Back to resultsTrial of VELCADE and Rituxan as Front-line Tx for Low-grade NHL
Primary Purpose
Non-Hodgkin's Lymphoma
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Rituximab
bortezomib
Sponsored by
About this trial
This is an interventional treatment trial for Non-Hodgkin's Lymphoma focused on measuring Non-Hodgkin's Lymphoma
Eligibility Criteria
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
Sites / Locations
- University of Miami Sylvester Comprehensive Cancer Center - Miami
- Hematology-Oncology Associates of Illinois
- Northwestern University
- Fox Chase Cancer Center - Philadelphia
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Bortezomib and Rituximab
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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
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
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.
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.
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
Full Information
NCT ID
NCT00369707
First Posted
August 24, 2006
Last Updated
August 26, 2019
Sponsor
Northwestern University
Collaborators
Robert H. Lurie Cancer Center
1. Study Identification
Unique Protocol Identification Number
NCT00369707
Brief Title
Trial of VELCADE and Rituxan as Front-line Tx for Low-grade NHL
Official Title
A Phase II Trial of Combination Bortezomib and Rituximab as Front-line Therapy for Low-grade Non-Hodgkin's Lymphoma
Study Type
Interventional
2. Study Status
Record Verification Date
October 2018
Overall Recruitment Status
Completed
Study Start Date
August 9, 2006 (Actual)
Primary Completion Date
May 22, 2012 (Actual)
Study Completion Date
October 10, 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Northwestern University
Collaborators
Robert H. Lurie Cancer Center
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Hodgkin's Lymphoma
Keywords
Non-Hodgkin's Lymphoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
42 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Bortezomib and Rituximab
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
Velcade, PS-341
Intervention Description
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.
Primary Outcome Measure Information:
Title
Overall Response Rate (Complete Response and Partial Response) After Three Inductions Cycles of Treatment.
Description
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.
Time Frame
At baseline and at the completion of 3 cycles of treatment where 1 cycle equals 35 days.
Secondary Outcome Measure Information:
Title
Overall Response Rate After 1 Course of Induction Therapy
Description
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.
Time Frame
At baseline and at the completion of cycle 1 (1 cycle =35 days)
Title
Overall Response Rate After Completion of Maintenance Therapy
Description
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.
Time Frame
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.
Title
Duration of Overall Response
Description
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.
Time Frame
Every 2 months for up to 12 months then every 6 months for 2 years and annually for 1 year
Title
Number of Patients That Experience Adverse Events With Bortezomib/Rituximab Combination Treatment
Description
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
Time Frame
Day 1 of each cycle and at the completion of cycles 1 and 3, during treatment up to 12 months
Title
Tissue Evaluation
Description
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
Time Frame
At baseline and at response assessment 1 after induction part A, 2, after induction part B and 3, maintenance period.
Title
Correlation of Tumor Burden
Description
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.
Time Frame
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.
Title
Percentage of Patients With Treatment Failure
Description
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.
Time Frame
Median follow up for all patients was 50 months and on intent to treat, TTF rate for all patients is reported at 4 years.
Title
Progression Free Survival (PFS) Rate
Description
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
Time Frame
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew M. Evens, DO, MS
Organizational Affiliation
Northwestern University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Miami Sylvester Comprehensive Cancer Center - Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Hematology-Oncology Associates of Illinois
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611-2998
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Fox Chase Cancer Center - Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111-2497
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
24761968
Citation
Evens AM, Smith MR, Lossos IS, Helenowski I, Millenson M, Winter JN, Rosen ST, Gordon LI. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-Hodgkin lymphoma: a multicentre phase II study. Br J Haematol. 2014 Aug;166(4):514-20. doi: 10.1111/bjh.12915. Epub 2014 Apr 25.
Results Reference
derived
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Trial of VELCADE and Rituxan as Front-line Tx for Low-grade NHL
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