituximab, C= Cyclophosphamide, H= Doxorubicin Hydrochloride (Hydroxydaunomycin), O= Vincristine Sulfate (Oncovin), P= Prednisone): Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine IV on day 1, and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients undergo fludeoxyglucose F18 positron emission tomography (PET) scanning and conventional restaging during course 3. Based on the PET results, patients are assigned to 1 of 2 treatment groups. Group I (PET negative): Patients receive 2 more courses of R-CHOP as above in the absence of disease progression or unacceptable toxicity. Group II (PET positive): Patients receive Rituximab 375 mg/m2 IV Day 1, Ifosfamide 5000 mg/m2 IV over 24 hours Day 2, Carboplatin AUC 5 (max: 800 mg) IV Day 2, Etoposide 100 mg/m2 IV Days 1, 2, 3 (R-ICE), Mesna 5000 mg/m2 IV over 24 hours Day 2, and Filgrastim 5 mcg/kg/day subcutaneous (SC) Day 4 until absolute neutrophil count (ANC) recovery every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 10 years from the date of study entry. ACCRUAL: A total of 100 patients were accrued for this study.

Official Title
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Response-Adapted Therapy for Aggressive Non-Hodgkin's Lymphomas Based on Early [18F] FDG-PET Scanning

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: filgrastim
* Biological: rituximab
* Drug: carboplatin
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: etoposide
* Drug: ifosfamide
* Drug: prednisone
* Drug: vincristine


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Diffuse large B-cell non-Hodgkin's lymphoma Bulky stage II (bulk defined as any lesion ≥ 10 cm) or stage III or IV disease The following lymphoma types are excluded: Primary central nervous system lymphoma Transformed low-grade lymphoma (prior history of low-grade lymphoma or clear presence of low-grade lymphoma on histologic sections) Primary mediastinal B-cell lymphoma or testicular lymphoma (consolidative radiotherapy is usually indicated) Immunodeficiency-related lymphoma (i.e., after organ or bone marrow transplant) Measurable disease Patient must have at least one objective measurable disease site (i.e., measurable in at least 2 perpendicular parameters) Measurable disease in the liver is required if the liver is the only site of lymphoma involvement Abnormal positron emission tomography scans will not constitute evaluable disease, unless verified by CT scan or other appropriate imaging Eastern Cooperative Oncology Group (ECOG) performance status 0-3 For patients > 50 years of age, a normal ejection fraction by ECHO or Multigated Acquisition Scan (MUGA) is required within 6 weeks prior to registration Absolute neutrophil count ≥ 1,500/mm^3 Platelet count > 100,000/mm^3 Creatinine < 2.0 mg/dL Bilirubin < 2 mg/dL (may be up to 3.0 mg/dL if due to liver involvement by lymphoma) EXCLUSION CRITERIA: Prior chemotherapy or radiation therapy for lymphoma Prior anthracyclines or platinum compounds used as systemic chemotherapy Prior radiation therapy to the mediastinum or to ≥ 25% of the bone marrow Concurrent pentostatin or trastuzumab (Herceptin®) Pregnant or nursing Prior malignancy within the past 5 years unless it was in situ OR was treated with curative intent AND the patient has remained relapse-free HIV positive

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (PET negative)<br>Patients receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine IV on day 1, and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. | Biological: rituximab<br>* Given IV<br>* Other names: IDEC-C2B8, Chimeric anti-CD20 monoclonal antibody, Rituxan.;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Cytoxan, Neosar, CTX, CPM.;Drug: doxorubicin hydrochloride<br>* Given IV<br>* Other names: hydroxydaunomycin, ADR.;Drug: prednisone<br>* Taken orally<br>* Other names: Deltasone, Orasone, Medicorten, Panasol-S, Liquid-Pred, others.;Drug: vincristine<br>* Given IV<br>* Other names: Oncovin, Vincasar PFS vincristine sulfate, VCR, leucocristine, LCR.;|
| Experimental: Group II (PET positive)<br>Patients receive R-ICE comprising rituximab IV on day 1, ifosfamide IV continuously over 24 hours and carboplatin IV over 30 minutes on day 2, and etoposide IV over 2 hours on days 1-3. Patients also receive filgrastim (G-CSF) subcutaneously once daily starting on day 4 and continuing until blood counts recover. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. | Biological: filgrastim<br>* Given subcutaneously or intravenous bolus.<br>* Other names: factor, granulocyte colony-stimulating factor, r-metHuG-CSF.;Biological: rituximab<br>* Given IV<br>* Other names: IDEC-C2B8, Chimeric anti-CD20 monoclonal antibody, Rituxan.;Drug: carboplatin<br>* Given IV<br>* Other names: CBDCA, Paraplatin, JM-8, NSC #241240.;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Cytoxan, Neosar, CTX, CPM.;Drug: etoposide<br>* Given IV<br>* Other names: VP-16, VePesid, epipodophyllotoxin;Drug: ifosfamide<br>* Given IV<br>* Other names: Isophosphamide, Ifex , Mitoxan , Holoxan , Naxamide ' NSC # 109724.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Progression-Free Survival (PFS) | 2-year progression-free survival is defined as the probability of patients who remain alive and progression free at 2 years from study entry. The method of Kaplan and Meier (1958) was used to estimate PFS. | Assessed every 4 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, then every 12 months if patient is 5-10 years from study entry. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year Overall Survival | 5-year overall survival is defined as the probability of patients who remain alive at 5 years from study entry. The method of Kaplan and Meier (1958) was used to estimate overall survival. | Every 4 months if patient is < 2 years from study entry, every 6 months if patient is 2-5 years from study entry, then every 12 months if patient is 5-10 years from study entry. | 

 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