Bone Marrow Transplantation and High Dose Post-Transplant Cyclophosphamide for Chimerism Induction and Renal Allograft Tolerance (ACCEPTOR)

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT02029638
First received: December 30, 2013
Last updated: January 6, 2014
Last verified: January 2014
  Purpose

Transplantation is a good treatment for people with end-stage kidney disease. However, there is still much to learn about how to best care for the transplanted kidney and keep it working for a long time.

Unless a person receiving a kidney from someone else takes drugs that reduce immune function, the kidney will be rejected. Those drugs must be continued life-long and cause many issues. Therefore, tolerance of the transplanted kidney, without chronic rejection and without the need for permanent immunosuppressive drug treatment, is a highly desirable goal. If this can be achieved, it would make "one kidney for life" possible.

The purpose of this study is to find out if the study treatment will allow people to accept their new kidney and be able to stop taking anti-rejection medications. The study treatment includes several days of study medications followed by a kidney and bone marrow transplant. After the transplant, the study treatment will continue with a few more doses of study medications and then anti-rejection medication is started. After a while, the anti-rejection medication is slowly stopped. Researchers will examine blood and tissue samples and try to identify genetic markers for certain conditions like chimerism, response to therapy, and tolerance.


Condition Intervention Phase
Kidney Transplantation
Biological: Antithymocyte globulin (ATG)
Drug: Fludarabine
Drug: Low dose Pre-transplant cyclophosphamide
Radiation: Total Body Irradiation
Drug: Acetaminophen
Drug: Diphenhydramine
Drug: Methylprednisolone
Biological: Bone Marrow
Drug: MESNA
Drug: Mycophenolate mofetil (MMF)
Drug: Prednisone
Drug: Filgrastim
Drug: High dose post-transplant cyclophosphamide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Bone Marrow Transplantation and High Dose Post-Transplant Cyclophosphamide for Chimerism Induction and Renal Allograft Tolerance (ITN054ST)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • The proportion of participants who achieve operational tolerance [ Time Frame: Week 52 Weeks after completion of immunosuppression withdrawal ] [ Designated as safety issue: No ]

    Operational tolerance is defined as remaining off all immunosuppression 52 weeks after completion of immunosuppression withdrawal with:

    1. no evidence of biopsy-proven allograft rejection and
    2. acceptable renal function, defined as a serum creatinine that has increased no more than 25% above baseline at the primary endpoint visit.


Secondary Outcome Measures:
  • The incidence of graft versus host disease (GVHD) in transplanted participants [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The incidence of engraftment syndrome in transplanted participants [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The proportion of transplanted participants who die. [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The proportion of transplanted participants with acute renal allograft rejection [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
    Acute renal allograft rejection demonstrated by a biopsy or clinically if a biopsy cannot be performed. If participant has allograft dysfunction and cannot undergo biopsy he or she will be presumed to have rejection without biopsy confirmation.

  • The histological severity of biopsies demonstrating acute rejection as measured by Banff Grade per Banff 2007 Classification Renal Allograft Pathology1. [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
    Measured by Banff Grade per Banff 2007 Classification Renal Allograft Pathology.

  • The proportion of transplanted participants with chronic T cell-mediated or antibody-mediated rejection. [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
    This assessment should also include progressive interstitial fibrosis/tubular atrophy (IF/TA), transplant glomerulopathy or chronic obliterative arteriopathy without an alternative, non-rejection-related cause. The Banff 2007 Classification Renal Allograft Pathology will be used

  • Time from transplant to the first episode of acute rejection requiring treatment. [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The incidence of adverse events including infection, wound complications, post-transplant diabetes, hemorrhagic cystitis and malignancy. [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The proportion of transplanted participants who develop donor specific antibody after initiation of immunosuppression withdrawal [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The proportion of transplanted participants who develop donor specific antibody at any time during trial participation [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The time to absolute neutrophil recovery. [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
    The time to absolute neutrophil recovery is defined as the interval from the neutrophil nadir to the first day of three consecutive daily neutrophil counts ≥ 500 per µL. The neutrophil nadir is defined as the first day post- transplant on which the absolute neutrophil count (ANC) is below 500 per µL.

  • The time to platelet count recovery. [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
    The time to platelet count recovery is defined as the interval from transplant to the first day of a platelet count of 20,000 per µL without a prior platelet transfusion in the preceding seven days

  • The proportion of transplanted participants who remain off immunosuppression for at least 52 weeks including those in whom the 52 week biopsy was not performed. [ Time Frame: Week 154 ] [ Designated as safety issue: No ]
  • The proportion of participants who remain free from return to immunosuppression for the duration of the study. [ Time Frame: Week 154 ] [ Designated as safety issue: No ]
  • In participants who complete tacrolimus withdrawal: Immunosuppression-free duration [ Time Frame: Week 154 ] [ Designated as safety issue: No ]
    Immunosuppression-free duration is defined as time from completion of tacrolimus to end of trial participation or to time of restarting immunosuppression.

  • In participants who complete tacrolimus withdrawal: Time from completion of tacrolimus withdrawal to first episode of acute rejection or presumed acute rejection [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
    Acute rejection or presumed acute rejection is defined per Banff 2007 Classification Renal Allograft Pathology

  • In participants who complete tacrolimus withdrawal: Time from completion of tacrolimus withdrawal to first diagnosis of chronic T cell mediated or antibody-mediated rejection. [ Time Frame: Week 154 ] [ Designated as safety issue: No ]
    This assessment includes IF/TA, transplant glomerulopathy or chronic obliterative arteriopathy without an alternative, non-rejection related cause. Based on Banff 2007 Classification Renal Allograft Pathology

  • The severity of graft versus host disease (GVHD) in transplanted participants [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The duration of graft versus host disease (GVHD) in transplanted participants [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The severity of engraftment syndrome in transplanted participants [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The duration of engraftment syndrome in transplanted participants [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The severity of adverse events including infection, wound complications, post-transplant diabetes, hemorrhagic cystitis and malignancy. [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]
  • The duration of adverse events including infection, wound complications, post-transplant diabetes, hemorrhagic cystitis and malignancy. [ Time Frame: Week 154 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 6
Study Start Date: January 2013
Estimated Study Completion Date: November 2020
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Kidney Transplantation Biological: Antithymocyte globulin (ATG)
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.
Drug: Fludarabine
Fludarabine at dose 30 mg/m2 will be administered daily by intravenous infusion over 30 minutes on Day -6 to Day -2.
Drug: Low dose Pre-transplant cyclophosphamide
Pre-transplant cyclophosphamide will be administered as an intravenous infusion over 1- 2 hours, (depending on volume) on Days -6 and -5. The dose of pre-transplantation cyclophosphamide is 14.5 mg/kg/day.
Radiation: Total Body Irradiation
Total body irradiation, consisting of 200 centigray cGy AP/PA with 4MV or 6MV photons at 8-12 cGy/min at the point of prescription will be administered in a single day on Day -1.
Drug: Acetaminophen
650 mg orally prior to antithymocyte globulin infusion
Drug: Diphenhydramine
25mg diphenhydramine orally prior to antithymocyte globulin infusion.
Drug: Methylprednisolone
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.
Biological: Bone Marrow
Unprocessed, unmanipulated bone marrow will be harvested from the donor and infused into the recipient on Day 0
Drug: MESNA
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.
Drug: Mycophenolate mofetil (MMF)
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.
Drug: Prednisone
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.
Drug: Filgrastim
All recipients will receive 5 microgram/kg per day of filgrastim as a single, subcutaneous injection from Day -5 until the absolute neutrophil count is greater than 1000/µl on three consecutive measurements over at least 2 days.
Drug: High dose post-transplant cyclophosphamide
High dose post- transplant 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 as an IV infusion over 1-2 hours depending on volume.

  Eligibility

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

Inclusion Criteria:

  • Recipient participants must meet all of the following criteria to be eligible for this study:

    1. Recipient of a first renal allograft from an 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.
    2. Age 18 to 65 years.
    3. Single solid organ recipients (kidney only).
    4. ABO compatibility with donor.
    5. Demonstration of absence of DSA using solid phase micro particle technology (by Luminex® phenotype panel or Luminex single antigen bead test) performed 30 days or less prior to transplant as assessed by local laboratories.
    6. 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.
    7. 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.
    8. Normal estimated left ventricular ejection fraction and no history of ischemic heart disease requiring revascularization, unless cleared by a cardiologist.
    9. Forced expiratory volume (FEV1) and forced vital capacity (FVC) > 40% of predicted at the screening visit.
    10. Serological evidence of prior Epstein-Barr virus (EBV) infection as documented by positive IgG and negative IgM antibodies against EBV.
    11. For women of childbearing potential, a negative serum or urine pregnancy test with sensitivity less than 50 mIU/m within 72 hours before the start of study medication.
    12. 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.
    13. Ability to receive oral medication.
    14. Ability to understand and provide informed consent.
  • Donor participants must meet all of the following criteria to be eligible for this study:

    1. 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.
    2. Age 18 to 65 years.
    3. 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.
    4. Meets institutional selection criteria for organ and bone marrow donation.
    5. Ability to understand and provide informed consent for all study procedures including kidney transplant and bone marrow harvest.
    6. Serologic evidence of prior EBV infection as documented by positive IgG and negative IgM antibodies against EBV.

Exclusion Criteria:

  • Recipient participants who meet any of the following criteria will not be eligible for this study:

    1. 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.
    2. Clinically important genital/urinary tract dysfunction.
    3. Body mass index (BMI) > 40.
    4. Women who are breastfeeding.
    5. 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.
    6. History of positive HIV-1 or HIV-2 serologies or nucleic acid test.
    7. 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).

      Participants demonstrating any one of the following will be excluded:

      1. positive hepatitis B surface antigen (HBsAg) or
      2. positive anti-HBc IgM.
      3. positive anti-HBc IgG
      4. positive HBV PCR
    8. 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.
    9. History of active tuberculosis (TB). All participants must demonstrate a negative QuantiFERON® assay result within 52 weeks of transplant regardless of PPD status. Participants with a positive QuantiFERON® (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 BCG vaccination are not exempt.
    10. Any active, severe local or systemic infection at the screening visit.
    11. Autoimmune disease requiring immunosuppressive drugs for maintenance.
    12. Use of investigational drug, other than the study medications specified by the protocol, within 30 days of transplantation.
    13. Receipt of a live vaccine within 30 days of receipt of study therapy.
    14. The presence of any medical condition that the Investigator deems incompatible with participation in the trial.
  • Donor participants who meet any of the following criteria will not be eligible for this study:

    1. History of type I or type II diabetes mellitus.
    2. History of severe cardiovascular disease, defined as New York Heart Association Class III or IV2.
    3. History of blood product donation to recipient.
    4. History of positive HIV-1 or HIV-2 serology or nucleic acid test.
    5. 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).

      Participants demonstrating any one of the following will be excluded:

      1. positive hepatitis B surface antigen (HBsAg) or
      2. positive anti-HBc IgM.
      3. positive anti-HBc IgG
      4. positive HBV PCR
    6. 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.
    7. Autoimmune disease requiring immunosuppressive drugs for maintenance.
    8. The presence of any medical condition that the Investigator deems incompatible with participation in the trial.
  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: NCT02029638

Locations
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21205
Contact: Elaina Burney    410-502-3161    eburney@jhmi.edu   
Principal Investigator: Lode Swinnen, MD         
Principal Investigator: Robert Montgomery, MD         
Principal Investigator: Ephraim Fuchs, MD         
Sponsors and Collaborators
Immune Tolerance Network (ITN)
Investigators
Study Chair: Lode Swinnen, MD Johns Hopkins University
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02029638     History of Changes
Other Study ID Numbers: DAIT ITN054ST
Study First Received: December 30, 2013
Last Updated: January 6, 2014
Health Authority: United States: Food and Drug Administration
United States: Data and Safety Monitoring Board
United States: Federal Government
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Kidney Transplantation
Renal Transplantation

Additional relevant MeSH terms:
Cyclophosphamide
Fludarabine phosphate
Mycophenolate mofetil
Antilymphocyte Serum
Fludarabine
Prednisone
Mycophenolic Acid
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Acetaminophen
Diphenhydramine
Promethazine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Inflammatory Agents
Glucocorticoids

ClinicalTrials.gov processed this record on September 18, 2014