Phase I/II Trial of VELCADE Plus Zevalin in Patients With Relapsed or Refractory Follicular Lymphoma

• Sponsor: Northwestern University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00372905
• Collaborator: Robert H. Lurie Cancer Center (Other)
• Enrollment: 18
• Locations: 2
• Arm: 1
• Actual Duration (Months): 71.5
• Patients Per Site: 9
• 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. 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. Radiolabeled monoclonal antibodies, such as yttrium Y 90 ibritumomab tiuxetan, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving bortezomib together with rituximab and yttrium Y 90 ibritumomab tiuxetan may kill more cancer cells.

This phase I/II trial is studying the side effects and best dose of bortezomib when given together with rituximab and yttrium Y 90 ibritumomab tiuxetan and to see how well they work in treating patients with relapsed or refractory follicular non-Hodgkin's lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Drug: rituximab; Drug: bortezomib; Drug: Ibritumomab tiuxetan	Phase 1/Phase 2

Detailed Description

This is a phase I, dose-escalation study of bortezomib followed by a phase II study.

Phase I:

• Induction therapy: Patients receive bortezomib IV over 3-5 seconds on days 1, 8, 15, and 22, rituximab IV on days 8 and 15, and yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes on day 15.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

• Consolidation therapy: Beginning 6-7 weeks after completing induction therapy, patients receive bortezomib IV over 3-5 seconds on days 1, 8, and 15. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.

Phase II: Patients receive induction therapy and consolidation therapy as in phase I, with bortezomib administered at the MTD determined in phase I.

After completion of study treatment, patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

A total of 24 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of Combined Weekly Bortezomib (VELCADE®) and Y-90-Ibritumomab Tiuxetan (Zevalin) in Patients With Relapsed or Refractory Follicular Lymphoma and Transformed Non-Hodgkin's Lymphoma
• Actual Study Start Date: Jul 24, 2007
• Actual Primary Completion Date: Jun 22, 2010
• Actual Study Completion Date: Jul 8, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: bortezomib, Ibritumomab tiuxetan, rituximab Induction therapy will last 28 days. Bortezomib will be given on days 1, 8, 15, and 22. Rituximab will be given on days 8 and 15 along with 111-indium-ibritumomab tiuxetan. During consolidation therapy, Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle for a maximum of 3 cycles. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.

Drug: rituximab; Induction therapy will last 28 days. Bortezomib will be given on days 1, 8, 15, and 22. Rituximab will be given on days 8 and 15 along with 111-indium-ibritumomab tiuxetan. During consolidation therapy, Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle for a maximum of 3 cycles. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.; Other Names: Rituxan, IDEC-C2B8 ; Drug: bortezomib; Induction therapy will last 28 days. Bortezomib will be given on days 1, 8, 15, and 22. Rituximab will be given on days 8 and 15 along with 111-indium-ibritumomab tiuxetan. During consolidation therapy, Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle for a maximum of 3 cycles. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.; Other Names: Velcade ; Drug: Ibritumomab tiuxetan; Induction therapy will last 28 days. Bortezomib will be given on days 1, 8, 15, and 22. Rituximab will be given on days 8 and 15 along with 111-indium-ibritumomab tiuxetan. During consolidation therapy, Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle for a maximum of 3 cycles. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.; Other Names: 111-indium-ibritumomab tiuxetan, Y-90-ibritumomab tiuxetan

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) and Tolerability of Bortezomib Combined With Y-90-Ibritumomab Tiuxetan Determined by Number of Dose Limiting Toxicities in a Cohort. [During induction therapy, the first 28 days of treatment.]

   To determine the MTD using a 3+3 dose escalating design. There will be 3 dose cohorts:1.0mg/m2,1.3mg/m2 and1.6 mg/m2. 3 patients will be enrolled at dose of 1.0mg/m2 bortezomib. If no dose limiting toxicities (DLTs) are seen in the first 3 patients then dose will be escalated to next level and 3 patients will be treated at that dose level. If a DLT is seen at any dose, then 3 more patients will be enrolled at that dose level. If 1 patient out of 6, experience a DLT then MTD will be determined to be at this dose level. If 2 or more DLTs are seen in first 3 patients at that dose, then MTD will be one dose lower to the level where the DLTs were experienced. DLTs were defined using the National Cancer Institute Common Toxicity Criteria Version 3.0. DLTs=grade 3 nausea, vomiting, diarrhea or ileus more than 96h; grade 4 nausea, vomiting, diarrhea or ileus,neuropathic pain, peripheral sensory neuropathy, neutropenia, thrombocytopenia.

Secondary Outcome Measures

1. Number of Patients With Adverse Events Related to Treatment of Bortezomib Combined With Y-90-ibritumomab Tiuxetan [At start of treatment on days 1, 8, 15, 22 of induction, days 36 and 50 of recovery, days 1, 8, 15 of consolidation cycles for up to 3 cycles and 4 weeks after the completion of treatment.]

   To further explore the toxicity bortezomib combined with Y-90-ibritumomab tiuxetan by collecting data on adverse events (AE) reported by patient or collected lab results that are grade 3 or grade 4 that were determined to be at least possible related to any of the studies drugs. Toxicity will be collected on treatment days 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

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed follicular lymphoma

• CD20+ at time of diagnosis or subsequently

• More than 4 weeks since prior rituximab

• More than 3 weeks since prior anticancer therapy (6 weeks for nitrosourea or mitomycin

• More than 4 weeks since prior major surgery

• More than 2 weeks since prior investigational drugs

Exclusion Criteria:

• AIDS-related lymphoma

• History or evidence of CNS involvement

• Pregnant or nursing

• known HIV positivity

• serious medical or psychiatric illness that would preclude study participation

• myocardial infarction within the past 6 months

• congestive heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG evidence of acute ischemia or active conduction system abnormalities

• known hypersensitivity to rituximab, bortezomib, boron, or mannitol

• prior autologous or allogeneic stem cell transplantation

• prior radioimmunoconjugate therapy or prior exposure to murine antibodies

• prior external-beam irradiation to > 25% of active bone marrow

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University School of Medicine	Atlanta	Georgia	United States	30322
2	Northwestern University	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• Northwestern University
• Robert H. Lurie Cancer Center

Investigators

• Principal Investigator: Jane Winter, MD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Northwestern University
• ClinicalTrials.gov Identifier: NCT00372905
• Other Study ID Numbers: NU 05H9; STU00004871
• First Posted: Sep 7, 2006
• Last Update Posted: Sep 4, 2019
• Last Verified: Oct 1, 2018

• Keywords provided by Northwestern University: follicular lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Rituximab; Bortezomib; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	The study opened for accrual on August 11, 2006 with an accrual goal of up to 24 patients. Accrual was suspended on September 9 2009 and reopened on November 30, 2009. The study was closed permanently on August 15, 2013 due to slow accrual with 18 patients enrolled and 17 patients treated on study.

Arm/Group Title	Cohort 1: 1.0mg/m2 Bortezomib	Cohort 2: 1.3mg/m2 Bortezomib	Cohort 3: 1.6mg/m2 Bortezomib	Expansion Phase: 1.3mg/m2 Bortezomib
Arm/Group Description	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose (MTD), or as the determined MTD in the expansion phase. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.
Period Title: Cohort 1: Dose Level 1.0mg/m2
STARTED	3	0	0	0
Registered to Study	3	0	0	0
Treated 1 Cycle of Induction Therapy	3	0	0	0
Completed 3 Cycles of Consolidation	1	0	0	0
COMPLETED	1	0	0	0
NOT COMPLETED	2	0	0	0
Period Title: Cohort 1: Dose Level 1.0mg/m2
STARTED	0	3	0	0
Registered to Study	0	3	0	0
Treated 1 Cycle of Induction Therapy	0	3	0	0
Completed 3 Cycles of Consolidation	0	3	0	0
COMPLETED	0	3	0	0
NOT COMPLETED	0	0	0	0
Period Title: Cohort 1: Dose Level 1.0mg/m2
STARTED	0	0	4	0
Registered	0	0	4	0
Treated 1 Cycle of Induction Therapy	0	0	3	0
Completed 3 Cycles of Consolidation	0	0	1	0
COMPLETED	0	0	1	0
NOT COMPLETED	0	0	3	0
Period Title: Cohort 1: Dose Level 1.0mg/m2
STARTED	0	0	0	8
Registration	0	0	0	8
Treated 1 Cycle Induction Therapy	0	0	0	8
Completed 3 Cycles of Consolidation	0	0	0	6
COMPLETED	0	0	0	6
NOT COMPLETED	0	0	0	2
Period Title: Cohort 1: Dose Level 1.0mg/m2
STARTED	3	3	3	8
COMPLETED	3	2	3	5
NOT COMPLETED	0	1	0	3

Baseline Characteristics

Arm/Group Title	Bortezomib, Ibritumomab Tiuxetan, Rituximab
Arm/Group Description	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.
Overall Participants	18
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	13 72.2%
>=65 years	5 27.8%
Sex: Female, Male (Count of Participants)
Female	9 50%
Male	9 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5.6%
Not Hispanic or Latino	17 94.4%
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	0 0%
Black or African American	1 5.6%
White	17 94.4%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	18 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) and Tolerability of Bortezomib Combined With Y-90-Ibritumomab Tiuxetan Determined by Number of Dose Limiting Toxicities in a Cohort.
Description	To determine the MTD using a 3+3 dose escalating design. There will be 3 dose cohorts:1.0mg/m2,1.3mg/m2 and1.6 mg/m2. 3 patients will be enrolled at dose of 1.0mg/m2 bortezomib. If no dose limiting toxicities (DLTs) are seen in the first 3 patients then dose will be escalated to next level and 3 patients will be treated at that dose level. If a DLT is seen at any dose, then 3 more patients will be enrolled at that dose level. If 1 patient out of 6, experience a DLT then MTD will be determined to be at this dose level. If 2 or more DLTs are seen in first 3 patients at that dose, then MTD will be one dose lower to the level where the DLTs were experienced. DLTs were defined using the National Cancer Institute Common Toxicity Criteria Version 3.0. DLTs=grade 3 nausea, vomiting, diarrhea or ileus more than 96h; grade 4 nausea, vomiting, diarrhea or ileus,neuropathic pain, peripheral sensory neuropathy, neutropenia, thrombocytopenia.
Time Frame	During induction therapy, the first 28 days of treatment.

Outcome Measure Data

Analysis Population Description

Patients enrolled in dose escalation cohorts 1, 2 and 3 analyzed for this outcome measure.

Arm/Group Title	Cohort 1: 1.0mg/m2 Bortezomib	Cohort 2: 1.3mg/m2 Bortezomib	Cohort 3: 1.6mg/m2 Bortezomib
Arm/Group Description	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.
Measure Participants	3	3	3
Number [DLT]	0	0	2

2. Secondary Outcome

Title	Number of Patients With Adverse Events Related to Treatment of Bortezomib Combined With Y-90-ibritumomab Tiuxetan
Description	To further explore the toxicity bortezomib combined with Y-90-ibritumomab tiuxetan by collecting data on adverse events (AE) reported by patient or collected lab results that are grade 3 or grade 4 that were determined to be at least possible related to any of the studies drugs. Toxicity will be collected on treatment days 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	At start of treatment on days 1, 8, 15, 22 of induction, days 36 and 50 of recovery, days 1, 8, 15 of consolidation cycles for up to 3 cycles and 4 weeks after the completion of treatment.

Outcome Measure Data

Analysis Population Description

Toxicity data for 9 patients enrolled in the dose escalating cohorts 1, 2 and 3 was collected and analyzed only. Data for the 3 cohorts are presented combined as the objective is to report grade 3 and 4 toxicities with this combination of drugs (dose of bortezomib is irrelevant)

Arm/Group Title	Cohort 1+ Cohort 2+ Cohort 3
Arm/Group Description	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.
Measure Participants	9
Leukopenia	3 16.7%
Lymphopenia	3 16.7%
Neutropenia	5 27.8%
Thrombocytopenia	4 22.2%
Cardiac	1 5.6%

3. Post-Hoc Outcome

Title	Overall Response Rate
Description	The overall response rate at the completion of treatment was defined as complete response plus partial response. Complete response (CR)=A post-treatment residual mass of any size is permitted as long as it is PET-negative and normalization of those biochemical abnormalities. Partial response (PR)=50% decrease in SPD of the six largest dominant nodes or nodal masses, no increase in the size of the other nodes, liver or spleen, and no new sites of disease. Stable disease=Failing to attain the criteria for PR or CR, but not fulfilling those for progressive disease. Progressive disease(PD)=At least a 50% increase from nadir in the SPD of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size.
Time Frame	At baseline, after induction cycle (1 cycle =28 days) and consolidation therapy of a maximum of 3 cycles (1cycle =28 days), up to approximately 6 months

Outcome Measure Data

Analysis Population Description

Data for first 9 patients enrolled in phase I dose escalation portion of the study were collected, analyzed and reported on. Cohort results for this outcome measure are combined as the objective was to determine the ORR of patients with this drug combination (dose was irrelevant)

Arm/Group Title	Cohort 1+ Cohort 2+ Cohort 3
Arm/Group Description	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.
Measure Participants	9
Number [percentage of patients]	89

4. Post-Hoc Outcome

Title	Median Progression Free Survival
Description	Median progression free survival (PFS) will be assessed by CT scans after induction therapy, consolidation therapy, every 3 months for the first year following treatment and every 6 months for the second year. Progressive disease is defined as the appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size or at least a 50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis.
Time Frame	At start of treatment, at completion of induction therapy, at completion of consolidation therapy, every 3 months for 1 year, and every 6 months for 1 year

Outcome Measure Data

Analysis Population Description

The first 9 patients data that were enrolled in the phase I dose escalation portion were collected, analyzed and reported on. Cohort results for this outcome measure are combined as the objective was to determine the PFS of patients with this drug combination (dose was irrelevant)

Arm/Group Title	Cohort 1+ Cohort 2+ Cohort 3
Arm/Group Description	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.
Measure Participants	9
Median (Full Range) [Months]	6.5

Adverse Events

Time Frame	Adverse events (AE) for the study were collected over a 5 year period. AEs for each patient were collected during treatment through 30 days post last treatment. Treatment consisted of one 28 day induction cycle followed by 71 day recovery period and then a maximum of 3 consolidation cycles each of 28 days.
Arm/Group Title	Cohort 1: 1.0mg/m2 Bortezomib		Cohort 2: 1.3mg/m2 Bortezomib		Cohort 3: 1.6mg/m2 Bortezomib		Expansion Phase: 1.3mg/m2 Bortezomib
Arm/Group Description	Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.		Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.		Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.		Induction therapy will last one cycle of 28 days. Bortezomib will be given on days 1, 8, 15, and 22. 250mg/m2 of Rituximab will be given on days 8 and 15. 0.4mCi/kg of y-90-ibritumomab tiuxetan will be given on day 15. During induction therapy patients will receive either 1.0mg/m2, 1.3mg/m2, or 1.6mg/m2 of bortezomib as the study is designed as a 3+3 dose escalation of bortezomib to find the maximum tolerated dose (MTD) or at the determined MTD in the expansion phase. Consolidation therapy will last a maximum of 3 cycles and will start on day 71 (1 cycle = 28 days) During consolidation therapy, 1.6mg/m2 of Bortezomib will be given intravenously on days 1, 8, and 15 of each cycle. Rituximab or Y-90-ibritumomab tiuxetan will not be given during consolidation therapy.
All Cause Mortality
	Cohort 1: 1.0mg/m2 Bortezomib		Cohort 2: 1.3mg/m2 Bortezomib		Cohort 3: 1.6mg/m2 Bortezomib		Expansion Phase: 1.3mg/m2 Bortezomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/8 (12.5%)
Serious Adverse Events
	Cohort 1: 1.0mg/m2 Bortezomib		Cohort 2: 1.3mg/m2 Bortezomib		Cohort 3: 1.6mg/m2 Bortezomib		Expansion Phase: 1.3mg/m2 Bortezomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	Cohort 1: 1.0mg/m2 Bortezomib		Cohort 2: 1.3mg/m2 Bortezomib		Cohort 3: 1.6mg/m2 Bortezomib		Expansion Phase: 1.3mg/m2 Bortezomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		3/3 (100%)		8/8 (100%)
Blood and lymphatic system disorders
Hemoglobin (anemia)	1/3 (33.3%)		2/3 (66.7%)		3/3 (100%)		4/8 (50%)
Neutrophils (neutropenia)	3/3 (100%)		2/3 (66.7%)		2/3 (66.7%)		2/8 (25%)
Leukocytes (total white blood cells)	3/3 (100%)		3/3 (100%)		3/3 (100%)		2/8 (25%)
Lymphopenia	3/3 (100%)		3/3 (100%)		3/3 (100%)		2/8 (25%)
Platelets (thrombocytopenia)	2/3 (66.7%)		3/3 (100%)		3/3 (100%)		6/8 (75%)
Edema in limb(s)	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/8 (0%)
Edema of trunk/gential	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Edema of head/neck	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Cardiac disorders
Hypertension	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/8 (0%)
Cardiac NOS	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Palpitations	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Ventricular arrhythmia	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Tachycardia	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Ear and labyrinth disorders
Otitis (non infectious)	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Hearing loss	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Gastrointestinal disorders
Cavity - Root canal	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Anorexia	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/8 (12.5%)
Constipation	1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		2/8 (25%)
Diarrhea	2/3 (66.7%)		3/3 (100%)		2/3 (66.7%)		5/8 (62.5%)
Distension/bloating abdominal	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/8 (12.5%)
Mucositis/stomatitis	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/8 (0%)
Nausea	1/3 (33.3%)		2/3 (66.7%)		3/3 (100%)		3/8 (37.5%)
Vomiting	1/3 (33.3%)		2/3 (66.7%)		1/3 (33.3%)		1/8 (12.5%)
Stomach upset	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
General disorders
Malaise	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Fatigue	1/3 (33.3%)		2/3 (66.7%)		3/3 (100%)		5/8 (62.5%)
Fever	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Insomnia	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/8 (25%)
Sweating	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/8 (0%)
Weight loss	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Hematoma	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/8 (0%)
Nose bleed	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/8 (0%)
Infections and infestations
Infection NOS	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/8 (0%)
Ear infection	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Pneumonia	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Bronchus infection	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Sinus infection	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		3/8 (37.5%)
Upper respiratory infection	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Cellulitis (skin rash)	1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Metabolism and nutrition disorders
Alkaline phosphatase increase	0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		0/8 (0%)
Transaminase	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/8 (0%)
ALT increase (serum glutamic pyruvic transaminase)	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/8 (12.5%)
Bilirubin increase	1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		0/8 (0%)
Creatinine increase	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/8 (0%)
Calcium, serum high	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/8 (0%)
Calcium, serum low	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Glucose, serum high	2/3 (66.7%)		3/3 (100%)		1/3 (33.3%)		2/8 (25%)
Glucose, serum low	0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		0/8 (0%)
Lactic acid dehydrogenase increase (LDH)	0/3 (0%)		2/3 (66.7%)		0/3 (0%)		0/8 (0%)
Potassium, serum high	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/8 (0%)
Potassium, serum low	0/3 (0%)		0/3 (0%)		2/3 (66.7%)		1/8 (12.5%)
Sodium, serum high	2/3 (66.7%)		0/3 (0%)		0/3 (0%)		0/8 (0%)
Uric acid, serum high	1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/8 (0%)
Flank pain	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Back pain	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/8 (12.5%)
Joint pain	0/3 (0%)		0/3 (0%)		2/3 (66.7%)		1/8 (12.5%)
Mid thoracic pain	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/8 (0%)
Nervous system disorders
Neuropathy - motor	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Neuropathy - sensory	1/3 (33.3%)		1/3 (33.3%)		2/3 (66.7%)		3/8 (37.5%)
Dizziness	2/3 (66.7%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Anxiety (Mood alteration)	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/8 (12.5%)
Agitation (Mood alteration)	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Syncope (Fainting episode)	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Headache	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		3/8 (37.5%)
Reproductive system and breast disorders
Pain in groin	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Chest pain	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Sinus pain	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Cough	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Shortness of breath (dyspnea)	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/8 (25%)
Hypoxia	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Skin and subcutaneous tissue disorders
Brusing	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/8 (0%)
Pruritis/itching	0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/8 (0%)
Rash/desquamation	0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		2/8 (25%)
Shingles	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)
Hot flashes/flushes	0/3 (0%)		0/3 (0%)		0/3 (0%)		2/8 (25%)
Ecchymosis	0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/8 (0%)
Vascular disorders
Deep vein thrombosis	0/3 (0%)		0/3 (0%)		0/3 (0%)		1/8 (12.5%)

Limitations/Caveats

The study closed permanently due to slow accrual with only 17 patients treated on study. This was before the expected accrual goal of 24 patients

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.