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Inducing Graft Tolerance in HLA Haplotype Matched Related and 3 Ag Matched Unrelated Living Donor Kidney Transplantation (CIRM)

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ClinicalTrials.gov Identifier: NCT03292445
Recruitment Status : Recruiting
First Posted : September 25, 2017
Last Update Posted : September 25, 2017
Sponsor:
Collaborator:
California Institute for Regenerative Medicine
Information provided by (Responsible Party):
Samuel Strober, Stanford University

Brief Summary:
This research study is to determine if donor blood stem cells given after living, related, HLA antigen (Ag) haplotype match or living, unrelated, 3 HLA antigen matched (HLA-A, -B, and -DR) donor kidney transplantation will change the immune system such that immunosuppressive drugs can be completely withdrawn or reduced to minimal dose without kidney rejection.

Condition or disease Intervention/treatment Phase
Immune Tolerance Procedure: Immune tolerance after kidney transplant Drug: Donor blood stem cells and T cells Early Phase 1

Detailed Description:
The objectives of this study are to determine whether patients undergoing kidney transplants for end stage renal disease (ESRD) can be taken off immune suppression drugs given to prevent kidney rejection or can be maintained on low dose immune suppression while maintaining normal kidney function. Patients will receive blood stem cell transfusions from their donors 11 days after transplant to reduce the risk of graft rejection while tapering the post-transplant immune suppression drug regimen. Patients will be treated with total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (rATG) followed by transfusion of enriched CD34+ hematopoietic cells containing blood stem cells and CD3+ T cells from their donors in order to induce blood cell mixed chimerism. These chimeric patients produce blood cells from both their own and their donors' blood stem cells. Donors will have blood collected by apheresis after treatment with drugs to "mobilize" blood stem cells from their bone marrow. Collection of the donor's cells will occur 6-8 weeks before kidney donation surgery. After transplant, patients will receive a 14 week course of corticosteroid therapy (e.g., Prednisolone) with gradual dose reduction. They will also receive a 12 month course of mycophenolate mofetil (MMF) with dose tapering beginning 9 months post-transplant and an 18 month course of Tacrolimus with tapering also beginning at 9 months post-transplant. Patients will be monitored for renal function, mixed blood cell chimerism, the appearance of donor specific antibodies (DSA) from their own immune cells reacting to the transplanted kidney, and evidence of rejection in any biopsies of the donor kidney after transplant. Immune suppression drug withdrawal will begin and continue as long as mixed chimerism is maintained, the patient shows no evidence of graft versus host disease (GVHD), the transplanted kidney functions well, and there is no indication of kidney rejection in biopsies. Patients not meeting these criteria will be maintained on low dose immunosuppressive drug therapy unless more extensive treatments are needed to prevent rejection. Potential candidates need to be approved for kidney transplant under this protocol and available for close follow-up post-transplant. This study, sponsored by the California Institute for Regenerative Medicine (CIRM), is being conducted in parallel with NCT01165762 sponsored by the National Institutes of Health with distinct reporting and separation of funding support for the patients enrolled under each sponsor.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T Cell Transfusion in HLA Haplotype Matched Related and 3 Ag HLA Matched Unrelated Living Donor Kidney Transplantation
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Induction of Immune Tolerance by Total Lymphoid Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+ and T Cell Transfusion in HLA Haplotype Matched Related and 3 Antigen HLA Matched Unrelated Living Donor Kidney Transplantation
Actual Study Start Date : February 14, 2017
Estimated Primary Completion Date : February 14, 2020
Estimated Study Completion Date : February 14, 2024

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Immune tolerance after kidney transplant
Immune tolerance after kidney transplant will be induced by transfusion of enriched donor blood stem cells and T cells to initiate blood cell mixed chimerism in patients conditioned with total lymphoid irradiation and rabbit anti-thymocyte globulin after kidney transplant. Patients will receive corticosteroids for 14 weeks with gradual dose reduction. They will also receive 12 months of mycophenolate mofetil and 18 months of tacrolimus with dose tapering beginning 9 months post-transplant and continuing as long as mixed chimerism is maintained and there is no evidence of graft versus host disease and no kidney rejection evident. Patients losing chimerism will continue on low dose immunosuppressive drug doses unless additional kidney rejection therapy is needed.
Procedure: Immune tolerance after kidney transplant
Induction of immune tolerance after kidney and hematopoietic cell transplantation with a conditioning regimen of total lymphoid irradiation and anti-thymocyte globulin followed by immunosuppressive drugs for 18 months. Immunosuppressive drugs are stopped if stable chimerism is achieved and there is no kidney rejection.
Drug: Donor blood stem cells and T cells
Immune tolerance after kidney transplantation resulting from mixed blood cells chimerism will be induced by donor blood stem cells and T cells given to the kidney recipient. Donor cells will be collected by apheresis after "mobilization" of blood stem cells from bone marrow 6-8 weeks before kidney transplant. Collected cells will undergo CD34 selection to recover >10 million donor blood stem cells/kg of patient weight to be combined with up to 150 million donor T cells/kg for transfusion soon after kidney transplant. The IND for this study covers the infusion of donor blood stem cells.
Other Name: Immune tolerance after kidney transplant



Primary Outcome Measures :
  1. Reduction of dependence on immunosuppressive drugs to prevent graft rejection. [ Time Frame: 24 months post-transplant ]
    Percentage of patients able to maintain normal renal function after coming off all immunosuppressive drug therapy and percentage of patients maintaining normal renal function with only minimum effective dose immunosuppressive drug monotherapy.


Secondary Outcome Measures :
  1. Incidence of rejection episodes requiring corticosteroid therapy [ Time Frame: 24 months post-transplant ]
    Percentage of patients experiencing biopsy proven rejection episodes requiring corticosteroid therapy.

  2. Incidence of graft loss. [ Time Frame: 24 months post-transplant ]
    Percentage of patients experiencing loss of transplanted kidneys.



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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. All consenting adults (18 years of age) living donor renal transplant recipients at Stanford University Medical Center who have a one haplotype match donor.
  2. Patients who agree to participate in the study and sign an Informed Consent.
  3. Patients who have no known contraindication to administration of rabbit ATG or radiation.
  4. Males and females of reproductive potential who agree to practice a reliable form of contraception for at least 24 months posttranplant.

Exclusion Criteria:

  1. Previous treatment with rabbit ATG or known allergy to rabbit proteins.
  2. History of malignancy with the exception of non-melanoma skin malignancies.
  3. Pregnant women or nursing mothers.
  4. Serological evidence of HIV, Hepatitis B or Hepatitis C infection.
  5. Seronegative for Epstein-Barr virus , if donor is seropositive.
  6. Leukopenia (with a white blood cell count < 3000/mm3) or thrombocytopenia (with a platelet count < 100,000/mm3)
  7. Panel Reactive antibody greater then 20% or demonstration of donor specific antibody (DSA).
  8. Prior organ transplantation.
  9. High risk of primary kidney disease recurrence (i.e. primary FSGS).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03292445


Contacts
Contact: Asha Shori, CCRP 6507360245 ashas@stanford.edu
Contact: Stephan Busque, MD,MS 650-498-6189 sbusque@stanford.edu

Locations
United States, California
Stanford University Medical Center Recruiting
Palo Alto, California, United States, 94304
Contact: Asha Shori, CCRP    650-736-0245    ashas@stanford.edu   
Contact: Stephan Busque, MD, MS    650-498-6189    sbusque@stanford.edu   
Principal Investigator: John D Sandling, MD         
Sub-Investigator: Judith A Shizuru, MD         
Sub-Investigator: Marc L Melcher, MD         
Sub-Investigator: Richard T Hoppe, MD         
Sub-Investigator: Robert Lowsky, MD         
Principal Investigator: Samuel Strober, MD         
Principal Investigator: Stephan Busque, MD         
Sponsors and Collaborators
Samuel Strober
California Institute for Regenerative Medicine
Investigators
Study Chair: Samuel Md Strober, MD Stanford University

Publications of Results:
Other Publications:
Responsible Party: Samuel Strober, Professor of Medicine, Stanford University
ClinicalTrials.gov Identifier: NCT03292445     History of Changes
Other Study ID Numbers: 40442
First Posted: September 25, 2017    Key Record Dates
Last Update Posted: September 25, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Antilymphocyte Serum
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents