HLA Sensitization
Conditions
Keywords
Alloantibody, Desensitization, Kidney Transplantation, Nephrology, Plasma Cells, Translational Research/Science
Brief summary
To determine if deletional strategies will provide effective desensitization.
Detailed description
A prospective iterative trial of proteasome inhibitor (PI)-based therapy for reducing HLAantibody (Ab) levels was conducted in five phases differing in bortezomib dosing density and plasmapheresis timing. Phases included 1 or 2 bortezomib cycles (1.3mg/m2,6-8 doses), one rituximab dose and plasmapheresis. HLA Abs were measured by solid phase and flow cytometry (FCM) assays. Immunodominant Ab (iAb) was defined as highest HLA Ab level. Forty-four patients received 52 desensitization courses (7 patients enrolled in multiple phases): Phase 1 (n=20), Phase 2 (n=12), Phase 3 (n=10), Phase 4 (n=5), Phase 5 (n=5).
Interventions
DRUGplasmapheresis
Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.
DRUGBortezomib
Patients will receive bortezomib as described in protocol
DRUGRituximab
Patients will receive rituximab as described in protocol
DRUGMethylprednisolone
Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).
Sponsors
Millennium Pharmaceuticals, Inc.
University of Cincinnati
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age between 18 and 65 * Voluntary written informed consent * Patient on deceased donor wait list with a current or peak cytotoxic or calculated panel reactive antibody (PRA) \> 20%
Exclusion criteria
* Myocardial infarction within 6 months * Patient received investigational drug within 14 days prior to initiation of study treatment * Serious medical or psychological illness * Diagnosed with malignancy within three years, except complete research of basal cell carcinoma or squamous cell carcinoma of skin, an insitu malignancy or low risk prostate cancer after curative therapy * Absolute neutrophil count (ANC) \< 1000 * Receipt of live vaccine within 4 weeks of study entry * Female subject that is breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Living Donor Transplant Candidates That Are Transplanted | 1 year post baseline | Number of living donor transplant candidates who convert to a negative flow T- and B-cell crossmatch via desensitization and are subsequently transplanted |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Safety of Bortezomib | Study Day 62 | Incidence of grade 3 and above non-hematologic toxicities. Incidence of grade 4 hematologic toxicities. Incidence of all grades of peripheral neuropathy. Incidence of Cytomegalovirus (CMV), Polyomavirus Allograft Nephropathy (PVN), and Posttransplant Lymphoproliferative Disorder (PTLD). |
| Number of Patients Whose Cytotoxic Panel Reactive Antibody (PRA) is Decreased by 50% | 46 days | Number of patients on the waiting list whose cytotoxic PRA is decreased by 50%. |
| Acute Rejection Rate | 6 months post transplant | Acute rejection rate at 6 months of all desensitized and transplanted patients |
Countries
United States
Participant flow
Recruitment details
Subjects could be enrolled in multiple study phases. Enrollment in phases 1-2 was an adaptive approach and was fixed a priori in Phases 3-5. The adaptive approach was based on treatment effect (immunodominant antibody (iAb) reduction).
Pre-assignment details
44 subjects received 52 treatments in this study. 7 subjects were enrolled in multiple phases. Four patients received treatment in two study phases (two patients were enrolled in Phases 1 and 2, one patient was enrolled in study Phases 1 and 3, and one patient was enrolled in Phases 2 and 3). One patient was enrolled in Phases 1, 2 and 4.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Combined study participants, all phases. | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Phase 1 | Adverse Event | 4 |
| Phase 1 | Withdrawal by Subject | 1 |
| Phase 2 | Adverse Event | 1 |
| Phase 2 | Physician Decision | 1 |
| Phase 3 | Adverse Event | 2 |
| Phase 4 | Adverse Event | 1 |
| Phase 4 | Physician Decision | 1 |
| Phase 5 | Adverse Event | 3 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 45.2 years STANDARD_DEVIATION 10.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 16 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 | 28 Participants |
| Region of Enrollment United States | 44 participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 20 | 4 / 12 | 4 / 10 | 0 / 5 | 1 / 5 |
| serious Total, serious adverse events | 6 / 20 | 1 / 12 | 4 / 10 | 2 / 5 | 2 / 5 |
Outcome results
Primary
Number of Living Donor Transplant Candidates That Are Transplanted
Number of living donor transplant candidates who convert to a negative flow T- and B-cell crossmatch via desensitization and are subsequently transplanted
Time frame: 1 year post baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1, Cycle 1 | Number of Living Donor Transplant Candidates That Are Transplanted | 19 participants |
Secondary
Acute Rejection Rate
Acute rejection rate at 6 months of all desensitized and transplanted patients
Time frame: 6 months post transplant
Population: One graft loss occurred due to graft thrombosis within 24 hours (due to unrecognized hypercoagulability disorder without AMR). Two patients were transplanted at other centers and data was not available. This dropped the number of analyzed patients to 16 from 19.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1, Cycle 1 | Acute Rejection Rate | 3 participants |
Secondary
Number of Patients Whose Cytotoxic Panel Reactive Antibody (PRA) is Decreased by 50%
Number of patients on the waiting list whose cytotoxic PRA is decreased by 50%.
Time frame: 46 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1, Cycle 1 | Number of Patients Whose Cytotoxic Panel Reactive Antibody (PRA) is Decreased by 50% | 6 participants |
Secondary
Overall Safety of Bortezomib
Incidence of grade 3 and above non-hematologic toxicities. Incidence of grade 4 hematologic toxicities. Incidence of all grades of peripheral neuropathy. Incidence of Cytomegalovirus (CMV), Polyomavirus Allograft Nephropathy (PVN), and Posttransplant Lymphoproliferative Disorder (PTLD).
Time frame: Study Day 62
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Anemia (<8.0-6.5 g/dL) | 1 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Thrombocytopenia | 0 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 1 PN | 1 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 2 PN | 5 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Thrombocytopenia | 1 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 3 PN | 1 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | CMV D+/R- Status | 0 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Malignancy | 0 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | CMV Viremia or Invasive Disease | 0 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Neutropenia | 0 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 4 PN | 0 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Neutropenia | 0 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Polyomavirus Allograft Nephropathy (PVN) | 0 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 5 PN | 1 participants |
| Phase 1, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Anemia (<6.5g/dL) | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Neutropenia | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 2 PN | 3 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 1 PN | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Anemia (<8.0-6.5 g/dL) | 2 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Polyomavirus Allograft Nephropathy (PVN) | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Anemia (<6.5g/dL) | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Malignancy | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | CMV Viremia or Invasive Disease | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Thrombocytopenia | 2 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 5 PN | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Thrombocytopenia | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | CMV D+/R- Status | 0 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 4 PN | 1 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Neutropenia | 1 participants |
| Phase 1 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 3 PN | 3 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Anemia (<8.0-6.5 g/dL) | 1 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | CMV Viremia or Invasive Disease | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 4 PN | 1 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 2 PN | 2 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Polyomavirus Allograft Nephropathy (PVN) | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Malignancy | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 1 PN | 3 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Neutropenia | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | CMV D+/R- Status | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Thrombocytopenia | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 5 PN | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 3 PN | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Anemia (<6.5g/dL) | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Neutropenia | 0 participants |
| Phase 2, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Thrombocytopenia | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Thrombocytopenia | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Anemia (<8.0-6.5 g/dL) | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Anemia (<6.5g/dL) | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Thrombocytopenia | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 4 PN | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Neutropenia | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Neutropenia | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 1 PN | 2 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 2 PN | 3 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 3 PN | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 5 PN | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | CMV D+/R- Status | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | CMV Viremia or Invasive Disease | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Polyomavirus Allograft Nephropathy (PVN) | 0 participants |
| Phase 2 Cycle 2 | Overall Safety of Bortezomib | Malignancy | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Thrombocytopenia | 1 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 2 PN | 2 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | CMV D+/R- Status | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 4 PN | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Malignancy | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Neutropenia | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Polyomavirus Allograft Nephropathy (PVN) | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Thrombocytopenia | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Anemia (<8.0-6.5 g/dL) | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Anemia (<6.5g/dL) | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 3 PN | 1 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 5 PN | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Neutropenia | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | CMV Viremia or Invasive Disease | 0 participants |
| Phase 3, Cycle 1 | Overall Safety of Bortezomib | Incidence of new onset level 1 PN | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | CMV Viremia or Invasive Disease | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | CMV D+/R- Status | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Malignancy | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Neutropenia | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 3 PN | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Anemia (<6.5g/dL) | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Polyomavirus Allograft Nephropathy (PVN) | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Thrombocytopenia | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 4 PN | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 2 PN | 1 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Neutropenia | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Anemia (<8.0-6.5 g/dL) | 0 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 5 PN | 1 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of new onset level 1 PN | 1 participants |
| Phase 3, Cycle 2 | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Thrombocytopenia | 1 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Neutropenia | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 2 PN | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 3 PN | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Thrombocytopenia | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 4 PN | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Thrombocytopenia | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 5 PN | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | CMV D+/R- Status | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | CMV Viremia or Invasive Disease | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Anemia (<8.0-6.5 g/dL) | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Malignancy | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Polyomavirus Allograft Nephropathy (PVN) | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Neutropenia | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Anemia (<6.5g/dL) | 0 participants |
| Phase 4, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 1 PN | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Malignancy | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Thrombocytopenia | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 3 PN | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 4 PN | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Thrombocytopenia | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 2 PN | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Polyomavirus Allograft Nephropathy (PVN) | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Neutropenia | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Anemia (<8.0-6.5 g/dL) | 1 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 4 Anemia (<6.5g/dL) | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | CMV D+/R- Status | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 5 PN | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of CTCAE Grade 3 Neutropenia | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | CMV Viremia or Invasive Disease | 0 participants |
| Phase 5, Single Stage | Overall Safety of Bortezomib | Incidence of new onset level 1 PN | 1 participants |