Desensitization in Kidney Transplantation

This study has been completed.
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
E. Steve Woodle, University of Cincinnati
ClinicalTrials.gov Identifier:
NCT00908583
First received: May 26, 2009
Last updated: March 4, 2016
Last verified: March 2016
  Purpose
To determine if deletional strategies will provide effective desensitization.

Condition Intervention Phase
HLA Sensitization
Drug: plasmapheresis
Drug: Bortezomib
Drug: Rituximab
Drug: Methylprednisolone
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Desensitization for Preformed Anti-HLA Antibodies in Kidney Transplantation

Resource links provided by NLM:


Further study details as provided by University of Cincinnati:

Primary Outcome Measures:
  • Number of Living Donor Transplant Candidates That Are Transplanted [ Time Frame: 1 year post baseline ] [ Designated as safety issue: No ]
    Number of living donor transplant candidates who convert to a negative flow T- and B-cell crossmatch via desensitization and are subsequently transplanted


Secondary Outcome Measures:
  • Overall Safety of Bortezomib [ Time Frame: Study Day 62 ] [ Designated as safety issue: Yes ]
    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% [ Time Frame: 46 days ] [ Designated as safety issue: No ]
    Number of patients on the waiting list whose cytotoxic PRA is decreased by 50%.

  • Acute Rejection Rate [ Time Frame: 6 months post transplant ] [ Designated as safety issue: No ]
    Acute rejection rate at 6 months of all desensitized and transplanted patients


Enrollment: 44
Study Start Date: May 2009
Study Completion Date: November 2012
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase 1, two stages
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
Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.
Drug: Bortezomib
Patients will receive bortezomib as described in protocol
Other Name: Velcade
Drug: Rituximab
Patients will receive rituximab as described in protocol
Other Name: Rituxan
Drug: Methylprednisolone
Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).
Other Name: Medrol
Experimental: Phase 2, two stages
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
Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.
Drug: Bortezomib
Patients will receive bortezomib as described in protocol
Other Name: Velcade
Drug: Rituximab
Patients will receive rituximab as described in protocol
Other Name: Rituxan
Drug: Methylprednisolone
Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).
Other Name: Medrol
Experimental: Phase 3, two stages
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
Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.
Drug: Bortezomib
Patients will receive bortezomib as described in protocol
Other Name: Velcade
Drug: Rituximab
Patients will receive rituximab as described in protocol
Other Name: Rituxan
Drug: Methylprednisolone
Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).
Other Name: Medrol
Experimental: Phase 4, single stage
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
Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.
Drug: Bortezomib
Patients will receive bortezomib as described in protocol
Other Name: Velcade
Drug: Rituximab
Patients will receive rituximab as described in protocol
Other Name: Rituxan
Drug: Methylprednisolone
Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).
Other Name: Medrol
Experimental: Phase 5, single stage
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
Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.
Drug: Bortezomib
Patients will receive bortezomib as described in protocol
Other Name: Velcade
Drug: Rituximab
Patients will receive rituximab as described in protocol
Other Name: Rituxan
Drug: Methylprednisolone
Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).
Other Name: Medrol

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).
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00908583

Locations
United States, Ohio
The Christ Hospital
Cincinnati, Ohio, United States, 45267
University of Cincinnati
Cincinnati, Ohio, United States, 45267
Sponsors and Collaborators
University of Cincinnati
Millennium Pharmaceuticals, Inc.
Investigators
Principal Investigator: E. Steve Woodle, MD University of Cincinnati
  More Information

Responsible Party: E. Steve Woodle, MD, FACP, University of Cincinnati
ClinicalTrials.gov Identifier: NCT00908583     History of Changes
Other Study ID Numbers: X05295 
Study First Received: May 26, 2009
Results First Received: October 21, 2015
Last Updated: March 4, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Cincinnati:
Alloantibody
Desensitization
Kidney Transplantation
Nephrology
Plasma Cells
Translational Research/Science

Additional relevant MeSH terms:
Rituximab
Bortezomib
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Neuroprotective Agents
Protective Agents
Antineoplastic Agents, Hormonal

ClinicalTrials.gov processed this record on July 28, 2016