S0213 Chemotherapy Plus Rituximab in Treating Patients With Mantle Cell 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. Combining rituximab with chemotherapy may kill more cancer cells. PURPOSE: Phase II pilot study to study the effectiveness of combining chemotherapy with rituximab in treating patients who have newly diagnosed mantle cell lymphoma.

Detailed Description
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OBJECTIVES: Determine the 1-year progression-free survival probability in patients with previously untreated mantle cell lymphoma treated with courses of rituximab and cyclophosphamide, doxorubicin, vincristine, and dexamethasone alternating with courses of rituximab and high-dose cytarabine and methotrexate with leucovorin calcium. Determine the response rate (complete unconfirmed and complete and partial responses) and survival of patients treated with this regimen. Determine the toxicity of this regimen in these patients. Correlate chromosomal breakpoints, translocated immunoglobulin regulatory sequences, and cyclins D1, D2, and D3 with response and progression-free survival in patients treated with this regimen. Correlate gene expression (measured by DNA microarray analysis) with response and progression-free survival in patients treated with this regimen. OUTLINE: This is a pilot, multicenter study. Courses 1, 3, 5, and 7: Patients receive rituximab IV on day 1 (courses 1, 3, and 5 only); cyclophosphamide IV over 3 hours twice a day on days 2-4; doxorubicin IV over 24 hours on days 5-7; vincristine IV on days 5 and 12; dexamethasone orally or IV four times a day on days 2-5 and 12-15; and filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 8 and continuing until blood counts recover. Courses 2, 4, 6, and 8: Patients receive rituximab IV on day 1 (courses 2, 4, and 6 only); high-dose methotrexate IV over 24 hours on day 2; high-dose cytarabine IV over 2 hours twice a day on days 3-4; oral leucovorin calcium 4 times a day on days 3-10; and G-CSF SC daily beginning on day 5 and continuing until blood counts recover. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed within 30 days, every 3 months for 2 years, and then every 6 months for 3 years. Patients with disease progression are followed annually for up to 5 years from study entry. PROJECTED ACCRUAL: Approximately 50 patients will be accrued for this study within 25 months.

Official Title
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Pilot Trial of Hyper-CVAD and Methotrexate/ARA C Plus Rituximab in Patients With Previously Untreated Mantle Cell Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: filgrastim
* Biological: rituximab
* Drug: cyclophosphamide
* Drug: cytarabine
* Drug: dexamethasone
* Drug: doxorubicin
* Drug: leucovorin
* Drug: methotrexate
* Drug: vincristine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically proven stage III/IV or bulky stage II mantle cell lymphoma of one of the following histologic subtypes: Nodular Diffuse Mantle zone Blastic Newly diagnosed and previously untreated disease Bidimensionally measurable disease PATIENT CHARACTERISTICS: Age: 18 to 69 Performance status: Zubrod 0-2 Life expectancy: Not specified Hematopoietic: Absolute neutrophil count at least 1,000/mm^3 Platelet count at least 100,000/mm^3 (50,000/mm^3 if marrow involvement present) Hepatic: Bilirubin no greater than 1.5 mg/dL (5.0 mg/dL if hepatic involvement present) Renal: Creatinine no greater than 2.0 mg/dL Creatinine clearance greater than 50 mL/min Cardiovascular: Ejection fraction at least 50% by MUGA or 2-D echocardiogram No significant abnormalities by EKG Other: Not pregnant or nursing Fertile patients must use effective contraception Willing to receive blood product transfusions No known sensitivity to E. coli-derived proteins No known AIDS syndrome or HIV-associated complex 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 antibody therapy Chemotherapy: No prior chemotherapy for lymphoma Endocrine therapy: Not specified Radiotherapy: No prior radiotherapy for lymphoma Surgery: Not specified

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 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: Hyper-CVAD + MTX/Ara-C + Rituximab<br>21-day cycles of Hyper-CVAD and high-dose methotrexate/cytarabine are alternated beginning with Hyper-CVAD for a maximum of 8 cycles. Rituximab is given for cycles 1-6. Hyper-CVAD (cycles 1,3,5,7): rituximab 375 mg/m^2 on day 1, mesna 600 mg/m^2 on days 2-4, cyclophosphamide 300 mg/m^2 on days 2-4, doxorubicin 16.6 mg/m^2/day on days 5-7, vincristine 1.4 mg/m^2 on days 5 and 12, dexamethasone 40 mg on days 2-5 and 12-15, and filgrastim 5 ug/kg on days 8-21. Methotrexate/Ara-C (cycles 2,4,6,8): rituximab 375 mg/m^2 on day 1, methotrexate 1000 mg/m^2 over days 2-3, Ara-C 12 g/m^2 over days 3-4, leucovorin 170 mg over days 3-5, and G-CSF 5 ug/kg on days 5-21. | Biological: filgrastim<br>* 5 ug/kg<br>* Other names: G-CSF;Biological: rituximab<br>* 375 mg/m^2 on day 1 of cycles 1-6<br>Drug: cyclophosphamide<br>* 300 mg/m^2 on days 2-4 of cycles 1,3,5,7<br>* Other names: cytoxan;Drug: cytarabine<br>* 12 g/m^2 over days 3-4 of cycles 2,4,6,8<br>* Other names: Ara-C;Drug: dexamethasone<br>* 40 mg on days 2-5 and 12-15 of cycles 1,3,5,7<br>Drug: doxorubicin<br>* 16.6 mg/m^2/day for days 5-7 of cycles 1,3,5,7<br>* Other names: adriamycin;Drug: leucovorin<br>* 170 mg over days 3-5 of cycles 2,4,6,8<br>* Other names: leucovorin calcium;Drug: methotrexate<br>* 1000 mg/m^2 over days 2-3 of cycles 2,4,6,8<br>* Other names: MTX;Drug: vincristine<br>* 1.4 mg/m^2 on days 5 and 12 of cycles 1,3,5,7<br>* Other names: vincristine sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-Free Survival (PFS) rate at 1 year. PFS measured from date of registration to date of first observation of progressive disease or death due to any cause. Progressive disease is a 50% increase in the sum of products of greatest diameters (SPD) of target measurable lesions over the smallest sum observed if a complete response (confirmed, or unconfirmed) was not previously achieved; appearance of a new lesion/site; unequivocal progression of non-measurable disease; or death due to disease without prior documentation of progression. | assessed after cycle 4, after completion of treatment, then every 3 months until 1 year after registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response | Complete (CR), complete unconfirmed (CRU) and partial responses (PR). CR is complete disappearance of all measurable and non-measurable disease with the exception of nodes; no new lesions; previously enlarged organs must have regressed in size; and if bone marrow positive at baseline, it must be negative. CRU is complete disappearance of all measurable and non-measurable disease; regressed, non-palpable organs; and one or more exceptions not qualifying for CR (see protocol section 10). PR applies to patients with at least one measurable lesion who do not qualify for CR or CRU. PR is a 50% decrease in sum of products of greatest diameters (SPD) for up to six identified dominant lesions identified at baseline; no new lesions; no increase in the size of liver, spleen or other nodes; and splenic and hepatic nodules must have regressed in size by at least 50% in SPD. | assessed after cycle 4 and after completion of treatment (168 days) | 
| Overall Survival | Overall Survival rate at 1 year. Time to death is from date of registration to date of death due to any cause. | assessed after cycle 4, after completion of treatment, then every 3 months for 2 years, then every 6 months thereafter until 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III mantle cell lymphoma, stage IV mantle cell lymphoma, contiguous stage II mantle cell lymphoma, noncontiguous stage II mantle cell lymphoma