Study of the Combination of Bortezomib, Dexamethasone, and Rituximab in Patients With Waldenstroms Macroglobulinemia

Study Overview
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Brief Summary
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The purpose of this study is to find out if the combination of bortezomib (Velcade), dexamethasone (Decadron) and rituximab (Rituxan) is effective in treating Waldenstrom's macroglobulinemia.

Detailed Description
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This is an open-label study which means both the patient and the doctor will know what drugs and doses the patient is receiving throughout the study. Patients will receive 8 cycles of study treatment with bortezomib, dexamethasone and rituximab. Each cycle is 21 days long. Therapy is given on the first, fourth, eighth and eleventh day of each cycle, followed by a 10 day rest period. The first 4 cycles will be given one after the other. Three months after completing the fourth cycle of therapy, patients will receive one cycle of therapy every three months for a total of four more cycles. On the first, fourth, eighth and eleventh day of each cycle, the patient will receive bortezomib and dexamethasone as an intravenous injection through a needle in your vein. On the eleventh day only, the patient will also receive rituximab as an intravenous infusion after getting bortezomib and dexamethasone. Prior to each infusion of rituximab therapy, the patient will be asked to take some medications to prevent or reduce side effects of rituximab. These medications are benadryl, tylenol, and possibly more steroids. The doctor will determine which of these drugs are appropriate for the individual patient. During the rituximab infusion, the patients blood pressure and pulse will be monitored frequently and the infusion rate may be decreased depending upon the side effects experienced. After therapy is completed, the patient will be followed every three months for 2 more years for office visits and laboratory tests to determine how well they are doing and if the therapy continues to benefit them.

Official Title
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A Phase II Study of the Combination Bortezomib (Velcade, PS-341), Dexamethasone, and Rituximab in Patients With Waldenstroms Macroglobulinemia

Conditions
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Waldenstrom's Macroglobulinemia

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Dexamethasone
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinicopathological diagnosis of Waldenstrom's macroglobulinemia (WM) No previous therapy for WM Measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level of greater than or equal to 2 times the upper limit of each institution's normal value CD20 positive disease based on any previous bone marrow immuno-histochemistry or flow cytometric analysis performed up to 3 months prior to enrollment Karnofsky performance status > 60 Life expectancy > 3 months AST (SGOT) < 3 x ULN ALT (SGPT) < 3 x ULN Total bilirubin < 2 x ULN Calculated or measured creatinine clearance > 30mL/minute Serum sodium > 130 mmol/L 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 Exclusion Criteria: Previous therapy for Waldenstrom's macroglobulinemia Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association 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 dexamethasone, boron or mannitol Pregnant or breast-feeding women Serious medical or psychiatric illness likely to interfere with participation in this clinical study

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: Bortezomib, Dexamethasone, Rituximab<br>A cycle of therapy consisted of bortezomib 1.3 mg/m(2) intravenously; dexamethasone 40 mg on days 1, 4, 8, and 11; and rituximab 375 mg/m(2) on day 11. Patients received four consecutive cycles for induction therapy and then four more cycles, each given 3 months apart, for maintenance therapy. | Drug: Bortezomib<br>* Given intravenously on days 1, 4, 8, and 11 of a 21-day cycle for 8 cycles<br>* Other names: Bortezomib (Velcade);Drug: Dexamethasone<br>* Given intravenously on days 1, 4, 8, and 11 of a 21-day cycle for 8 cycles<br>* Other names: Dexamethasone (Decadron);Drug: Rituximab<br>* Given intravenously after bortezomib and dexamethasone on day 11 of a 21-day cycle for 8 cycles<br>* Other names: Rituximab (Rituxan);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | This outcome measure was to assess the safety and tolerability of bortezomib, dexamethasone and rituximab in patients with untreated Waldenstroms macroglobulinemia. | 33.2 months | 
| Response Rate | This outcome measure was to determine the response rate along with attainment of stable disease and time to disease progression following treatment with this patient population. The response rates were defined as follows. A complete response (CR) was defined as having resolution of all symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, absence of bone marrow disease by bone marrow biopsy and aspiration, and resolution of any adenopathy or splenomegaly. A near complete response (nCR) was defined as fulfilling all CR criteria in the presence of a positive immunofixation study. Patients with very good partial response (VGPR), partial response (PR), and minor response (MR) were defined as having a ≥ 90%, ≥ 50%, and 25% to 49% reduction in serum IgM levels, respectively. Progressive disease (PD) occurred when a more than 25% increase in serum IgM level or progression of clinically significant disease parameters was observed. | 33.2 months | 
| Time to Best Response |  | 33.2 months | 
| Time to Progression | Progressive Disease (PD) will be defined as a greater than 25% increase in serum IgM monoclonal protein levels from the lowest attained response value as determined by serum electrophoresis, confirmed by at least one other investigation, or progression of clinically significant disease related symptom(s). | 42 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bortezomib, dexamethasone, rituximab