Bortezomib and Rituximab in Treating Patients With Mantle Cell Lymphoma Who Have Previously Undergone Stem Cell Transplantation

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. 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 rituximab may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving bortezomib and rituximab together works in treating patients with mantle cell lymphoma who have previously undergone stem cell transplantation

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the two year disease free survival in mantle cell lymphoma (MCL) patients treated with bortezomib + rituximab after hematopoietic stem cell transplantation (HSCT). SECONDARY OBJECTIVES: I. To evaluate the toxicity profile, safety, overall survival, time to treatment failure, remission duration, and biological markers of mantle cell lymphoma patients treated with bortezomib + rituximab after autologous hematopoietic stem cell transplantation. OUTLINE: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) over 3-5 seconds and rituximab IV on days 1, 8, 15, and 22. Treatment with bortezomib repeats every 3 months for up to 8 courses and treatment with rituximab repeats every 6 months for up to 4 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 3 years.

Official Title
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A Phase II Study of Weekly Maintenance Bortezomib and Rituximab in Mantle Cell Lymphoma Post Autologous Hematopoietic Cell Transplantation

Conditions
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Contiguous Stage II Mantle Cell Lymphoma, Noncontiguous Stage II Mantle Cell Lymphoma, Recurrent Mantle Cell Lymphoma, Stage I Mantle Cell Lymphoma, Stage III Mantle Cell Lymphoma, Stage IV Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: bortezomib
* Biological: rituximab
* Other: laboratory biomarker analysis
* Other: immunohistochemistry staining method
* Genetic: RNA analysis
* Genetic: gene expression analysis
* Genetic: DNA analysis
* Other: pharmacological study
* Other: pharmacogenomic studies
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histological documented or cytological confirmed mantle cell lymphoma; cyclin D1 must be present as evidenced by either fluorescence in situ hybridization (FISH) or immunohistochemical staining Patients must have undergone autologous hematopoietic stem cell transplantation (AHCT) and achieved engraftment by day (D)60-180 as evidenced by absolute neutrophil count (ANC) > 1000/mcL and platelets (Plt) > 75,000/mcL Patients must be in complete remission at D60-180 after AHCT as evidenced by computed tomography (CT) scan of the neck/chest/abdomen (abd)/pelvis or CT/positron emission tomography (PET) scans Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study Male subject agrees to use an acceptable method for contraception for the duration of the study Life expectancy of greater than 3 months Karnofsky > 60% ANC > 1000/mcL Plts > 75,000/mcL Total bilirubin within normal institutional limits, patients with elevation of unconjugated bilirubin alone, as in Gilbert's disease, are eligible Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 x institutional upper limit of normal Creatinine up to and including 2 mg/dL Exclusion Criteria: Patient has >= grade 2 peripheral neuropathy within 14 days before enrollment and at D60-180 after AHCT; patients who had >= grade 2 peripheral neuropathy within 14 days before enrollment but resolves to grade 1 or lower peripheral neuropathy at D60-D180 after AHCT can be enrolled at this time Patient has > 1.5 x upper limit of normal (ULN) total bilirubin unless history of Gilbert's syndrome Myocardial infarction within 6 months prior to enrollment 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; prior to study entry, any electrocardiographic (ECG) abnormality at screening has to be documented by the investigator as not medically relevant Patient has hypersensitivity to bortezomib, boron or mannitol Female subject is pregnant or breast-feeding; confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women Patient has received other investigational drugs with 14 days before treatment of treatment with bortezomib + rituximab Serious medical or psychiatric illness likely to interfere with participation in this clinical study Diagnosed or treated for another malignancy within 3 years of enrollment, with 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 Patients with other active malignancies (no evidence of other cancer or life expectancy greater than 5 years) are ineligible for this study Human immunodeficiency virus (HIV) positive patients or hepatitis B or C positive patients Patients with active central nervous system (CNS) disease or history of brain metastases (mets) are excluded from study Prior exposure to either bortezomib or rituximab is not an exclusion criteria

Ages Eligible for Study
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Minimum Age: 19 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: Treatment (bortezomib and rituximab)<br>Doses of bortezomib given is 1.3 mg/m2 weekly x 4 weeks given every 3 month x 8 cycles. Doses of RITUXAN given is 375 mg/m2 give weekly x 4 weeks given every 6 month for 4 cycles. | Drug: bortezomib<br>* Given SC or IV<br>* Other names: VELCADE;Biological: rituximab<br>* Given IV<br>* Other names: Rituxan;Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Genetic: RNA analysis<br>* Correlative studies<br>Genetic: gene expression analysis<br>* Correlative studies<br>Genetic: DNA analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: pharmacogenomic studies<br>* Correlative studies<br>* Other names: Pharmacogenomic Study;Other: Questionnaire Administration<br> <br> * Other names: Ancillary Studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two-year Disease-free Survival | Assessed by Kaplan-Meier survival analysis. 95% confidence intervals will be calculated using Greenwood's formula. | Participants were followed up to 5 years after initial treatment and Kaplan-Meier survival analysis was used to generate the two-year disease-free survival estimate presented. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two-year Overall Survival | Assessed by Kaplan-Meier survival analysis. 95% confidence intervals will be calculated using Greenwood's formula. | Participants were followed up to 5 years after initial treatment and Kaplan-Meier survival analysis was used to generate the two-year overall survival estimate presented. | 
| Grade 3 or 4 Toxicities of Bortezomib and Rituximab Treatment | Observed toxicities will be summarized in terms of type, severity (graded by NCI CTCAE version 4.0) and attribution. | Participants were followed up to 5 years after initial treatment. |