Bortezomib Plus Rituximab for EBV+ PTLD

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01058239
• Collaborator: Dana-Farber Cancer Institute (Other), Brigham and Women's Hospital (Other), Beth Israel Deaconess Medical Center (Other), Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 7
• Locations: 3
• Arm: 1
• Actual Duration (Months): 72
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

Post transplant lymphoproliferative disease (PTLD) is a type of B-cell non-Hodgkin lymphoma that occurs in patients with weakened immune systems due to immunosuppressive medications taken after organ or stem cell transplantation. This is usually related to a virus called Epstein-Barr (EPV). Rituximab is a type of drug called an "antibody" that specifically destroys both normal and cancerous B-cells, and is commonly used for PTLD. Bortezomib is a drug that has been approved by the Food and Drug Administration (FDA) to treat multiple myeloma and a B-cell non-Hodgkin lymphoma called Mantle Cell Lymphoma, and shows significant activity in lymphoma cells caused by EBV. In this research study, we hope to learn if the addition of bortezomib to rituximab treatment can increase the rate of complete remissions and cures of PTLD after organ or stem cell transplant.

Condition or Disease	Intervention/Treatment	Phase
Post-transplant Lymphoproliferative Disease; Solid Organ Transplant; Stem Cell Transplant (Bone Marrow Transplant); Epstein Barr Virus Infections	Drug: bortezomib; Drug: rituximab	Phase 2

Detailed Description

• Both rituximab and bortezomib will be given to participants intravenously. Each cycle of treatment will consist of 21 days. Rituximab will be given on Days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles. Bortezomib will be given on Days 1, 4, 8 and 11 of every cycle. Participants will receive a maximum of 4 cycles.

• The following study procedures will be performed during each cycle throughout the study: Medical history review; Physical exam; Performance Status; Questionnaire; Blood draws and; PET/CT scans (After cycles 2, 4 and 6 only).

• After Cycle 4, if the study doctor feels the participant has had a complete response to treatment, then they will continue onto the Post-Treatment Surveillance period, which will consist of regular clinic visits over two years.

• However, if the study doctor feels the participant has had a partial response to treatment and that they may benefit from continuing, they will receive an additional two cycles of bortezomib and be given daily tablets of the antiviral drug valganciclovir to help further target EBV.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Bortezomib Plus Rituximab for EBV + Post Transplant Lymphoproliferative Disease (PTLD)
• Actual Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Nov 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab plus Bortezomib This is a single arm trial adding the new drug bortezomib to the standard drug rituximab	Drug: bortezomib; Given intravenously on days 1, 4, 8 and 11 of every cycle; Other Names: Velcade ; Drug: rituximab; given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles; Other Names: Rituxan Mabthera

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [4 months]

   Overall response rate includes both complete and partial responses assessed by PET/CT following completion of therapy. Response was evaluated using the International Working Group criteria for lymphoma response. The complete list of criteria used to evaluate response is too long to be detailed in the allotted space here, but response is defined more generally as: Complete Response (CR): Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial Response (PR): ≥ 50% decrease in the sum of the products of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses.

Secondary Outcome Measures

1. Complete Response Rate [4 Months]

   The number of participants with complete responses as assessed by PET/CT following completion of therapy. Response was evaluated using the International Working Group criteria for lymphoma response. Complete Response (CR): Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.

2. Six-Month Progression Free Survival [six months]

   Percent of participants with progression free survival (alive without disease progression) six months after registration. Progression was evaluated using the International Working Group criteria for lymphoma response. > Progressive Disease (PD) or Relapsed Disease (RD): Appearance of any new lesion > 1.5 cm in any axis during or at end of therapy. Increased Radiolabeled[18F]-2-fluoro-2-deoxy-D-glucose (FDG) uptake in a previously unaffected site will be considered PD/RD only after confirmation by other modalities. ≥ 50% increase from nadir in the sum of the products of the largest diameters (SPD) of any previously involved node, or in a single involved node, or in the sizes of other lesions. ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. PET (positron emission tomography) positive prior to therapy: post-treatment PET should be positive unless lesion is too small to be detected with current PET sys

3. Overall Survival [6 months, 1 year]

   The percent of participants surviving at 6 months and 1 year.

4. Effects of Bortezomib/Rituximab on EBV Quantitative Viral Load [baseline, 21, 42, 63, 84 days (end of cycles 1, 2, 3, 4)]

   The Mean epstein barr virus (EBV) viral load at the given time points.

5. Treatment Related Toxicities [2 years]

   The toxicities experienced by participants that were deemed to be related to the study treatment. Data is shown as the number of participants that experienced any grade toxicity that was deemed to be related to treatment. Toxicities were assessed with the use of Common Toxicology Criteria for Adverse Events (CTCAE).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have had a prior solid organ or allogeneic stem cell transplant.

• Patients may be newly-diagnosed or relapsed after prior therapy

• Patients must have histologically confirmed CD20+ B-cell PTLD diagnosed according to WHO criteria. PTLD may be characterized as early lesions, PTLD/polymorphic, PTLD/monomorphic, or PTLD/other, all of which are eligible for this trial. B-cell PTLD must be associated with EBV as demonstrated either by detection of EBV antigens in tumor samples, or by increased EBV quantitative viral load in serum.

• Patients must have measurable disease

• 18 years of age or older

• Estimated life expectancy of > 3 months

• ECOG Performance status of 0, 1, or 2

• Adequate organ and marrow function

• Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation.

Exclusion Criteria:

• Patients receiving any other study agents. Patients already on prophylactic doses of ganciclovir or valganciclovir because of a prior history of CMV infection or because of risk factors for CMV infection are eligible for the study and may continue CMV prophylaxis.

• Patients with known brain metastases or central nervous system (CNS) involvement of their lymphoma.

• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib, rituximab, ganciclovir or valgancyclovir.

• Patients with Grade 2 or greater neuropathy within 14 days before enrollment.

• Myocardial infarction within 6 months prior to enrollment or has NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.

• Psychiatric illness/social situations that would limit compliance with study requirements.

• Pregnant or breastfeeding women

• Individuals with a history of malignancy are ineligible except for those outlined in the protocol

• Known HIV positive individuals

• Active HBV infection may be included only if they are on appropriate anti-hepatitis B therapy and have an undetectable HBV viral load

• Patient has received other investigational drugs within 14 days before enrollment

• Prior bortezomib

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
3	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Massachusetts General Hospital
• Dana-Farber Cancer Institute
• Brigham and Women's Hospital
• Beth Israel Deaconess Medical Center
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Jeremy Abramson, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jeremy Abramson, MD, Director, Lymphoma Program, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01058239
• Other Study ID Numbers: 09-346; X05289
• First Posted: Jan 28, 2010
• Last Update Posted: Feb 15, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Jeremy Abramson, MD, Director, Lymphoma Program, Massachusetts General Hospital: bortezomib; rituximab; PTLD; EBV; transplantation
• Additional relevant MeSH terms: Epstein-Barr Virus Infections; Lymphoproliferative Disorders; Rituximab; Bortezomib

Study Results

Participant Flow

Arm/Group Title	Rituximab Plus Bortezomib
Arm/Group Description	This is a single arm trial adding the new drug bortezomib to the standard drug rituximab bortezomib: Given intravenously on days 1, 4, 8 and 11 of every cycle rituximab: given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Period Title: Overall Study
STARTED	7
COMPLETED	7
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Rituximab Plus Bortezomib
Arm/Group Description	This is a single arm trial adding the new drug bortezomib to the standard drug rituximab bortezomib: Given intravenously on days 1, 4, 8 and 11 of every cycle rituximab: given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Overall Participants	7
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	67
Age, Customized (Count of Participants)
≤ 50 years	1 14.3%
51-60 years	0 0%
61-70 years	3 42.9%
71+ years	3 42.9%
Sex: Female, Male (Count of Participants)
Female	2 28.6%
Male	5 71.4%
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	0 0%
White	7 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%
ECOG Performance Status (Count of Participants)
0	4 57.1%
1	2 28.6%
2	1 14.3%
WHO Classification (Count of Participants)
PTLD/polymorphic	2 28.6%
PTLD/monomorphic, DLBCL	5 71.4%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Overall response rate includes both complete and partial responses assessed by PET/CT following completion of therapy. Response was evaluated using the International Working Group criteria for lymphoma response. The complete list of criteria used to evaluate response is too long to be detailed in the allotted space here, but response is defined more generally as: Complete Response (CR): Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial Response (PR): ≥ 50% decrease in the sum of the products of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab Plus Bortezomib
Arm/Group Description	This is a single arm trial adding the new drug bortezomib to the standard drug rituximab bortezomib: Given intravenously on days 1, 4, 8 and 11 of every cycle rituximab: given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Measure Participants	7
Count of Participants [Participants]	3 42.9%

2. Secondary Outcome

Title	Complete Response Rate
Description	The number of participants with complete responses as assessed by PET/CT following completion of therapy. Response was evaluated using the International Working Group criteria for lymphoma response. Complete Response (CR): Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.
Time Frame	4 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab Plus Bortezomib
Arm/Group Description	This is a single arm trial adding the new drug bortezomib to the standard drug rituximab bortezomib: Given intravenously on days 1, 4, 8 and 11 of every cycle rituximab: given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Measure Participants	7
Count of Participants [Participants]	3 42.9%

3. Secondary Outcome

Title	Six-Month Progression Free Survival
Description	Percent of participants with progression free survival (alive without disease progression) six months after registration. Progression was evaluated using the International Working Group criteria for lymphoma response. > Progressive Disease (PD) or Relapsed Disease (RD): Appearance of any new lesion > 1.5 cm in any axis during or at end of therapy. Increased Radiolabeled[18F]-2-fluoro-2-deoxy-D-glucose (FDG) uptake in a previously unaffected site will be considered PD/RD only after confirmation by other modalities. ≥ 50% increase from nadir in the sum of the products of the largest diameters (SPD) of any previously involved node, or in a single involved node, or in the sizes of other lesions. ≥ 50% increase in the longest diameter of any single previously identified node > 1 cm in its short axis. PET (positron emission tomography) positive prior to therapy: post-treatment PET should be positive unless lesion is too small to be detected with current PET sys
Time Frame	six months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab Plus Bortezomib
Arm/Group Description	This is a single arm trial adding the new drug bortezomib to the standard drug rituximab bortezomib: Given intravenously on days 1, 4, 8 and 11 of every cycle rituximab: given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Measure Participants	7
Number (90% Confidence Interval) [percentage of participants]	43 614.3%

4. Secondary Outcome

Title	Overall Survival
Description	The percent of participants surviving at 6 months and 1 year.
Time Frame	6 months, 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab Plus Bortezomib
Arm/Group Description	This is a single arm trial adding the new drug bortezomib to the standard drug rituximab bortezomib: Given intravenously on days 1, 4, 8 and 11 of every cycle rituximab: given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Measure Participants	7
6 month	86 1228.6%
12 Month	86 1228.6%

5. Secondary Outcome

Title	Effects of Bortezomib/Rituximab on EBV Quantitative Viral Load
Description	The Mean epstein barr virus (EBV) viral load at the given time points.
Time Frame	baseline, 21, 42, 63, 84 days (end of cycles 1, 2, 3, 4)

Outcome Measure Data

Analysis Population Description

Not all participants completed four cycles of treatment. The number of participants analyzed in each row differs according to the number of participants available for analysis at each time point.

Arm/Group Title	Rituximab Plus Bortezomib
Arm/Group Description	This is a single arm trial adding the new drug bortezomib to the standard drug rituximab bortezomib: Given intravenously on days 1, 4, 8 and 11 of every cycle rituximab: given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Measure Participants	7
Baseline	13.02 (3.39)
End of Cycle 1 (21 days)	10.12 (3.18)
End of Cycle 2 (42 days)	9.11 (6.19)
End of Cycle 3 (63 days)	8.98 (2.29)
End of Cycle 4 (84 days)	7.85 (0.34)

6. Secondary Outcome

Title	Treatment Related Toxicities
Description	The toxicities experienced by participants that were deemed to be related to the study treatment. Data is shown as the number of participants that experienced any grade toxicity that was deemed to be related to treatment. Toxicities were assessed with the use of Common Toxicology Criteria for Adverse Events (CTCAE).
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab Plus Bortezomib
Arm/Group Description	This is a single arm trial adding the new drug bortezomib to the standard drug rituximab bortezomib: Given intravenously on days 1, 4, 8 and 11 of every cycle rituximab: given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Measure Participants	7
Febrile Neutropenia	1 14.3%
Leukocytosis	1 14.3%
Lymph Node Pain	2 28.6%
Abdominal Pain	1 14.3%
Nausea	1 14.3%
Neutrophil Count Decreased	2 28.6%
Platelet Count Decreased	4 57.1%
Alkalosis	1 14.3%
Anorexia	1 14.3%
Peripheral Sensory Neuropathy	2 28.6%

Adverse Events

Time Frame	From baseline until the participant is off study, median duration of 14.9 months
Adverse Event Reporting Description	Adverse events were assessed with the use of regularly scheduled physical exams, laboratory tests, and patient self reports.
Arm/Group Title	Rituximab Plus Bortezomib
Arm/Group Description	This is a single arm trial adding the new drug bortezomib to the standard drug rituximab bortezomib: Given intravenously on days 1, 4, 8 and 11 of every cycle rituximab: given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
All Cause Mortality
	Rituximab Plus Bortezomib
	Affected / at Risk (%)	# Events
Total	1/7 (14.3%)
Serious Adverse Events
	Rituximab Plus Bortezomib
	Affected / at Risk (%)	# Events
Total	2/7 (28.6%)
Cardiac disorders
Cardiac arrest	1/7 (14.3%)	1
Investigations
Platelet count decreased	1/7 (14.3%)	1
Lymphocyte count decreased	1/7 (14.3%)	1
Other (Not Including Serious) Adverse Events
	Rituximab Plus Bortezomib
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Blood and lymphatic system disorders
Leukocytosis	2/7 (28.6%)	3
Cardiac disorders
Cardiac arrest	1/7 (14.3%)	1
Gastrointestinal disorders
Abdominal pain	1/7 (14.3%)	1
Diarrhea	1/7 (14.3%)	1
Nausea	1/7 (14.3%)	2
Infections and infestations
Catheter related infection	1/7 (14.3%)	1
Lung infection	1/7 (14.3%)	1
Investigations
Lymphocyte count decreased	4/7 (57.1%)	19
Neutrophil count decreased	7/7 (100%)	38
Platelet count decreased	7/7 (100%)	37
Alkaline phosphatase increased	1/7 (14.3%)	4
Aspartate aminotransferase increased	1/7 (14.3%)	1
Metabolism and nutrition disorders
Anorexia	1/7 (14.3%)	1
Hyperkalemia	1/7 (14.3%)	2
Hyponatremia	2/7 (28.6%)	6
Nervous system disorders
Peripheral motor neuropathy	7/7 (100%)	37
Peripheral sensory neuropathy	7/7 (100%)	37
Renal and urinary disorders
Urinary tract pain	1/7 (14.3%)	1

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.