Clinical trial NCT02029638: BMT and High Dose Post-Transplant Cyclophosphamide for Chimerism Induction and Renal Allograft Tolerance
Official title: Bone Marrow Transplantation and High Dose Post-Transplant Cyclophosphamide for Chimerism Induction and Renal Allograft Tolerance (ITN054ST)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Kidney Transplantation
Keywords: renal transplantation
conditioning regimen
BMT
high dose post-transplant cyclophosphamide (PT/Cy)
renal allograft tolerance
immunosuppression withdrawal
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2014-01-08
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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 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.

\*\*\* IMPORTANT NOTICE: \*\*\* The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

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.

Primary outcomes:
measure: Percent of Participants Who Achieved Operational Tolerance
timeFrame: Transplantation through 52 Weeks after Discontinuation of All Immunosuppression
Secondary outcomes:
measure: Number of Participants Experiencing an Incidence of Graft-versus-Host Disease Post-Transplant
timeFrame: Transplant to Two Years Post-Transplant
measure: Severity of Graft-versus-Host Disease in Transplanted Participants
timeFrame: Transplant to Two Years Post-Transplant
measure: Duration in Days of Graft-versus-Host Disease in Transplanted Participants
timeFrame: Transplant to Two Years Post-Transplant
measure: Number of Transplanted Participants With Engraftment Syndrome
timeFrame: Transplant to End of Study (Up to 25 months After Enrollment)
measure: Duration in Days of Engraftment Syndrome in Transplanted Participants
timeFrame: Transplant to End of Study (Up to 25 months After Enrollment)
measure: Number of Transplanted Participants Who Died
timeFrame: Transplant to End of Study (Up to 25 months After Enrollment)
measure: Number of Transplanted Participants With Acute Renal Allograft Rejection
timeFrame: Transplant to End of Study (Up to 25 months After Enrollment)
measure: Histological Severity of Biopsies Demonstrating Acute Rejection as Defined by Banff 2007 Classification Renal Allograft Pathology
timeFrame: Transplant to End of Study (Up to 25 months After Enrollment)
measure: Number of Transplanted Participants With Chronic T Cell-Mediated or Antibody-Mediated Rejection
timeFrame: Transplant to End of Study (Up to 25 months After Enrollment)
measure: Number of Days Post-Transplant to the First Episode of Acute Rejection Requiring Treatment
timeFrame: Transplant to End of Study (Up to 25 months After Enrollment)
measure: Number of Adverse Events (AEs)- Including Infection, Wound Complications, Post-transplant Diabetes, Hemorrhagic Cystitis and Malignancy
timeFrame: First Dose of Study Medication to End of Study (Up to 25 Months After Enrollment)
measure: Number of Adverse Events (AEs) by Severity- Including Infection, Wound Complications, Post-Transplant Diabetes, Hemorrhagic Cystitis and Malignancy
timeFrame: First Dose of Study Medication to End of Study (Up to 25 Months After Enrollment)
measure: Duration in Days of Adverse Events (AEs)- Including Infection, Wound Complications, Post-transplant Diabetes, Hemorrhagic Cystitis and Malignancy
timeFrame: First Dose of Study Medication to End of Study (Up to 25 Months After Enrollment)
measure: Number of Transplanted Participants Who Developed Donor- Specific Antibody After Initiation of Immunosuppression Withdrawal
timeFrame: Initiation of Immunosuppression Withdrawal to End of Study (to 25 months)
measure: Number of Transplanted Participants Who Developed Donor-Specific Antibody During Study Participation
timeFrame: Transplant to End of Study (Up to 25 months)
measure: Number of Days From Neutrophil Nadir to Absolute Neutrophil Recovery
timeFrame: Post-Transplant Neutrophil Nadir to Neutrophil Recover
measure: Number of Days From Transplant to Platelet Count Recovery
timeFrame: Transplant to Platelet Count Recovery
measure: Number of Transplanted Participants Who Remained Off Immunosuppression for at Least 52 Weeks, Including Those in Whom the 52 Week Biopsy Was Not Performed
timeFrame: Transplant to 52 Weeks after Discontinuation of All Immunosuppression
measure: Number of Participants Free From Return to Immunosuppression for the Duration of the Study
timeFrame: Transplant to End of Study (Up to 25 Months)
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Lode Swinnen, MD
role: STUDY_CHAIR
References:
citation: Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008 Apr;8(4):753-60. doi: 10.1111/j.1600-6143.2008.02159.x. Epub 2008 Feb 19.