S0601 Rituximab, Combination Chemotherapy, and Bortezomib Followed by Bortezomib Alone in Treating Patients With Newly Diagnosed Mantle Cell 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. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving rituximab together with combination chemotherapy and bortezomib may kill more cancer cells. Giving bortezomib as maintenance therapy may keep the cancer from progressing. PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy and bortezomib followed by bortezomib alone works in treating patients with newly diagnosed mantle cell lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the 2-year progression-free survival rate in patients with newly diagnosed mantle cell lymphoma treated with induction therapy comprising rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone, and bortezomib followed by bortezomib maintenance (VM) therapy. Secondary Determine the response rate (complete, complete unconfirmed, and partial responses) in patients treated with this regimen. Determine the toxicity of VM in these patients. OUTLINE: This is a multicenter study. Induction therapy: Patients receive R-CHOP-V induction therapy comprising rituximab IV over ≤ 6 hours, cyclophosphamide IV over 15-45 minutes, doxorubicin hydrochloride IV over 5-20 minutes, and vincristine IV over 5-15 minutes on day 1; oral prednisone once daily on days 1-5; and bortezomib IV over 30-90 minutes on days 1 and 4. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of 6 courses, patients with stable disease or better proceed to bortezomib maintenance therapy. Maintenance therapy: Beginning 3 months after completion of R-CHOP-V induction therapy, patients receive bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 3 months for up to 8 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 4 years and then annually for 3 years. PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

Official Title
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A Phase II Study of Combination Rituximab-CHOP and Bortezomib (Velcade®) (R-CHOP-V) Induction Therapy Followed by Bortezomib Maintenance (VM) Therapy for Patients With Newly Diagnosed Mantle Cell Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: rituximab
* Drug: bortezomib
* Drug: cyclophosphamide
* Drug: doxorubicin hydrochloride
* Drug: prednisone
* Drug: vincristine sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed mantle cell lymphoma (MCL) meeting the following criteria: Stage III-IV or bulky stage II disease Confirmation of positivity for the following phenotypes by immunohistochemistry or flow cytometry: Cluster of differentiation antigen 19 (CD19) (or CD20) Cyclin D1 OR evidence of t(11;14) translocation by cytogenetic analysis or fluorescent in situ hybridization Newly diagnosed, previously untreated disease Bidimensionally measurable disease by conventional techniques No nonmeasurable disease only Adequate tumor tissue from original diagnostic specimen available Tissue obtained by needle aspiration or cytology not allowed No clinical evidence of central nervous system (CNS) involvement by lymphoma Co-registration on protocols SWOG-8947 and SWOG-8819 is strongly encouraged PATIENT CHARACTERISTICS: Zubrod performance status 0-2 Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No peripheral neuropathy ≥ grade 2 No hypersensitivity to bortezomib, boron, or mannitol No other prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer for which the patient is currently in complete remission, or any other cancer for which the patient has been disease free for the past 5 years HIV negative PRIOR CONCURRENT THERAPY: No prior chemotherapy, radiotherapy, or antibody therapy for lymphoma More than 14 days since prior investigational drugs

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 + Velcade<br>6 21-day cycles of standard R-CHOP with 1.3 mg/m^2 Bortezomib given on days 1 and 4 of each cycle. This is followed by 8 3-month cycles of maintenance with 1.3 mg/m^2 Bortezomib on days 1, 4, 8 and 11 of each cycle. | Biological: rituximab<br>* 375 mg/m^2 on day 1 for cycles 1-6.<br>* Other names: Rituxan;Drug: bortezomib<br>* 1.3 mg/m^2 on days 1, 4 of cycles 1-6 and on days 1, 4, 8, 11 of cycles 7-14.<br>* Other names: Velcade;Drug: cyclophosphamide<br>* 750 mg/m^2 on day 1 of cycles 1-6.<br>Drug: doxorubicin hydrochloride<br>* 50 mg/m^2 on day 1 of cycles 1-6.<br>Drug: prednisone<br>* 100 mg on days 1-5 of cycles 1-6.<br>Drug: vincristine sulfate<br>* 1.4 mg/m^2 on day 1 of cycles 1-6.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-year Progression-free Survival in Patients Treated With Rituximab-CHOP-bortezomib Induction Therapy (RCHOP-V) Followed by Bortezomib Maintenance Therapy (VM) | Measured from date of registration to date of first observation of relapsed or progressive disease, or death due to any cause. | 0-2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate in Patients Treated With Rituximab-CHOPbortezomib Induction Therapy (R-CHOP-V) Followed by Bortezomib Maintenance Therapy(VM). | 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. | At the time of restaging (between Cycles 6 and 7), every 6 months during Cycles 7-14, and at the end of protocol treatment | 
| 2-year Overall Survival in Patients Treated With Rituximab-CHOP-bortezomib Induction Therapy (RCHOP-V) Followed by Bortezomib Maintenance Therapy (VM) | Measured from date of registration to date of death due to any cause or last contact | 0-2 years | 
| 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. | Assessed prior to each cycle (for Cycles 2-6), at restaging (between Cycle 6 and 7), every 3 months ( for Cycle 7-14), and at the end of protocol treatment. | 

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