BMT and High Dose Post-Transplant Cyclophosphamide for Chimerism Induction and Renal Allograft Tolerance
Condition: Kidney Transplantation
Intervention: anti-thymocyte globulin; Fludarabine; Cyclophosphamide; Total Body Irradiation; acetaminophen; diphenhydramine; methylprednisolone; bone marrow transplant; MESNA; mycophenolate mofetil; prednisone; filgrastim
Intervention description: An initial dose of 0.5 mg/kg IV will be administered over 6 hours on Day -9. Thereafter the daily dose will be increased to 2 mg/kg IV given over 4 hours on Days -8 and -7. No more than 150 mg of ATG may be administered per day.; Fludarabine at dose 30 mg/m^2 will be administered daily by intravenous infusion over 30 minutes on Day -6 to Day -2.; Low dose pre-transplant cyclophosphamide will be administered intravenously (IV) over 1- 2 hours, (depending on volume) on Days -6 and -5. The dose of pre-transplant cyclophosphamide is 14.5 mg/kg/day.
High dose cyclophosphamide [50mg/kg (Ideal Body Weight)] will be administered on Day 3 post-transplant (within 60 to 72 hours of marrow infusion) and on Day 4 post-transplant. Cyclophosphamide will be given IV over 1-2 hours depending on volume.; Total body irradiation, consisting of 200 centigray (cGy) Anterior-Posterior/Posterior-Anterior (AP/PA) with 4 Megavolts (MV) or 6 MV photons at 8-12 cGy/min at the point of prescription will be administered in a single day on Day -1.; 650 mg orally prior to antithymocyte globulin infusion.; 25mg diphenhydramine orally prior to antithymocyte globulin infusion.; On Days -9 to -7 methylprednisolone 1mg/kg IV 1 hour prior ATG. This dose may be repeated once 3 hours after the first dose of steroids. On Day -6 and -5, methylprednisolone 0.75 mg/kg/ IV as a single dose; on Days -4 and -3, methylprednisolone 0.5 mg/kg/ IV as a single dose; on Day -2 methylprednisolone 0.25 mg/kg/ IV as a single dose.; Unprocessed, unmanipulated bone marrow will be harvested from the donor and infused into the recipient on Day 0.; A series of MESNA doses will be administered for each dose of high dose, post-transplant cyclophosphamide. The total daily dose of MESNA is equal to 80% of the total daily dose of cyclophosphamide.; MMF will be administered at a dose of 15 mg/kg orally three times per day based upon actual body weight, with the maximum of 3 grams a day from Day 5 to 35. The dose will then be reduced to the standard 1 g twice daily thereafter.; Prednisone will be administered at a dose of 10 mg orally daily from Day 5 for 12 weeks. Thereafter the dose will be reduced to 5 mg orally daily.; All recipients will receive 5 microgram/kg per day of filgrastim as a single, subcutaneous injection from Day 5 post-transplant until the absolute neutrophil count is greater than 1000/µl on three consecutive measurements over at least 2 days.
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Mycophenolic Acid; Prednisone; Methylprednisolone; Cyclophosphamide; Fludarabine; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: renal transplantation; conditioning regimen; BMT; high dose post-transplant cyclophosphamide (PT/Cy); renal allograft tolerance; immunosuppression withdrawal

Summary:

      The primary objective of this study is to assess the ability of bone marrow transplantation
      (BMT) and high-dose post-transplantation cyclophosphamide (PT/Cy) to induce renal allograft
      tolerance and thus enable discontinuation of immunosuppressive therapy in haploidentical
      living related donor renal transplant recipients.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Recipient participants must meet all of the following criteria to be eligible for this
             study:

               -  Recipient of a first renal allograft from an Human Leukocyte Antigen
                  (HLA)-haploidentical, living related donor. The donor and recipient must be HLA
                  identical for at least one allele (using high resolution DNA based typing) at the
                  following genetic loci: HLA-A, HLA-B, HLA-C and HLA-DRB1. Fulfillment of this
                  criterion shall be considered sufficient evidence that the donor and recipient
                  share one HLA haplotype.

               -  Age 18 to 65 years.

               -  Single solid organ recipients (kidney only).

               -  Blood Group System (ABO) compatibility with donor.

               -  Donor-Specific Antibody (DSA) will be assessed by the local laboratory 30 days or
                  less prior to transplant using solid phase micro particle technology (by Luminex®
                  phenotype panel or Luminex single antigen bead test.) The following criteria
                  apply:

          -  Participants without detectable DSA will be deemed eligible if they meet other entry
             criteria.

          -  Participants with detectable DSA and a positive flow cytometric crossmatch may undergo
             de-sensitization per standard of care if they are cytotoxic crossmatch negative. Such
             participants must demonstrate a negative flow cytometric crossmatch by day -9 in order
             to receive the first dose of study therapy (ATG). Participants who do not demonstrate
             an acceptable response to de-sensitization by day -9 will be considered screen
             failures and will be terminated from the study.

          -  Participants with a positive cytotoxicity crossmatch will be excluded.

          -  No known history of anti-HLA antibodies. Recipients with low- level anti-HLA
             antibodies not considered to be clinically significant may be eligible, following
             consultation with the Protocol Chairs, the local HLA Laboratory Director, the NIAID
             Medical Monitor and the ITN Clinical Trial Physician.

          -  Negative T and B cell flow crossmatches with the designated donor; as assessed by
             local laboratories. If one or more of the crossmatches is positive, the participant
             will be considered a screen failure unless combined results of antibody and cross
             match testing implicate a non-HLA antibody as the cause of the positive flow
             crossmatch. In this case, the Protocol Chair must approve the participant as a
             screening success after consultation with the local HLA Laboratory Director.

          -  Normal estimated left ventricular ejection fraction and no history of ischemic heart
             disease requiring revascularization, unless cleared by a cardiologist.

          -  Forced expiratory volume (FEV1) and forced vital capacity (FVC) > 40% of predicted at
             the screening visit.

          -  Serological evidence of prior Epstein-Barr virus (EBV) infection as documented by
             positive IgG and negative IgM antibodies against EBV.

          -  For women of childbearing potential, a negative serum or urine pregnancy test with
             sensitivity less than 50 Milli-International unit (mIU)/m within 72 hours before the
             start of study medication.

          -  Use of two forms of contraception with less than a 5% failure rate or abstinence by
             all transplanted participants for 18 months after the first dose of study therapy. For
             the first 60 days post-transplant, recipients should be encouraged to use non-hormonal
             contraceptives due to the potential adverse effect of hormones on bone marrow
             engraftment.

          -  Ability to receive oral medication.

          -  Ability to understand and provide informed consent.

          -  All participants must demonstrate a negative QuantiFERON® (QFT) assay result within 52
             weeks of transplant regardless of Purified Protein Derivative (PPD) status.
             Participants with a positive QFT assay will not be eligible for the study unless they
             have completed treatment for latent TB and have a negative chest x-ray. QFT testing
             done within 52 weeks before transplant is acceptable as long as there is documentation
             of the results. Prior recipients of a Bacillus Calmette-Guérin (BCG) vaccination are
             not exempt.

          -  Donor participants must meet all of the following criteria to be eligible for this
             study:

               -  HLA-haploidentical, first-degree relatives or half-siblings of the recipient
                  participant at the allele or allele group. The donor and recipient must be HLA
                  identical for at least one allele (using high resolution DNA based typing) at the
                  following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this
                  criterion shall be considered sufficient evidence that the donor and recipient
                  share one HLA haplotype.

               -  Age 18 to 65 years.

               -  Creatinine clearance >80 ml/minute as measured from a 24 hour urine collection
                  within 26 weeks of the screening visit. If a serum creatinine drawn at the
                  screening visit is > 20% higher than the serum creatinine drawn at the time of
                  the 24 urine collection, the creatinine clearance must be re-evaluated by a
                  repeat 24 hour urine test. If the new value is ≤80mg/dL the donor will be
                  excluded.

               -  Meets institutional selection criteria for organ and bone marrow donation.

               -  Ability to understand and provide informed consent for all study procedures
                  including kidney transplant and bone marrow harvest.

               -  Serologic evidence of prior EBV infection as documented by positive
                  Immunoglobulin G (IgG) and negative Immunoglobulin M (IgM) antibodies against
                  EBV.

        Exclusion Criteria:

          -  Recipient subjects who meet any of the following criteria will not be eligible for
             this study:

               -  Underlying renal disease with a high risk of disease recurrence in the
                  transplanted kidney, including:

                    1. Focal segmental glomerulosclerosis (FSGS).

                    2. Type I or II membranoproliferative glomerulonephritis.

                    3. Hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura.

               -  Clinically important genital/urinary tract dysfunction.

               -  Body mass index (BMI) > 40.

               -  Women who are breastfeeding.

               -  History of cancer within the last 5 years, except for nonmelanoma skin cancer,
                  stage 1 renal cell carcinoma, stage 1 prostate cancers cured by local resection
                  and any curatively treated carcinomas in situ.

               -  History of positive HIV-1 or HIV-2 serologies or nucleic acid test.

               -  Evidence of prior hepatitis B infection as evaluated by hepatitis B surface
                  antigen (HBsAg), total hepatitis B core antibody (anti-HBc IgM and IgG) and
                  Hepatitis B surface antibody (anti-HBsAb).

        Subjects demonstrating any one of the following will be excluded:

          -  Positive hepatitis B surface antigen (HBsAg) or

          -  Positive anti-HBc IgM.

          -  Positive anti-HBc IgG.

          -  Positive Hepatitis B virus (HBV) Polymerase chain reaction (PCR).

          -  Positive anti-hepatitis C (HCV) antibodies and a positive serum HCV RNA PCR. All
             positive HCV antibody results must be assessed by an Electroimmunoassay (EIA) assay
             and confirmed by a quantitative serum HCV RNA assay. Participants with positive HCV
             antibodies but undetectable serum HCV RNA may be considered for eligibility.
             Participants with negative anti-HCV antibodies but unexplained liver enzyme
             abnormalities must undergo a quantitative serum RNA assay to rule out false negative
             HCV serologies.

          -  History of active Tuberculosis (TB).

          -  Any active, severe local or systemic infection at the screening visit.

          -  Autoimmune disease requiring immunosuppressive drugs for maintenance.

          -  Use of investigational drug, other than the study medications specified by the
             protocol, within 30 days of transplantation.

          -  Receipt of a live vaccine within 30 days of receipt of study therapy.

          -  The presence of any medical condition that the Investigator deems incompatible with
             participation in the trial.

          -  Donor subjects who meet any of the following criteria will not be eligible for this
             study:

               -  History of type I or type II diabetes mellitus.

               -  History of severe cardiovascular disease, defined as New York Heart Association
                  Class III or IV.

               -  History of blood product donation to recipient.

               -  History of positive HIV-1 or HIV-2 serology or nucleic acid test.

               -  Evidence of prior hepatitis B infection.

        Subjects demonstrating any one of the following will be excluded:

          -  Positive hepatitis B surface antigen (HBsAg) or

          -  Positive anti- hepatitis B core antigen (HBc) IgM.

          -  Positive anti-HBc IgG.

          -  Positive HBV PCR

          -  Positive anti-hepatitis C (HCV) antibodies and a positive serum HCV RNA PCR. All
             positive HCV antibody results must be assessed by an EIA assay and confirmed by a
             quantitative serum HCV RNA assay. Participants with positive HCV antibodies but
             undetectable serum HCV RNA may be considered for eligibility. Participants with
             negative anti-HCV antibodies but unexplained liver enzyme abnormalities must undergo a
             quantitative serum RNA assay to rule out false negative HCV serologies.

          -  Autoimmune disease requiring immunosuppressive drugs for maintenance.

          -  The presence of any medical condition that the Investigator deems incompatible with
             participation in the trial.