Bortezomib, Cladribine, and Rituximab in Treating Patients With Advanced Mantle Cell Lymphoma or Indolent Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cladribine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 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. Giving bortezomib together with cladribine and rituximab may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving bortezomib together with cladribine and rituximab works in treating patients with advanced mantle cell lymphoma or indolent lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the 2-year progression-free survival of patients with advanced mantle cell lymphoma or indolent lymphoma treated with bortezomib, cladribine, and rituximab. Secondary Determine the 2-year overall survival of patients treated with this regimen. Determine the complete response and overall response rate in patients treated with this regimen. Describe the long- and short-term toxicity of this regimen in these patients. Determine the prognostic importance of Aurora kinase A in patients treated with this regimen. Determine the cytokine profiles for each lymphoma subtype and how they change with this regimen. Evaluate the prognostic importance of major carcinogenic pathways using tissue microarray. OUTLINE: Patients receive bortezomib IV on days 1 and 4, cladribine IV over 2 hours on days 1-5, and rituximab IV on day 1. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and after course 1 for cytokine profile studies. Previously collected tissue samples are obtained for analysis of Aurora kinase A and B, Ki-67, cyclin D, Bcl-2, phosphor-HisH3, c-Met, and VEGF expression by using tissue microarray (IHC staining), reverse transcriptase-PCR, and/or western blotting. After completion of study therapy, patients are followed up every 3 months for 2 years.

Official Title
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A Phase II, Open-Label Study of Bortezomib (Velcade), Cladribine and Rituximab (VCR) in Advanced, Newly Diagnosed and Relapsed/Refractory Mantle Cell and Indolent Lymphomas

Conditions
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SLL, Lymphoma, Mantle Cell Lymphoma, Indolent Lymphoma

Intervention / Treatment
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* Drug: rituximab
* Drug: bortezomib
* Drug: cladribine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary consent before performance of any study-related procedure Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control Male subject agrees to use an acceptable method for contraception for the duration of the study. Biopsy-proven mantle cell, marginal zone, lymphoplasmacytic, small lymphocytic lymphoma, or follicular lymphoma CD20-positive disease Patients with marginal zone, lymphoplasmacytic, small lymphocytic, or follicular lymphoma - at least one criterion for initiation of treatment must be met: Symptomatic disease Cytopenia related to lymphoma Leukemic phase (> 5,000 malignant lymphocytes/µl) Mass over 5 cm in greatest diameter For lymphoplasmacytic lymphoma: additional treatment criteria are serum viscosity ≥ 4 cp, serum monoclonal protein > 5 g/L, concurrent primary systemic AL amyloidosis, cold agglutinin disease Age over 18 Prior treatment with bortezomib and/or rituximab is acceptable For follicular lymphoma only, at least one prior treatment Exclusion Criteria: Platelet count of < 100 X10 /L within 14 days before enrollment, unless due to bone marrow infiltration with lymphoma, or due to autoimmune thrombocytopenia because of lymphoma. Patient has an absolute neutrophil count of < 1.0 X 10/L within 14 days before registration, unless due to bone marrow infiltration with lymphoma. Patient has a calculated or measured creatinine clearance of <20 mL/minute within 14 days before registration. (Creatinine Clearance is indicated through the Serum Creatinine. If the Serum Creatinine is abnormal, the physician may then due a 24 hour urine to further clarify Creatinine Clearance. A 24 hour urine test is not required per study.) Patient has ≥ Grade 2 peripheral neuropathy within 14 days before registration. Myocardial infarction within 6 months prior to registration or has New York Heart Association (NYHA) Class III or IV heart failure. uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Hypersensitivity to bortezomib, boron or mannitol. Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant Patient received other investigational drugs with 14 days before registration Serious medical or psychiatric illness likely to interfere with study participation Diagnosed or treated for another malignancy within 3 years of registration, w/ the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. CNS involvement with lymphoma. Known HIV-positive. History of disease refractory to a purine analog (defined as remission duration of < 6 months to therapy that included fludarabine, pentostatin, or cladribine). History of intolerance of bortezomib, boron, mannitol, cladribine, or rituximab. Patient has > 1.5 X ULN Total Bilirubin Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: VCR (Velcade, Cladribine and Rituximab)<br>Rituximab 375 mg/m2 IV day1 Cladribine 4 mg/m2 IV over 2 hours days 1-5 Bortezomib 1.3 mg/m2 IV days 1 and 4 Repeat every 28 days for a maximum of 6 cycles | Drug: rituximab<br>* 375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles.<br>* Other names: Rituxan;Drug: bortezomib<br>* 1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles.<br>* Other names: Velcade;Drug: cladribine<br>* 4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.<br>* Other names: Leustatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival at 2 Years | PFS was calculated from the first dose of study drug to the first documentation of disease progression, death regardless of cause, or change in therapy due to disease progression, whichever occurred first. If disease progression did not occur by the end of treatment, patients were evaluated every 3 months until progression with physical examination, laboratory studies, and conventional computed tomographic imaging, up to a maximum of 2 years. The Kaplan-Meier product-limit method will be used to estimate progression-free survival in the presence of censoring. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at 2 Years |  | 2 years | 
| Complete Response Rate |  | Two years | 
| Partial Response |  | Two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent mantle cell lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, recurrent marginal zone lymphoma, stage III marginal zone lymphoma, stage IV marginal zone lymphoma, Waldenstrom macroglobulinemia, recurrent small lymphocytic lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, 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, extranodal marginal zone BCL mucosa assoc lymphoid tissue, nodal marginal zone B Cell lymphoma, splenic marginal zone lymphoma