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

Brief Title

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

Official Title

Sequential, Related Donor Partial Liver Transplantation Followed by Bone Marrow Transplantation for Fibrolamellar or Non-fibrolamellar Hepatocellular Carcinoma (HCC) Including Fibrolamellar HCC

Brief Summary

      This trial is a phase II, single arm, open-label, single center study to assess a
      reduced-intensity conditioning regimen, bone marrow transplantation and high dose 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 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.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

1 year disease-free survival (at 1 year after BMT)

Secondary Outcome

 Occurrence of Graft versus Host Disease

Condition

Fibrolamellar Hepatocellular Carcinoma

Intervention

living related donor partial liver transplantation

Study Arms / Comparison Groups

 part. liver transplant and BMT
Description:  Patients receive living related donor partial liver transplantation performed according to standard practices. Patients will be maintained on tacrolimus, MMF, and prednisone after liver transplantation.
Upon recovery, patient must undergo eligibility screening for bone marrow transplantation (BMT).
If eligible, patients will begin:
Antithymocyte globulin (ATG): Day -16 to Day -14; fludarabine: Days -6 to Day -2 low-dose cyclophosphamide: Day -6 and -5. Tacrolimus, mycophenolate mofetil (MMF), and prednisone: day -7 and day -6. Total body irradiation on Day -1 Bone marrow infusion on Day 0. High dose cyclophosphamide plus MESNA: Day 3 and 4th Filgrastim, tacrolimus,MMF, and prednisone: Day 5 until neutrophil counts recover.
Patients followed up through post transplant day 60, then weekly following discharge.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

0

Start Date

March 2016

Completion Date

January 3, 2018

Primary Completion Date

January 3, 2018

Eligibility Criteria

        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.
      

Gender

All

Ages

16 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02702960

Organization ID

J15171

Secondary IDs

IRB00080373

Responsible Party

Sponsor

Study Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

 Fibrolamellar Cancer Foundation

Study Sponsor

, , 


Verification Date

June 2018