Combination Chemotherapy With or Without Rituximab in Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. It is not yet known whether combination chemotherapy is more effective with or without rituximab in treating patients with non-Hodgkin's lymphoma. PURPOSE: This randomized phase III trial is studying four different combination chemotherapy regimens and rituximab to see how well they work compared to four different combination chemotherapy regimens alone in treating patients with non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Compare the time to treatment failure in patients with CD20-positive diffuse large B-cell non-Hodgkin's lymphoma treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy with vs without rituximab. Compare the tumor control, progression rate, and complete remission rate in patients treated with these regimens. Compare the disease-free and overall survival rate of patients treated with these regimens. Compare the toxicity of these regimens in these patients. OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center, bulky disease (no vs yes), International Prognostic Index score (0 vs 1), and chemotherapy (CHOP vs CHOEP vs PMitCEBO vs MACOP-B). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive 1 of the following chemotherapy regimens according to participating country: CHOP: Patients receive cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1 and oral prednisone or prednisolone on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. CHOEP-21: Patients receive cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1; etoposide IV on days 1-3; and oral prednisone on days 1-5. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. PMitCEBO: Patients receive mitoxantrone IV, cyclophosphamide IV, and etoposide IV on day 1; vincristine IV and bleomycin IV on day 8; and oral prednisolone daily during weeks 1-4 and every other day during week 5. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. MACOP-B: Patients receive cyclophosphamide IV and doxorubicin IV on days 1, 15, 29, 43, 57, and 71; methotrexate IV and vincristine IV on days 8, 36, and 64; bleomycin IV and vincristine IV on days 22, 50, and 78; and oral or intramuscular prednisone on days 1-84. Treatment continues in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive arm I regimens (according to participating country) and rituximab as follows: CHOP and rituximab: Patients receive CHOP as in arm I and rituximab IV on day 1. CHOEP-21 and rituximab: Patients receive CHOEP-21 as in arm I and rituximab IV on day 1. PMitCEBO and rituximab: Patients receive PMitCEBO as in arm I and rituximab IV on day 1 during courses 1 and 4; on day 8 during courses 2 and 5; and on day 1 at 1 and 4 weeks after completion of the last course of PMitCEBO chemotherapy. MACOP-B and rituximab: Patients receive MACOP-B as in arm I and rituximab IV on days 1, 22, 43, 64, 85, and 106. Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 820 patients will be accrued for this study within approximately 2 years.

Official Title
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Randomized Intergroup Trial of First Line Treatment for Patients With Diffuse Large B-Cell Non-Hodgkin's Lymphoma With a CHOP-Like Chemotherapy Regimen With or Without the Anti-CD20 Antibody Rituximab

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: CHOP regimen


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diffuse large B-cell non-Hodgkin's lymphoma according to REAL classification Diagnosed within the past 6 weeks CD20+ disease Ann Arbor stage II, III, or IV disease or stage I bulky disease International Prognostic Index (IPI) score of 0 or 1 Score 0 defined by all of the following: Stage I or II disease ECOG performance status of 0 or 1 Lactic dehydrogenase (LDH) no greater than upper limit of normal (ULN) Score 1 defined by 1 of the following: Stage I or II disease; ECOG performance status of 0 or 1; and LDH greater than ULN Stage I or II disease; ECOG performance status 2 or 3; and LDH no greater than ULN Stage III or IV disease; ECOG performance status 0 or 1; and LDH no greater than ULN Previously untreated disease Mediastinal B-cell lymphoma allowed No secondary lymphoma after prior chemotherapy or radiotherapy for other malignancies No transformed lymphoma No primary CNS lymphoma No primary gastrointestinal (MALT) lymphoma No post-transplant lymphoproliferative disorder PATIENT CHARACTERISTICS: Age 18 to 60 Performance status See Disease Characteristics ECOG 0-3 Life expectancy At least 3 months Hematopoietic Not specified Hepatic Bilirubin no greater than 2.0 mg/dL* Transaminases no greater than 3 times normal* No active chronic hepatitis B or C infection NOTE: *Unless related to lymphoma Renal Creatinine no greater than 2 times normal* NOTE: *Unless related to lymphoma Cardiovascular No myocardial infarction within the past 6 months No uncompensated heart failure No dilatative cardiomyopathy No coronary heart disease with ST segment depression on ECG No severe uncompensated hypertension Pulmonary No chronic lung disease with hypoxemia Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception HIV negative No known allergic reactions against foreign proteins No other prior malignancy except basal cell skin cancer or carcinoma in situ of the cervix No concurrent disease that would preclude study treatment No active infections requiring systemic antibiotics or antiviral medications No severe uncompensated diabetes mellitus No clinical signs of cerebral dysfunction No severe psychiatric disease PRIOR CONCURRENT THERAPY: Biologic therapy No prior murine antibodies Chemotherapy No other concurrent anticancer chemotherapy Endocrine therapy Not specified Radiotherapy No concurrent response-adapted (slow response or unconfirmed complete response) radiotherapy Surgery Not specified Other No prior lymphoma-specific treatment More than 12 weeks since prior participation in another clinical trial No prior participation in this study No other concurrent study medication

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: CHOP-21<br>Cyclophosphamide 750 mg/m² i.v. day 1 Doxorubicin 50 mg/m² i.v. day 1 Vincristine 2 mg (abs.) i.v. day 1 Prednisone 100 mg/d p.o. days 1 to 5 Recycle: day 22 Total number of cycles 6 | Drug: CHOP regimen<br>* Cyclophosphamide 750 mg/m² i.v. day 1 Doxorubicin 50 mg/m² i.v. day 1 Vincristine 2 mg (abs.) i.v. day 1 Prednisone 100 mg/d p.o. days 1 to 5 Recycle day 22 Total number of cycles: 6<br>|
| Active Comparator: Arm B: CHOP-21 + Rituximab<br>Rituximab 375 mg/m² i.v. day 1* Cyclophosphamide 750 mg/m² i.v. day 1 Doxorubicin 50 mg/m² i.v. day 1 Vincristine 2 mg (abs.) i.v. day 1 Prednisone 100 mg/d p.o. days 1 to 5 Recycle day 22 Total number of cycles: 6 | Biological: rituximab<br>* Rituximab 375 mg/m² i.v. day 1<br>Drug: CHOP regimen<br>* Cyclophosphamide 750 mg/m² i.v. day 1 Doxorubicin 50 mg/m² i.v. day 1 Vincristine 2 mg (abs.) i.v. day 1 Prednisone 100 mg/d p.o. days 1 to 5 Recycle day 22 Total number of cycles: 6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure (TTF) at 3 years |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission rate after completion of treatment |  | 3 years | 
| Overall survival at 3 years |  | 3 years | 
| Tumor control measured by TTF with non-tumor events censored at 3 years |  | 3 years | 
| Disease-free survival (DFS) measured by TTF after an event during and directly after treatment at 3 years |  | 3 years | 
| Progression rate determined by dividing the number of patients with disease progression by number of patients with evaluable outcome at 3 years |  | 3 years | 
| Time to progression measured at 3 years |  | 3 years | 
| Toxicity assessed by NCI CTC v2.0 after completion of treatment |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I adult diffuse large cell lymphoma, 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