BMT and High Dose Post-Transplant Cyclophosphamide for Chimerism Induction and Renal Allograft Tolerance

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.

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.