Trial of VELCADE and Rituxan as Front-line Tx for Low-grade NHL

Study Overview
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Brief Summary
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Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. 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. This phase II trial is studying how well giving bortezomib together with rituximab works as first-line therapy in treating patients with low-grade B-cell non-Hodgkin's lymphoma.

Detailed Description
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This is a multicenter, prospective study. Induction therapy: Patients receive bortezomib IV over 3-5 seconds on days 1, 8, 15, and 22. Patients also receive rituximab IV on days 1, 8, 15, and 22 of course 1 and on day 1 of all subsequent courses. Treatment repeats every 35 days for 3 courses. Patients achieving a complete response, partial response, or stable disease proceed to maintenance therapy. Maintenance therapy: Beginning 6-8 weeks after induction therapy, patients receive bortezomib IV over 3-5 seconds and rituximab IV on day 1. Treatment repeats every 60 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Blood and tissue samples are collected at baseline and periodically during study treatment. After completion of study therapy, patients are followed every 3 months for 2 years.

Official Title
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A Phase II Trial of Combination Bortezomib and Rituximab as Front-line Therapy for Low-grade Non-Hodgkin's Lymphoma

Conditions
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Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Rituximab
* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed low-grade B-lymphocyte non-Hodgkins lymphoma Life expectancy > 12 months Exclusion Criteria: No known history of HIV infection No other active infection No peripheral neuropathy ≥ grade 2 within the past 14 days No uncontrolled hypertension None of the following cardiac conditions: Myocardial infarction within the past 6 months No heart failure Uncontrolled angina Severe uncontrolled ventricular arrhythmias Electrocardiographic evidence of acute ischemia Active conduction system abnormalities No serious medical or psychiatric illness that would preclude study compliance Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No prior therapy for non-Hodgkins lymphoma No prior bortezomib or rituximab At least 3 weeks since prior chemotherapy, radiation therapy, immunotherapy, systemic anticancer biologic therapy, or anticancer hormonal therapy At least 2 weeks since prior investigational drugs No other concurrent systemic cytotoxic chemotherapy or investigational agents + No leukemia

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 and Rituximab<br>On days 1, 8, 15 and 22 of the 1st cycle, bortezomib will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab. How long it will take to infuse the dose of rituximab is dependent upon your weight and how well you tolerate the infusion; it is estimated this first infusion may take between 3-4 hours. During subsequent cycles, bortezomib will again be given on days 1, 8, 15 and 22. However, rituximab will only be given on day 1 of each cycle. | Drug: Rituximab<br>* On days 1, 8, 15 and 22 of the 1st cycle, bortezomib will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab. How long it will take to infuse the dose of rituximab is dependent upon your weight and how well you tolerate the infusion; it is estimated this first infusion may take between 3-4 hours. During subsequent cycles, bortezomib will again be given on days 1, 8, 15 and 22. However, rituximab will only be given on day 1 of each cycle.<br>* Other names: Rituxan;Drug: bortezomib<br>* On days 1, 8, 15 and 22 of the 1st cycle, bortezomib will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab. How long it will take to infuse the dose of rituximab is dependent upon your weight and how well you tolerate the infusion; it is estimated this first infusion may take between 3-4 hours. During subsequent cycles, bortezomib will again be given on days 1, 8, 15 and 22. However, rituximab will only be given on day 1 of each cycle.<br>* Other names: Velcade, PS-341;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (Complete Response and Partial Response) After Three Inductions Cycles of Treatment. | The primary objective of this study is to assess the overall response rate. Overall response rate at this time point will be defined as complete response [CR] plus partial response [PR]) after 3 cycles of bortezomib/rituximab induction therapy for patients with previously untreated low-grade, B-cell NHL. Complete response requires complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities (e.g., lactate dehydrogenase [LDH]) definitely assignable to NHL. There must also be complete disappearance of lymphoma involvement in the bone marrow (if initially present). Partial response (PR) requires 50% decrease in SPD of the six largest dominant nodes or nodal masses and no increase in the size of the other nodes, liver, or spleen. | At baseline and at the completion of 3 cycles of treatment where 1 cycle equals 35 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate After 1 Course of Induction Therapy | Overall response rate (ORR) after 1 cycle of bortezomib/rituximab induction therapy. Overall response rate at this time point will be defined as complete response [CR] plus partial response [PR]) after 1 cycle of bortezomib/rituximab induction therapy for patients with previously untreated low-grade, B-cell NHL. Complete response requires complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities (e.g., lactate dehydrogenase [LDH]) definitely assignable to NHL. There must also be complete disappearance of lymphoma involvement in the bone marrow (if initially present). Partial response (PR) requires 50% decrease in SPD of the six largest dominant nodes or nodal masses and no increase in the size of the other nodes, liver, or spleen. | At baseline and at the completion of cycle 1 (1 cycle =35 days) | 
| Overall Response Rate After Completion of Maintenance Therapy | Overall response rate at completion of bortezomib/rituximab maintenance therapy. Overall response rate at this time point will be defined as complete response [CR] plus partial response [PR]) after 3 cycles of bortezomib/rituximab induction therapy and up to 4 cycles of maintenance for patients with previously untreated low-grade, B-cell NHL. Complete response requires complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities (e.g., lactate dehydrogenase [LDH]) definitely assignable to NHL. There must also be complete disappearance of lymphoma involvement in the bone marrow (if initially present). Partial response (PR) requires 50% decrease in SPD of the six largest dominant nodes or nodal masses and no increase in the size of the other nodes, liver, or spleen. | At baseline and every 2 months during treatment of up to 3 cycles of induction (1 cycle =35days) and 4 cycles of maintenance (1 cycle =2 months) for up to 12 months. | 
| Duration of Overall Response | The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded)until the first date that recurrent or progressive disease is objectively documented. Complete response requires complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities (e.g., lactate dehydrogenase [LDH]) definitely assignable to NHL. There must also be complete disappearance of lymphoma involvement in the bone marrow (if initially present). Partial response (PR) requires 50% decrease in SPD of the six largest dominant nodes or nodal masses and no increase in the size of the other nodes, liver, or spleen. Progressive disease (PD) requires the appearance of any new lesion or increase by > 50% in the size of previously involved sites. | Every 2 months for up to 12 months then every 6 months for 2 years and annually for 1 year | 
| Number of Patients That Experience Adverse Events With Bortezomib/Rituximab Combination Treatment | Assess the safety and tolerance of bortezomib/rituximab as induction and maintenance therapy. Data will be collected for grade 3 and grade 4 adverse events experienced by patients that are determined to be at least possibly related to at least one study drug. Toxicity data for bortezomib/rituximab will be collected on day 1 of every cycle (1 cycle = 35 days) for up to 7 cycles during treatment according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE | Day 1 of each cycle and at the completion of cycles 1 and 3, during treatment up to 12 months | 
| Tissue Evaluation | Tissue microarray analysis from paraffin embedded tissue, gene expression profiling from frozen tissue (both from initial node biopsy collected/stored) and whole blood analysis of FCγR polymorphism | At baseline and at response assessment 1 after induction part A, 2, after induction part B and 3, maintenance period. | 
| Correlation of Tumor Burden | Correlation of tumor burden according to Groupe D'Etude des Lymphomes Follicularies (GELF) with recently developed Follicular Lymphoma International Prognostic Index (FLIPI) prognostic index. All patients enrolled in the study were required to have high tumor burden (HTB) as defined by GELF, where HTB is defined as representing higher risk disease and poorer outcomes than low tumor burden (LTB). Patients were put into low risk or high risk FLIPI groups. Low risk group with a score of 0-2 and high risk group with a score of 3-5. A FLIPI score of 0 to 1 = low risk with a 10 year overall survival of 70%. A score of 2= intermediate risk with a 10 year overall survival of 50%. Finally, a score of ≥ 3 is considered high risk with a 10 year overall survival of 35%. Data was collected in connection with high or low risk FLIPI and Progression Free Survival (PFS) or Overall Survival (OS) and is reported as percentage patient with high/low risk that are progression free or alive. | At the start of treatment and at Median follow up for all patients was 50 months (range 12-78 months) and on intent to treat, PFS and OS for all patients is reported at 4 years. | 
| Percentage of Patients With Treatment Failure | Time to Treatment Failure (TTF) rate measured, from the time of first treatment to disease progression, relapse, second tumor, death from any cause, treatment toxicity requiring termination from the study, or for any reason treatment is discontinued permanently. | Median follow up for all patients was 50 months and on intent to treat, TTF rate for all patients is reported at 4 years. | 
| Progression Free Survival (PFS) Rate | Progression Free Survival is measured from the time of first induction infusion to disease progression, relapse, second tumor, or death from any cause. Progressive disease (PD) requires the following: Appearance of any new lesion or increase by > 50% in the size of previously involved sites. Increase of > 50% in the SPD from nadir measurement of all involved dominant lymph nodes and liver nodules and spleen nodules or unequivocal progression in any non measurable disease or nondominant site. > 50% increase in greatest diameter of any previously identified node greater than 1 cm in its short axis or in the SPD of more than one node | Median follow up for all patients was 50 months (range 12-78 months) and on intent to treat, PFS for all patients is reported at 4 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Hodgkin's Lymphoma