S0433 Iodine I 131 Tositumomab, Rituximab, and Combination Chemotherapy in Treating Older Patients With Stage II, Stage III, or Stage IV Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Radiolabeled monoclonal antibodies, such as iodine I 131 tositumomab, can find cancer cells and carry cancer-killing substances to them without harming normal cells. 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, 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 a radiolabeled monoclonal antibody together with rituximab and combination chemotherapy may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving iodine I 131 tositumomab together with rituximab and combination chemotherapy works in treating older patients with stage II, stage III, or stage IV B-cell non-Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Determine the 2-year progression-free survival of older patients with previously untreated bulky stage II or stage III or IV diffuse large B-cell non-Hodgkin's lymphoma treated with iodine I 131 tositumomab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Determine the response rate (partial response, complete unconfirmed response, and complete response) in patients treated with this regimen. Determine the 2-year progression-free survival and response rate (partial response, complete unconfirmed response, and complete response) in B-cell lymphoma 2 (BCL-2) positive patients treated with this regimen. OUTLINE: This is a multicenter study. Rituximab and chemotherapy: Patients receive R-CHOP comprising rituximab IV over 6 hours; cyclophosphamide IV over 15-45 minutes; doxorubicin IV over 5-20 minutes; and vincristine IV over 5-15 minutes on day 1 and oral prednisone on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients then undergo a restaging evaluation. Patients without progressive disease receive CHOP chemotherapy comprising cyclophosphamide, doxorubicin, vincristine, and prednisone as outlined above. Treatment with CHOP chemotherapy repeats every 21 days for 2 courses. Radiolabeled monoclonal antibody therapy: Approximately 4-8 weeks after completion of chemotherapy, patients receive tositumomab IV over 1 hour followed by a dosimetric dose of iodine I 131 tositumomab IV over 20 minutes. Patients then undergo gamma scans over a 1-week period in order to determine the correct treatment dose of iodine I 131 tositumomab. No more than 2 weeks after administration of the dosimetric dose, patients receive tositumomab IV over 1 hour followed by a treatment dose of iodine I 131 tositumomab IV over 20 minutes. After completion of study treatment, patients are followed periodically for up to 5 years. PROJECTED ACCRUAL: A total of 80 patients will be accrued for this study within 15 months.

Official Title
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Iodine-131-Labeled Monoclonal Anti-B1 Antibody (I-131 Tositumomab) in Combination With Cyclophosphamide, Doxorubicin, Vincristine, Prednisone and Rituximab Therapy for Patients ≥ Age 60 With Advanced Stage Diffuse Large B-Cell NHL: A Phase II 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
* Radiation: tositumomab and iodine I 131 tositumomab


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of diffuse large B-cell non-Hodgkin's lymphoma, meeting 1 of the following stage criteria: Bulky stage II disease Stage III disease Stage IV disease Confirmed cluster of differentiation antigen 20 (CD20) antigen-positive disease Bidimensionally measurable disease Less than 20,000/mcL circulating lymphoid cells on white blood cell (WBC) differential count Adequate sections AND a paraffin block OR ≥ 10 unstained sections from the original diagnostic specimen available Needle aspiration or cytology are not considered adequate No clinical evidence of central nervous system (CNS) involvement by lymphoma No prior diagnosis of indolent lymphoma No histologic transformation PATIENT CHARACTERISTICS: Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic See Disease Characteristics Hepatic Not specified Renal Not specified Cardiovascular Ejection fraction ≥ 45% by multiple gated acquisition scan (MUGA) OR No significant abnormalities by echocardiogram Pulmonary No requirement for continuous supplemental oxygen Other Fertile patients must use effective contraception during and for 6 months after completion of study treatment No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, stage I or II cancer in complete remission, or carcinoma in situ of the cervix No known HIV positivity PRIOR CONCURRENT THERAPY: Biologic therapy No prior antibody therapy for lymphoma Chemotherapy No prior chemotherapy for lymphoma Endocrine therapy Not specified Radiotherapy No prior radiotherapy for lymphoma Surgery No prior solid organ transplantation Other Concurrent enrollment on protocol SWOG-8947 (lymphoma serum repository) or protocol SWOG-8819 (lymphoma tissue repository) is encouraged

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R-CHOP x 8 with I-131 Tositumomab<br>Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 cycles Unlabeled Anti-B1 Antibody 450 mg IV Day 170 Dosimetric dose 35 mg IV Day 170 Unlabeled Anti-B1 Antibody 450 mg IV Day 177 Therapeutic dose 35 mg IV Day 177 | Biological: rituximab<br> <br> Drug: cyclophosphamide<br> <br> Drug: doxorubicin hydrochloride<br> <br> Drug: prednisone<br> <br> Drug: vincristine sulfate<br> <br> Radiation: tositumomab and iodine I 131 tositumomab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) at 2 Years | Clinical responses were evaluated according to International Workshop NHL criteria (Cheson et al, 1999). Progression disease was defined as if a (CR, CRU) was not achieved at a previous assessment, a 50% increase in the SPD of target measurable lesions over the smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Appearance of a new lesion/site. Unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided). Death due to disease without prior documentation of progression. PFS is measured from date of registration to date of first observation of progressive disease, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact. | 0-2 years | 
| Response Rate (Complete, Complete Unconfirmed, and Partial) | 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. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 3.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal. | 6 months (assessed at the end of each cycle of chemotherapy for 8 cycles (1 cycle= 21 days), at restaging, and at the end of each radiolabeled antibody treatment) | 

 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