S0016 Combination Chemotherapy With Monoclonal Antibody Therapy in Newly Diagnosed Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies can locate tumor cells and either kill them or deliver radioactive tumor-killing substances to them without harming normal cells. It is not yet known which monoclonal antibody plus combination chemotherapy regimen is more effective in treating non-Hodgkin's lymphoma. PURPOSE: This randomized phase III trial is comparing 2 different monoclonal antibodies given together with combination chemotherapy to see how well they work in treating patients with newly-diagnosed non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Compare the progression-free survival and overall survival of patients with newly diagnosed follicular non-Hodgkin's lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without either rituximab or iodine I 131 tositumomab (monoclonal antibody anti-B1). (CHOP chemotherapy alone arm closed to accrual as of 12/15/02) Compare the response rate of these patients treated with these regimens. Compare the toxic effects of these regimens in these patients. Compare the molecular remission rates of this patient population treated with these regimens. Determine the incidence and time to development of human anti-mouse antibody positivity. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to whether microglobulin is greater than upper limit of normal (yes vs no). Patients are randomized to 1 of 3 treatment arms. (Arm I closed to accrual as of 12/15/02) Arm I (CHOP only): Patients receive cyclophosphamide IV over 15 minutes, doxorubicin IV over 5-20 minutes, and vincristine IV over 5-15 minutes on day 1. Patients also receive oral prednisone daily on days 1-5. Treatment continues every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. (Arm I closed to accrual as of 12/15/02) Arm II (CHOP + rituximab): Patients receive cyclophosphamide IV over 15 minutes, doxorubicin IV over 5-20 minutes, and vincristine IV over 5-15 minutes on days 8, 29, 50, 71, 92, and 113. Patients also receive oral prednisone daily on days 8-12, 29-33, 50-54, 71-75, and 113-117 and rituximab IV over 4-6 hours on days 1, 6, 48, 90, 134, and 141. Arm III (CHOP + tositumomab): Patients receive chemotherapy as in arm I and tositumomab (monoclonal antibody anti-B1) IV over 1 hour followed by iodine I 131 tositumomab IV over 20 minutes on days 134 and 141. Patients are followed on day 200, at 1 year, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: Approximately 500 patients (250 per treatment arm) will be accrued for this study within 5.5 years. (Arm I closed to accrual as of 12/15/02)

Official Title
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A Phase III Trial of CHOP Plus Rituximab vs CHOP Plus Iodine-131-Labeled Monoclonal Anti-B1 Antibody (Tositumomab) for Treatment of Newly Diagnosed Follicular Non-Hodgkin's Lymphomas

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: cyclophosphamide
* Drug: doxorubicin
* Drug: prednisone
* Drug: vincristine
* Radiation: tositumomab


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed previously untreated bulky stage II or stage III or IV follicular non-Hodgkin's lymphoma Grade I-III disease Cluster of differentiation antigen 20 (CD20) antigen positive Fewer than 5,000/mm^3 circulating lymphoid cells on a white blood cell (WBC) differential count Bidimensionally measurable disease Bone marrow aspiration and biopsy within the past 42 days No clinical evidence of central nervous system (CNS) involvement by lymphoma PATIENT CHARACTERISTICS: Age: 18 and over Performance status: Zubrod 0-2 Life expectancy: Not specified Hematopoietic: See Disease Characteristics Granulocyte count greater than 1,500/mm^3 Platelet count greater than 100,000/mm^3 Hepatic: Not specified Renal: Not specified Cardiovascular: No impaired cardiac status, including: Severe coronary artery disease Cardiomyopathy Congestive heart failure Serious arrhythmia Ejection fraction at least lower limit of normal by Multi Gated Acquisition Scan (MUGA) or 2-D echocardiogram for questionable cardiac history Other: No hypersensitivity to iodine Not pregnant or nursing Fertile patients must use effective contraception during and for 6 months after study participation HIV negative No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy: No prior monoclonal antibodies for cancer Chemotherapy: No prior chemotherapy for lymphoma Prior prednisone for non-lymphoma related illnesses allowed Endocrine therapy: Not specified Radiotherapy: No prior radiotherapy for lymphoma Surgery: See Disease Characteristics

Ages Eligible for Study
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Minimum Age: 18 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: Arm I (CHOP only)<br>Patients receive cyclophosphamide IV over 15 minutes, doxorubicin IV over 5-20 minutes, and vincristine IV over 5-15 minutes on day 1. Patients also receive oral prednisone daily on days 1-5. Treatment continues every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. (Arm I closed to accrual as of 12/15/02) | Drug: cyclophosphamide<br>* Given IV<br>* Other names: cytoxan;Drug: doxorubicin<br>* Given IV<br>* Other names: adriamycin;Drug: prednisone<br>* Given orally<br>* Other names: steroid;Drug: vincristine<br>* Given IV<br>* Other names: oncovin;|
| Experimental: Arm II (CHOP + rituximab)<br>Patients receive cyclophosphamide IV over 15 minutes, doxorubicin IV over 5-20 minutes, and vincristine IV over 5-15 minutes on days 8, 29, 50, 71, 92, and 113. Patients also receive oral prednisone daily on days 8-12, 29-33, 50-54, 71-75, and 113-117 and rituximab IV over 4-6 hours on days 1, 6, 48, 90, 134, and 141. | Biological: rituximab<br>* Given IV<br>* Other names: rituxan;Drug: cyclophosphamide<br>* Given IV<br>* Other names: cytoxan;Drug: doxorubicin<br>* Given IV<br>* Other names: adriamycin;Drug: prednisone<br>* Given orally<br>* Other names: steroid;Drug: vincristine<br>* Given IV<br>* Other names: oncovin;|
| Experimental: Arm III (CHOP + tositumomab)<br>Patients receive chemotherapy as in arm I and tositumomab (monoclonal antibody anti-B1) IV over 1 hour followed by iodine I 131 tositumomab IV over 20 minutes on days 134 and 141. | Drug: cyclophosphamide<br>* Given IV<br>* Other names: cytoxan;Drug: doxorubicin<br>* Given IV<br>* Other names: adriamycin;Drug: prednisone<br>* Given orally<br>* Other names: steroid;Drug: vincristine<br>* Given IV<br>* Other names: oncovin;Radiation: tositumomab<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival at 2 Years | Measured from time of registration to date of of first observation of progression/relapse, or death due to any cause, or last contact date | 0-2 years | 
| Progression-free Survival at 5 Years | Measured from time of registration to date of of first observation of progression/relapse, or death due to any cause, or last contact date | 0-5 years | 
| Overall Survival at 2 Years | Measured from date of registration to date of death due to any cause | 0-2 years | 
| Overall Survival at 5 Years | Measured from date of registration to date of death due to any cause | 0-5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response (Confirmed and Unconfirmed Complete and Partial Responses) | Complete Response(CR) is a complete disappearance of all disease with the exception of nodes. No new lesions. previously enlarged organs must have regressed and not be palpable. Bone marrow(BM) must be negative if positive at baseline. Normalization of markers. CR Unconfirmed (CRU) does not qualify for CR above, due to a residual nodal mass or an indeterminate BM. Partial Response(PR) is a 50% decrease in the sum of products of greatest diameters (SPD) for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes. | Assessed 200 days and 365 days after initiation of therapy and then every 6 months until death | 
| Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug | Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal | Patients were assessed for adverse events at end of cycle 1-6 of CHOP or R-CHOP, the end of cycle 1-6 of CHOP and once 2 weeks after the completion of I-131 treatment. For either arm, once 3 months after removal from protocol treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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, 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