Epstein Barr Virus Infections, Post-transplant Lymphoproliferative Disease, Solid Organ Transplant, Stem Cell Transplant (Bone Marrow Transplant)
Conditions
Keywords
bortezomib, rituximab, PTLD, EBV, transplantation
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.
Interventions
DRUGbortezomib
Given intravenously on days 1, 4, 8 and 11 of every cycle
DRUGrituximab
given intravenously on days 1, 8 and 15 of Cycle 1 and on Day 1 of subsequent cycles
Sponsors
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Beth Israel Deaconess Medical Center
Millennium Pharmaceuticals, Inc.
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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): 1. 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. 2. ≥ 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. 3. ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. 4. 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 | 6 months, 1 year | The percent of participants surviving at 6 months and 1 year. |
| 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. |
| 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Plus Bortezomib 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 | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Rituximab Plus Bortezomib |
|---|---|
| Age, Continuous | 67 years |
| Age, Customized ≤ 50 years | 1 Participants |
| Age, Customized 51-60 years | 0 Participants |
| Age, Customized 61-70 years | 3 Participants |
| Age, Customized 71+ years | 3 Participants |
| ECOG Performance Status 0 | 4 Participants |
| ECOG Performance Status 1 | 2 Participants |
| ECOG Performance Status 2 | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 Participants |
| WHO Classification PTLD/monomorphic, DLBCL | 5 Participants |
| WHO Classification PTLD/polymorphic | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 2 / 7 |
Outcome results
Primary
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.
Time frame: 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab Plus Bortezomib | Overall Response Rate | 3 Participants |
Secondary
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.
Time frame: 4 Months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab Plus Bortezomib | Complete Response Rate | 3 Participants |
Secondary
Effects of Bortezomib/Rituximab on EBV Quantitative Viral Load
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rituximab Plus Bortezomib | Effects of Bortezomib/Rituximab on EBV Quantitative Viral Load | Baseline | 13.02 Log2[(viral copies/ milliliter blood)+1] | Standard Deviation 3.39 |
| Rituximab Plus Bortezomib | Effects of Bortezomib/Rituximab on EBV Quantitative Viral Load | End of Cycle 1 (21 days) | 10.12 Log2[(viral copies/ milliliter blood)+1] | Standard Deviation 3.18 |
| Rituximab Plus Bortezomib | Effects of Bortezomib/Rituximab on EBV Quantitative Viral Load | End of Cycle 2 (42 days) | 9.11 Log2[(viral copies/ milliliter blood)+1] | Standard Deviation 6.19 |
| Rituximab Plus Bortezomib | Effects of Bortezomib/Rituximab on EBV Quantitative Viral Load | End of Cycle 3 (63 days) | 8.98 Log2[(viral copies/ milliliter blood)+1] | Standard Deviation 2.29 |
| Rituximab Plus Bortezomib | Effects of Bortezomib/Rituximab on EBV Quantitative Viral Load | End of Cycle 4 (84 days) | 7.85 Log2[(viral copies/ milliliter blood)+1] | Standard Deviation 0.34 |
Secondary
Overall Survival
The percent of participants surviving at 6 months and 1 year.
Time frame: 6 months, 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab Plus Bortezomib | Overall Survival | 6 month | 86 percentage of participants |
| Rituximab Plus Bortezomib | Overall Survival | 12 Month | 86 percentage of participants |
Secondary
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): 1. 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. 2. ≥ 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. 3. ≥ 50% increase in the longest diameter of any single previously identified node \> 1 cm in its short axis. 4. 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab Plus Bortezomib | Six-Month Progression Free Survival | 43 percentage of participants |
Secondary
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).
Time frame: 2 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Febrile Neutropenia | 1 participants |
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Leukocytosis | 1 participants |
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Lymph Node Pain | 2 participants |
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Abdominal Pain | 1 participants |
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Nausea | 1 participants |
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Neutrophil Count Decreased | 2 participants |
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Platelet Count Decreased | 4 participants |
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Alkalosis | 1 participants |
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Anorexia | 1 participants |
| Rituximab Plus Bortezomib | Treatment Related Toxicities | Peripheral Sensory Neuropathy | 2 participants |