Clinical trial NCT00908583
Conditions: HLA Sensitization
Keywords: Alloantibody Desensitization Kidney Transplantation Nephrology Plasma Cells Translational Research/Science
Sponsor: University of Cincinnati
Start date: 2009-05-01; Completion date: 2012-11-01
Enrollment: 44 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

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).

Arms: arm 1: 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. arm 2: 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. arm 3: 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. arm 4: 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. arm 5: 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.
Interventions: intervention 1: plasmapheresis intervention 2: Bortezomib intervention 3: Rituximab intervention 4: Methylprednisolone
Intervention descriptions: intervention 1: Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion. intervention 2: Patients will receive bortezomib as described in protocol intervention 3: Patients will receive rituximab as described in protocol intervention 4: Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).

Protocol documents: