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

Phase 2

Withdrawn

• Conditions: Fibrolamellar Hepatocellular Carcinoma; Hepatocellular Carcinoma (Fibrolamellar Variant); Hepatocellular Carcinoma
• Interventions: Procedure: living related donor partial liver transplantation; Radiation: Total body irradiation; Procedure: Bone marrow transplant from same donor; Drug: Cyclophosphamide; Drug: Mesna; Drug: Filgrastim; Drug: Tacrolimus; Drug: mycophenolate mofetil; Drug: Prednisone; Drug: Antithymocyte globulin; Drug: fludarabine

• Registration Number: NCT02702960
• Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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 Timeline

• Study First Submitted: 2016-02-26
• Study Start: 2016-03
• Study First Submitted QC: 2016-03-03
• Study First Posted: 2016-03-09
• Primary Completion: 2018-01-03
• Study Completion: 2018-01-03
• Status Verified: 2018-06
• Last Update Submitted: 2018-06-13
• Last Update Posted: 2018-06-15

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
part. liver transplant and BMT	living related donor partial liver transplantation	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.
part. liver transplant and BMT	Total body irradiation	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.
part. liver transplant and BMT	Bone marrow transplant from same donor	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.
part. liver transplant and BMT	Tacrolimus	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.
part. liver transplant and BMT	Antithymocyte globulin	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.
part. liver transplant and BMT	Cyclophosphamide	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.
part. liver transplant and BMT	Mesna	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.
part. liver transplant and BMT	Filgrastim	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.
part. liver transplant and BMT	mycophenolate mofetil	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.
part. liver transplant and BMT	Prednisone	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.
part. liver transplant and BMT	fludarabine	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.

Primary Outcome Measures

Name	Time	Method
1 year disease-free survival (at 1 year after BMT)	1 year	Disease-free is defined as the lack of radiographic evidence of recurrence by computed tomography or MRI.

Secondary Outcome Measures

Name	Time	Method
Occurrence of Graft versus Host Disease	1 year	Determine the cumulative incidences of acute grades II-IV, III-IV and chronic graft-versus-host disease
Death	1 year	Proportion of transplanted participants who die
Liver allograft failure	1 year	Determine the proportion of transplanted participants with liver allograft rejection demonstrated by a biopsy or clinically if a biopsy cannot be performed.

Trial Locations

Locations (1)

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 🇺🇸 Baltimore, Maryland, United States