Desensitization in Kidney Transplantation

NCT ID: NCT00908583

Last Updated: 2016-04-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-05-31
• Study Completion Date: 2012-11-30

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).

Conditions

HLA Sensitization

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

plasmapheresis

Intervention Type: DRUG

Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.

Bortezomib

Intervention Type: DRUG

Patients will receive bortezomib as described in protocol

Rituximab

Intervention Type: DRUG

Patients will receive rituximab as described in protocol

Methylprednisolone

Intervention Type: DRUG

Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).

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.

Group Type: EXPERIMENTAL

plasmapheresis

Intervention Type: DRUG

Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.

Bortezomib

Intervention Type: DRUG

Patients will receive bortezomib as described in protocol

Rituximab

Intervention Type: DRUG

Patients will receive rituximab as described in protocol

Methylprednisolone

Intervention Type: DRUG

Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).

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.

Group Type: EXPERIMENTAL

plasmapheresis

Intervention Type: DRUG

Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.

Bortezomib

Intervention Type: DRUG

Patients will receive bortezomib as described in protocol

Rituximab

Intervention Type: DRUG

Patients will receive rituximab as described in protocol

Methylprednisolone

Intervention Type: DRUG

Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).

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.

Group Type: EXPERIMENTAL

plasmapheresis

Intervention Type: DRUG

Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.

Bortezomib

Intervention Type: DRUG

Patients will receive bortezomib as described in protocol

Rituximab

Intervention Type: DRUG

Patients will receive rituximab as described in protocol

Methylprednisolone

Intervention Type: DRUG

Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).

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.

Group Type: EXPERIMENTAL

plasmapheresis

Intervention Type: DRUG

Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.

Bortezomib

Intervention Type: DRUG

Patients will receive bortezomib as described in protocol

Rituximab

Intervention Type: DRUG

Patients will receive rituximab as described in protocol

Methylprednisolone

Intervention Type: DRUG

Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).

Interventions

plasmapheresis

Patients will receive plasmapheresis 1.5 x plasma volume prior to each Bortezomib dose. Plasma volume replacement will be per physician discretion.

Intervention Type: DRUG

Bortezomib

Patients will receive bortezomib as described in protocol

Intervention Type: DRUG

Rituximab

Patients will receive rituximab as described in protocol

Intervention Type: DRUG

Methylprednisolone

Each bortezomib dose will be preceded by intravenous methylprednisolone (100mg for first two doses and 50mg for following doses).

Intervention Type: DRUG

Other Intervention Names

Velcade; Rituxan; Medrol

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

University of Cincinnati

OTHER

Sponsor Role: lead

Responsible Party

E. Steve Woodle

MD, FACP

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

E. Steve Woodle, MD

Role: PRINCIPAL_INVESTIGATOR

University of Cincinnati

Locations

The Christ Hospital

Cincinnati, Ohio, United States

University of Cincinnati

Cincinnati, Ohio, United States

Countries

United States

Other Identifiers

X05295

Identifier Type: -

Identifier Source: org_study_id