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Bortezomib Plus Rituximab for EBV+ PTLD

Primary Purpose

Post-transplant Lymphoproliferative Disease, Solid Organ Transplant, Stem Cell Transplant (Bone Marrow Transplant)

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
bortezomib
rituximab
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Post-transplant Lymphoproliferative Disease focused on measuring bortezomib, rituximab, PTLD, EBV, transplantation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Massachusetts General Hospital
  • Dana-Farber Cancer Institute
  • Beth Israel Deaconess Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Rituximab plus Bortezomib

Arm Description

This is a single arm trial adding the new drug bortezomib to the standard drug rituximab

Outcomes

Primary Outcome Measures

Overall Response Rate
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

Complete Response Rate
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.
Six-Month Progression Free Survival
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
Overall Survival
The percent of participants surviving at 6 months and 1 year.
Effects of Bortezomib/Rituximab on EBV Quantitative Viral Load
The Mean epstein barr virus (EBV) viral load at the given time points.
Treatment Related Toxicities
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).

Full Information

First Posted
January 26, 2010
Last Updated
January 18, 2018
Sponsor
Massachusetts General Hospital
Collaborators
Dana-Farber Cancer Institute, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Millennium Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01058239
Brief Title
Bortezomib Plus Rituximab for EBV+ PTLD
Official Title
Bortezomib Plus Rituximab for EBV + Post Transplant Lymphoproliferative Disease (PTLD)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2018
Overall Recruitment Status
Completed
Study Start Date
November 2011 (Actual)
Primary Completion Date
December 2016 (Actual)
Study Completion Date
November 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
Dana-Farber Cancer Institute, Brigham and Women's Hospital, Beth Israel Deaconess Medical Center, Millennium Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Post-transplant Lymphoproliferative Disease, Solid Organ Transplant, Stem Cell Transplant (Bone Marrow Transplant), Epstein Barr Virus Infections
Keywords
bortezomib, rituximab, PTLD, EBV, transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rituximab plus Bortezomib
Arm Type
Experimental
Arm Description
This is a single arm trial adding the new drug bortezomib to the standard drug rituximab
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
Velcade
Intervention Description
Given intravenously on days 1, 4, 8 and 11 of every cycle
Intervention Type
Drug
Intervention Name(s)
rituximab
Other Intervention Name(s)
Rituxan, Mabthera
Intervention Description
given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
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
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
Title
Overall Survival
Description
The percent of participants surviving at 6 months and 1 year.
Time Frame
6 months, 1 year
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)
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeremy Abramson, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

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Bortezomib Plus Rituximab for EBV+ PTLD

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