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| Name | Class |
|---|---|
| Millennium Pharmaceuticals, Inc. | INDUSTRY |
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To determine if deletional strategies will provide effective desensitization.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phase 1, two stages | Experimental | Patients will receive 1 dose of rituximab, 4 doses of bortezomib and plasmapheresis. Rituximab will be given at a dose of 375 mg/m2 on day 32. Patients will receive 1.3 mg/m2 of bortezomib via intravenous push (IVP) over 3-5 seconds. Bortezomib will be administered on days 1, 4, 8, and 11. For those patients who go on to Stage 2 of desensitization, bortezomib will be administered via IV push over 3-5 seconds during the pre-transplant period on days 32, 35, 39, 42. Methylprednisolone will be administered within 30 minutes of each bortezomib administration in both stages of desensitization. With the first and second doses, administer methylprednisolone 100mg via IV push. With the third and fourth doses, administer methylprednisolone 50mg IVP. |
|
| Phase 2, two stages | Experimental | Patients will receive 1 dose of rituximab, 4 doses of bortezomib and plasmapheresis. Rituximab will be given at a dose of 375 mg/m2 on day -7. Patients will receive 1.3 mg/m2 of bortezomib via intravenous push (IVP) over 3-5 seconds. Bortezomib will be administered on days 1, 4, 8, and 11. For those patients who go on to Stage 2 of desensitization, bortezomib will be administered via IV push over 3-5 seconds during the pre-transplant period on days 32, 35, 39, 42. Methylprednisolone will be administered within 30 minutes of each bortezomib administration in both stages of desensitization. With the first and second doses, administer methylprednisolone 100mg via IV push. With the third and fourth doses, administer methylprednisolone 50mg IVP. |
|
| Phase 3, two stages | Experimental | Patients will receive 1 dose of rituximab and 4 doses of bortezomib. Rituximab will be given at a dose of 375 mg/m2 on day -7. Patients will receive 1.3 mg/m2 of bortezomib via intravenous push (IVP) over 3-5 seconds. Bortezomib will be administered on days 1, 4, 8, and 11. For those patients who go on to Stage 2 of desensitization, bortezomib will be administered via IV push over 3-5 seconds during the pre-transplant period on days 23, 26, 30 and 33. Methylprednisolone will be administered within 30 minutes of each bortezomib administration in both stages of desensitization. With the first and second doses, administer methylprednisolone 100mg via IV push. With the third and fourth doses, administer methylprednisolone 50mg IVP. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| plasmapheresis | Drug | Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 1 year post baseline |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | Study Day 62 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| E. Steve Woodle, MD | University of Cincinnati | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Christ Hospital | Cincinnati | Ohio | 45267 | United States | ||
| University of Cincinnati |
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.
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).
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| ID | Title | Description |
|---|---|---|
| FG000 | All Study Participants | Combined study participants all phases. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase 1 |
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| Phase 2 |
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| Phase 3 |
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| Phase 4 |
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| Phase 5 |
|
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). "n" refers to the number of patients. Since patients were enrolled in multiple phases the numbers reported show the total enrollment of each phase.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | Combined study participants, all phases. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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). | Posted | Number | participants | Study Day 62 |
|
1 year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Phase 1, Two Stages | Deletional, two stage approach with terminal plasmapheresis Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Generalized Weakness | Musculoskeletal and connective tissue disorders | CTCAE (3.0) | Systematic Assessment | Patient admitted to hospital 6 days after completing the first bortezomib cycle for generalized weakness and malaise, which subsequently spontaneously resolved. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Infections and infestations | CTCAE (3.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| E. Steve Woodle | University of Cincinnati | 513-558-6001 | woodlees@ucmail.uc.edu |
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| ID | Term |
|---|---|
| D010956 | Plasmapheresis |
| D000069286 | Bortezomib |
| D000069283 | Rituximab |
| D008775 | Methylprednisolone |
| ID | Term |
|---|---|
| D001781 | Blood Component Removal |
| D013812 | Therapeutics |
| D016060 | Sorption Detoxification |
| D005112 | Extracorporeal Circulation |
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|
| Phase 4, single stage | Experimental | Patients will receive 1 dose of rituximab and 6 doses of bortezomib. Rituximab will be given at a dose of 375 mg/m2 on day -7. Patients will receive 1.3 mg/m2 of bortezomib via intravenous push (IVP) over 3-5 seconds. Bortezomib will be administered during the pre-transplant period on days 1, 4, 8, and 11, 14, and 17. Methylprednisolone will be administered within 30 minutes of each bortezomib administration in both stages of desensitization. With the first and second doses, administer methylprednisolone 100mg via IV push. With the third and fourth doses, administer methylprednisolone 50mg IVP. |
|
| Phase 5, single stage | Experimental | Phase 5 evaluated even greater bortezomib dosing density by eliminating the inter-cycle dosing interval. Phase 5 evaluated eight consecutive doses of bortezomib with one dose of rituximab. Rituximab will be given at a dose of 375 mg/m2 on day -7. Patient will receive 1.3 mg/m2 of bortezomib via intravenous push (IVP) over 3-5 seconds. Bortezomib will be administered on days 1, 4, 8, 11, 14, 17, 20, and 23. Methylprednisolone will be administered within 30 minutes of each bortezomib administration in both stages of desensitization. With the first and second doses, administer methylprednisolone 100mg via IV push. With the third and fourth doses, administer methylprednisolone 50mg IVP. |
|
| Bortezomib | Drug | Patients will receive bortezomib as described in protocol |
|
|
| Rituximab | Drug | Patients will receive rituximab as described in protocol |
|
|
| Methylprednisolone | Drug | Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses). |
|
|
| 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%. |
| 46 days |
| Acute Rejection Rate | Acute rejection rate at 6 months of all desensitized and transplanted patients | 6 months post transplant |
| Cincinnati |
| Ohio |
| 45267 |
| United States |
|
|
|
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG002 | Phase 2, Cycle 1 | Deletional, two stage approach with terminal plasmapheresis Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered |
| OG003 | Phase 2 Cycle 2 | Deletional, two stage approach with terminal plasmapheresis Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered |
| OG004 | Phase 3, Cycle 1 | Deletional, two stage approach with terminal plasmapheresis Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered |
| OG005 | Phase 3, Cycle 2 | Deletional, two stage approach with terminal plasmapheresis Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered |
| OG006 | Phase 4, Single Stage | Deletional, one stage approach with six doses of plasmapheresis prior to each bortezomib dose Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered |
| OG007 | Phase 5, Single Stage | Deletional, one stage approach with eight doses of plasmapheresis prior to each bortezomib dose Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered |
|
|
| 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 | Posted | Number | participants | 1 year post baseline |
|
|
|
| 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%. | Posted | Number | participants | 46 days |
|
|
|
| Secondary | Acute Rejection Rate | Acute rejection rate at 6 months of all desensitized and transplanted patients | 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. | Posted | Number | participants | 6 months post transplant |
|
|
|
| 6 |
| 20 |
| 2 |
| 20 |
| EG001 | Phase 2, Two Stages | Deletional, two stage approach with terminal plasmapheresis Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered | 1 | 12 | 4 | 12 |
| EG002 | Phase 3 | Deletional, two stage approach with terminal plasmapheresis Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered | 4 | 10 | 4 | 10 |
| EG003 | Phase 4, Single Stage | Deletional, one stage approach with six doses of plasmapheresis prior to each bortezomib dose Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered | 2 | 5 | 0 | 5 |
| EG004 | Phase 5, Single Stage | Deletional, one stage approach with eight doses of plasmapheresis prior to each bortezomib dose Deletional therapy/plasmapheresis: B lymphocyte/plasma cell deletional therapy will be administered | 2 | 5 | 1 | 5 |
|
| Pancreatitis | Hepatobiliary disorders | CTCAE (3.0) | Systematic Assessment | Patient admitted to the hospital with upper abdominal pain and slight elevation in lipase, but with normal amylase. Pain resolved within 48 hours and lipase returned to normal and was discharged. Event occurred during bortezomib therapy. |
|
| Elevated Liver Function Test | Hepatobiliary disorders | CTCAE (3.0) | Systematic Assessment | Eight days after the last bortezomib dose of cycle 1, patient developed malaise, nausea, vomiting. Evaluation revealed elevated liver enzymes (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) which both spontaneously resolved. |
|
| Chest Pain | Cardiac disorders | CTCAE (3.0) | Systematic Assessment | Patient developed chest pain at home with radiation to his left shoulder. Patient has a history of similar chest pain episodes. EKG was normal and troponins negative and patient was discharged from the hospital. |
|
| Seizure | Nervous system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Nausea/Vomiting | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Hypoxemia | General disorders | CTCAE (3.0) | Systematic Assessment |
|
| Peripheral Neuropathy | Nervous system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Atrial Fibrillation | Cardiac disorders | CTCAE (3.0) | Systematic Assessment | Patient experienced atrial fibrillation during routine dialysis at his local dialysis center. Patient was transferred to a local ER where elective cardioversion was performed. The patient fully recovered in the ER. |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Blurred Vision | Eye disorders | CTCAE (3.0) | Systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Headache | General disorders | CTCAE (3.0) | Systematic Assessment |
|
| Diarrhea | Endocrine disorders | CTCAE (3.0) | Systematic Assessment |
|
| Hypocalcemia | Metabolism and nutrition disorders | CTCAE (3.0) | Systematic Assessment |
|
| Perivascular Dermatitis | Skin and subcutaneous tissue disorders | CTCAE (3.0) | Systematic Assessment |
|
| Facial Weakness | General disorders | CTCAE (3.0) | Systematic Assessment |
|
| Upper Respiratory Infection | Infections and infestations | CTCAE (3.0) | Systematic Assessment |
|
| Peripheral Sensory Neuropathy (PN) | Nervous system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | CTCAE (3.0) | Systematic Assessment |
|
| Foot Infection | Infections and infestations | CTCAE (3.0) | Systematic Assessment |
|
| Pulmonary Edema | Respiratory, thoracic and mediastinal disorders | CTCAE (3.0) | Systematic Assessment |
|
| Upper Respiratory Viral Infection | Infections and infestations | CTCAE (3.0) | Systematic Assessment |
|
| Cardiopulomonary Instability | Cardiac disorders | CTCAE (3.0) | Systematic Assessment |
|
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| D013514 | Surgical Procedures, Operative |
| D001897 | Boronic Acids |
| D000148 | Acids, Noncarboxylic |
| D000143 | Acids |
| D007287 | Inorganic Chemicals |
| D001896 | Boron Compounds |
| D009930 | Organic Chemicals |
| D011719 | Pyrazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D011239 | Prednisolone |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |