Sequential, Related Donor Partial Liver Transplantation Followed by Bone Marrow Transplantation for Hepatocellular Carcinoma (HCC)

The purpose of this study is to characterize the safety and anti-tumor efficacy of sequential
partial liver transplantation followed by bone marrow transplantation from the same living
related donor. This treatment applies to patients whose cancer remains confined to the liver
but is too widespread to be removed by surgery or treated by a liver transplant from a
deceased donor. The purpose of this combined treatment is to reduce the risk of the cancer
coming back after the liver transplant The bone marrow transplant may reduce the risk of
cancer relapse in two ways. First, patients who have combined bone marrow and solid organ
transplants may be able to get off all anti-rejection drugs, which inhibit the immune system
from destroying cancer cells. Second, the donor's bone marrow contains cells of the immune
system, which can attack any cancer cells that remain after the liver transplant.

This trial is a phase II, single arm, open-label, single center pilot study to assess a
reduced-intensity conditioning regimen, bone marrow transplantation and high dose
post-transplantation cyclophosphamide (PTCy) in recipients of a partial liver allograft from
a Human Leukocyte Antigen (HLA)-matched or -haploidentical living related donor in patients
with HCC. The trial includes analyses of tumor characteristics and the number and phenotype
of tumor infiltrating lymphocytes in the explanted tumor. The trial also includes periodic
monitoring of circulating hepatocytes to correlate with tumor response.

The study is expected to take two years to complete accrual of six patients, and the primary
objective of this trial is to characterize recurrence-free survival at 1 year following bone
marrow transplantation among recipients of prior partial liver transplantation from the same
donor. Secondary objectives include documenting percentage of patients who become tolerant of
the transplanted liver, i.e. off immunosuppression for >6 months without biochemical evidence
of liver rejection, and characterizing the relationship between donor chimerism and
transplantation tolerance.

Inclusion Criteria:

RECIPIENT

1. Histologic diagnosis of liver-confined fibrolamellar or non-fibrolamellar HCC.
Ineligible for curative resection or deceased donor liver transplantation by virtue of
NOT meeting the Milan criteria or down-staging criteria:

1. Single viable tumor ≤5 cm in size or ≤3 tumors each ≤3 cm in size based on CT or
Magnetic resonance (MR) imaging

2. Pretransplant alpha fetoprotein (AFP) level of ≤400.

2. Available human leukocyte antigen (HLA)-matched or -haploidentical, living related
donor who is willing to donate bone marrow and part of liver. 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. Fulfilment of this
criterion shall be considered sufficient evidence that the donor and recipient share
one HLA haplotype.

3. Age 16 to 65 years.

4. Normal estimated left ventricular ejection fraction ( >30% ) and no history of
ischemic heart disease requiring revascularization, unless cleared by a cardiologist
(as per normal liver and bone marrow (BM) transplant eligibility requirements). Those
with an ejection fraction between 30-40%, will require a cardiology consultation and
clearance for transplantation.

5. Forced expiratory volume (FEV1) and forced vital capacity (FVC) > 40% of predicted at
the screening visit.

6. Serum creatinine <2.0 mg/dl

7. 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.

8. Use of two forms of contraception with less than a 5% failure rate or abstinence by
all transplanted participants for 12 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.

9. Ability to receive oral medication.

10. Ability to understand and provide informed consent.

11. Must meet all other criteria for listing for liver transplantation

DONOR:

1. HLA-matched or -haploidentical, parent, child, sibling, or half-sibling of the
recipient

2. Meets all requirements for live liver donation based on established criteria

3. Ability to understand and provide informed consent for all study procedures including
partial liver transplant and bone marrow harvest.

4. Age < 60 years

5. Body Mass Index (BMI) <35

Exclusion Criteria:

RECIPIENT

1. Extrahepatic disease at the time of enrollment.

2. Macrovascular invasion by tumor as seen on imaging

3. Anti-donor HLA antibody with a level that produces a positive test on flow cytometric
crossmatch. [Note: patients with a positive flow cytometric crossmatch may undergo
desensitization and may become eligible, at the discretion of the protocol
investigators, if desensitization decreases the antibody concentration to a level that
produces a negative flow cytometric crossmatch.]

4. Ineligible for liver transplantation per institutional criteria (see Appendix 1)

5. Women who are breastfeeding.

6. History of positive HIV-1 or HIV-2 serologies or nucleic acid test.

7. Active hepatitis B infection as documented by positive Hepatitis B assay

8. Any active, severe local or systemic infection at the screening visit.

9. Use of investigational drug, other than the study medications specified by the
protocol, within 30 days of transplantation.

10. Receipt of a live vaccine within 30 days of receipt of study therapy.

11. The presence of any medical condition that the Investigator deems incompatible with
participation in the trial.

DONOR

1. Age: less than age 18 or older than age 60

2. BMI >35

3. History of blood product donation to the recipient

4. Significant cardiovascular disease (per cardiology consultation)

5. Significant pulmonary disease (per pulmonology consultation)

6. Significant renal disease

7. History of diabetes mellitus

8. Ongoing malignancies

9. Severe local or systemic infection

10. Severe neurologic deficits

11. Active substance abuse

12. Untreatable/unstable psychiatric illness

13. History of positive HIV-1 or HIV-2 serology or nucleic acid test.

14. Evidence of prior hepatitis B infection as evaluated by hepatitis B surface antigen
(HBsAg), total hepatitis B core antibody, and hepatitis B surface antibody
(anti-HBsAb).

15. Positive HBV PCR

16. Positive anti-hepatitis C (HCV) antibodies and a positive serum HCV RNA PCR. All
positive HCV antibody results must be assessed by an electroimmunoassay enzyme-linked
immunosorbent assay (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.

17. Autoimmune disease requiring immunosuppressive drugs for maintenance.

18. The presence of any medical condition that the Investigator deems incompatible with
participation in the trial.