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

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00369707
• Collaborator: Robert H. Lurie Cancer Center (Other)
• Enrollment: 42
• Locations: 4
• Arm: 1
• Actual Duration (Months): 98
• Patients Per Site: 10.5
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma	Drug: Rituximab; Drug: bortezomib	Phase 2

Detailed Description

This is a multicenter, prospective study.

• Induction therapy: Patients receive bortezomib IV over 3-5 seconds on days 1, 8, 15, and

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Combination Bortezomib and Rituximab as Front-line Therapy for Low-grade Non-Hodgkin's Lymphoma
• Actual Study Start Date: Aug 9, 2006
• Actual Primary Completion Date: May 22, 2012
• Actual Study Completion Date: Oct 10, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Bortezomib and Rituximab 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; 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.; Other Names: Rituxan ; Drug: bortezomib; 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.; Other Names: Velcade, PS-341

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (Complete Response and Partial Response) After Three Inductions Cycles of Treatment. [At baseline and at the completion of 3 cycles of treatment where 1 cycle equals 35 days.]

   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

1. Overall Response Rate After 1 Course of Induction Therapy [At baseline and at the completion of cycle 1 (1 cycle =35 days)]

   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.

2. Overall Response Rate After Completion of Maintenance Therapy [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.]

   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.

3. Duration of Overall Response [Every 2 months for up to 12 months then every 6 months for 2 years and annually for 1 year]

   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.

4. Number of Patients That Experience Adverse Events With Bortezomib/Rituximab Combination Treatment [Day 1 of each cycle and at the completion of cycles 1 and 3, during treatment up to 12 months]

   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

5. Tissue Evaluation [At baseline and at response assessment 1 after induction part A, 2, after induction part B and 3, maintenance period.]

   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

6. Correlation of Tumor Burden [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.]

   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.

7. Percentage of Patients With Treatment Failure [Median follow up for all patients was 50 months and on intent to treat, TTF rate for all patients is reported at 4 years.]

   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.

8. Progression Free Survival (PFS) Rate [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.]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida	United States	33136
2	Hematology-Oncology Associates of Illinois	Chicago	Illinois	United States	60611-2998
3	Northwestern University	Chicago	Illinois	United States	60611
4	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497

Sponsors and Collaborators

• Northwestern University
• Robert H. Lurie Cancer Center

Investigators

• Principal Investigator: Andrew M. Evens, DO, MS, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Northwestern University
• ClinicalTrials.gov Identifier: NCT00369707
• Other Study ID Numbers: NU 06H1; STU00005335
• First Posted: Aug 29, 2006
• Last Update Posted: Sep 6, 2019
• Last Verified: Oct 1, 2018

• Keywords provided by Northwestern University: Non-Hodgkin's Lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Rituximab; Bortezomib

Study Results

Participant Flow

Recruitment Details	The study opened for accrual on August 8, 2006 with an accrual goal of up to 43 patients. The study was designed to enroll 15 patients initially to do an interim efficacy assessment. Accrual was suspended on November 14 2007 for this analysis and reopened on December 20, 2007. The study was closed on August 10, 2012 after 42 patients were enrolled.

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Period Title: Induction Part A (1 Cycle -35 Days)
STARTED	42
COMPLETED	42
NOT COMPLETED	0
Period Title: Induction Part A (1 Cycle -35 Days)
STARTED	42
COMPLETED	35
NOT COMPLETED	7
Period Title: Induction Part A (1 Cycle -35 Days)
STARTED	35
COMPLETED	27
NOT COMPLETED	8
Period Title: Induction Part A (1 Cycle -35 Days)
STARTED	41
COMPLETED	38
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Overall Participants	42
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	27 64.3%
>=65 years	15 35.7%
Sex: Female, Male (Count of Participants)
Female	20 47.6%
Male	22 52.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 7.1%
Not Hispanic or Latino	39 92.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	1 2.4%
Black or African American	4 9.5%
White	37 88.1%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	42 100%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	42
Number [percentage of patients]	71

2. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	42
Number [percentage of patients]	33

3. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	42
Number [percentage of patients]	71

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Data was not collected or analyzed for duration of response.

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	0

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	42
Neutropenia	2 4.8%
Fever	2 4.8%
Infection	2 4.8%
Infusion reaction (rituximab)	2 4.8%
Cardiac	2 4.8%
Fatigue	2 4.8%
Throbocytopenia	1 2.4%
Diarrhea	1 2.4%
Hypokalemia	1 2.4%
Bowel obstruction	1 2.4%
Dehydration	1 2.4%

6. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

Insufficient tumor samples were submitted for insufficient number of patients. No data was collected or analyzed.

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	0

7. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	42
4 year PFS high risk FLIPI	26
4 year PFS low risk FLIPI	60
4 year OS high risk FLIPI	81
4 year OS low risk FLIPI	92

8. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	42
Number [percentage of patients]	26

9. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	42
Number [percentage of patients]	44

10. Post-Hoc Outcome

Title	Overall Survival Rate
Description	Overall survival (OS) will be measured from the time of first treatment to death from any cause.
Time Frame	Median follow up for all patients was 50 months (range 12-78 months) and on intent to treat, OS rate for all patients is reported at 4 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
Measure Participants	42
Number [percentage of patients]	87

Adverse Events

Time Frame	Adverse events were collected for the whole study over a 6 year and 4 month period. On average adverse event information for each patient was collected during patients treatment, for a maximum of 12 months.
Adverse Event Reporting Description	Adverse events were collected via systematic assessment during patients treatment visit days.
Arm/Group Title	Bortezomib and Rituximab
Arm/Group Description	Induction Part A will be 1 cycle of 35 days. On days 1, 8, 15 and 22 of the cycle, bortezomib 1.6mg/m2 will be administered intravenously (through a vein) over 3-5 seconds followed by an intravenous infusion of rituximab 375mg/m2 which may take between 3-4 hours. Induction Part B will be up to 2 cycles of 35 days each. Bortezomib will be given on days 1, 8, 15 and 22. Rituximab will only be given on day 1 of each cycle. Maintenance period will be up to 4 cycles where 1 cycle= 2 months. Bortezomib and Rituximab will be given on day 1 of each cycle only.
All Cause Mortality
	Bortezomib and Rituximab
	Affected / at Risk (%)	# Events
Total	6/42 (14.3%)
Serious Adverse Events
	Bortezomib and Rituximab
	Affected / at Risk (%)	# Events
Total	7/42 (16.7%)
Cardiac disorders
Diastolic heart failure	1/42 (2.4%)	1
Congestive Heart Failure exacerbation	1/42 (2.4%)	1
Congenital, familial and genetic disorders
Anal squamous cell carcinoma	1/42 (2.4%)	1
Gastrointestinal disorders
Dehydration	1/42 (2.4%)	1
General disorders
Fever with normal ANC	2/42 (4.8%)	2
Infections and infestations
Pneumonia	1/42 (2.4%)	1
Musculoskeletal and connective tissue disorders
Lumbar disk pain	1/42 (2.4%)	1
Nervous system disorders
Fainting episode (Syncope)	1/42 (2.4%)	1
Other (Not Including Serious) Adverse Events
	Bortezomib and Rituximab
	Affected / at Risk (%)	# Events
Total	42/42 (100%)
Blood and lymphatic system disorders
Hemoglobin (anemia)	18/42 (42.9%)	28
Neutrophils (neutropenia)	10/42 (23.8%)	15
Leukocytes (total white blood cells)	19/42 (45.2%)	27
Lymphopenia	24/42 (57.1%)	38
Platelets (thrombocytopenia)	14/42 (33.3%)	15
Edema	4/42 (9.5%)	4
Edema in limbs	5/42 (11.9%)	6
Eye disorders
Swelling of the eye	4/42 (9.5%)	5
Gastrointestinal disorders
Anorexia	6/42 (14.3%)	7
Constipation	9/42 (21.4%)	10
Diarrhea	22/42 (52.4%)	29
Abdominal distension/bloating	3/42 (7.1%)	3
Mucositis/stomatitis	4/42 (9.5%)	4
Heartburn/dyspepsia	3/42 (7.1%)	4
Nausea	25/42 (59.5%)	30
Vomiting	10/42 (23.8%)	11
Pain in abdomen	5/42 (11.9%)	6
General disorders
Fatigue	24/42 (57.1%)	24
Fever	8/42 (19%)	9
Insomnia	5/42 (11.9%)	5
Rigors	3/42 (7.1%)	3
Sweating	7/42 (16.7%)	8
Weight loss	7/42 (16.7%)	7
General pain NOS	6/42 (14.3%)	9
Flu like syndrome	6/42 (14.3%)	7
Immune system disorders
Allergic reaction/hypersensitivity	14/42 (33.3%)	16
Allergic rhinitis	10/42 (23.8%)	10
Infections and infestations
Upper airway infection	3/42 (7.1%)	3
Eye infection	4/42 (9.5%)	4
Infection (NOS)	3/42 (7.1%)	3
Metabolism and nutrition disorders
Transaminase	6/42 (14.3%)	6
ALT, SGPT (serum glutamic pyruvic transaminase)	4/42 (9.5%)	4
AST, SGOT (serum glutamic oxaloacetic transaminase)	5/42 (11.9%)	5
Albumin, serum low	5/42 (11.9%)	5
Bilirubin, serum high	8/42 (19%)	8
Bicarbonate- low	3/42 (7.1%)	3
Creatinine, serum high	3/42 (7.1%)	5
Calcium, serum low	5/42 (11.9%)	6
Glucose, serum high	18/42 (42.9%)	24
Glucose, serum low	6/42 (14.3%)	6
Lactic acid dehydrogenase (LDH)	4/42 (9.5%)	9
Magnesium, serum low	3/42 (7.1%)	3
Potassium, serum high	4/42 (9.5%)	8
Potassium, serum low	6/42 (14.3%)	10
Sodium, serum high	3/42 (7.1%)	3
Uric acid, serum high	3/42 (7.1%)	3
Musculoskeletal and connective tissue disorders
Pain in extremity - limb	4/42 (9.5%)	4
Pain in joints	4/42 (9.5%)	5
Nervous system disorders
Sensory neuropathy	10/42 (23.8%)	11
Headache	7/42 (16.7%)	7
Respiratory, thoracic and mediastinal disorders
Cough	10/42 (23.8%)	11
Shortness of breath (dyspnea)	6/42 (14.3%)	7
Skin and subcutaneous tissue disorders
Flushing	3/42 (7.1%)	3
Pruritus/itching	7/42 (16.7%)	7
Rash/desquamation	11/42 (26.2%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.