Desensitization in Kidney Transplantation

Study Overview
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Brief Summary
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To determine if deletional strategies will provide effective desensitization.

Detailed Description
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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).

Official Title
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Desensitization for Preformed Anti-HLA Antibodies in Kidney Transplantation

Conditions
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HLA Sensitization

Intervention / Treatment
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* Drug: plasmapheresis
* Drug: Bortezomib
* Drug: Rituximab
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1, two stages<br>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. | Drug: plasmapheresis<br>* Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.<br>Drug: Bortezomib<br>* Patients will receive bortezomib as described in protocol<br>* Other names: Velcade;Drug: Rituximab<br>* Patients will receive rituximab as described in protocol<br>* Other names: Rituxan;Drug: Methylprednisolone<br>* Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).<br>* Other names: Medrol;|
| Experimental: Phase 2, two stages<br>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. | Drug: plasmapheresis<br>* Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.<br>Drug: Bortezomib<br>* Patients will receive bortezomib as described in protocol<br>* Other names: Velcade;Drug: Rituximab<br>* Patients will receive rituximab as described in protocol<br>* Other names: Rituxan;Drug: Methylprednisolone<br>* Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).<br>* Other names: Medrol;|
| Experimental: Phase 3, two stages<br>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. | Drug: plasmapheresis<br>* Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.<br>Drug: Bortezomib<br>* Patients will receive bortezomib as described in protocol<br>* Other names: Velcade;Drug: Rituximab<br>* Patients will receive rituximab as described in protocol<br>* Other names: Rituxan;Drug: Methylprednisolone<br>* Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).<br>* Other names: Medrol;|
| Experimental: Phase 4, single stage<br>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. | Drug: plasmapheresis<br>* Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.<br>Drug: Bortezomib<br>* Patients will receive bortezomib as described in protocol<br>* Other names: Velcade;Drug: Rituximab<br>* Patients will receive rituximab as described in protocol<br>* Other names: Rituxan;Drug: Methylprednisolone<br>* Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).<br>* Other names: Medrol;|
| Experimental: Phase 5, single stage<br>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. | Drug: plasmapheresis<br>* Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.<br>Drug: Bortezomib<br>* Patients will receive bortezomib as described in protocol<br>* Other names: Velcade;Drug: Rituximab<br>* Patients will receive rituximab as described in protocol<br>* Other names: Rituxan;Drug: Methylprednisolone<br>* Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).<br>* Other names: Medrol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alloantibody, Desensitization, Kidney Transplantation, Nephrology, Plasma Cells, Translational Research/Science