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

NCT02702960 | Withdrawn Phase 2 DMC

• 2 other identifiers: J15171IRB00080373
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

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.

Conditions

Fibrolamellar Hepatocellular Carcinoma; Hepatocellular Carcinoma (Fibrolamellar Variant); Hepatocellular Carcinoma

Keywords

FL-HCC; living donor liver transplant; HLA matched first degree relative; Milan Criteria; Ephraim Fuchs; Fibrolamellar Cancer Foundation; fibrolamellar; non-fibrolamellar

Outcome Measures

Primary Outcomes (1)

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

  Disease-free is defined as the lack of radiographic evidence of recurrence by computed tomography or MRI.

  1 year

Secondary Outcomes (3)

• Occurrence of Graft versus Host Disease

  1 year

• Death

  1 year

• Liver allograft failure

  1 year

Other Outcomes (2)

• Efficacy measure - proportion disease free

  1 year

• Efficacy measure- proportion off immunosuppression without graft versus host disease (GVHD) or liver rejection

  1 year

Study Arms (1)

part. liver transplant and BMT

EXPERIMENTAL

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.

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

Interventions

living related donor partial liver transplantation PROCEDURE

HLA matched or haploidentical related living donor partial liver transplant followed by tacrolimus, prednisone, and MMF immunosuppression for \>3 wks

part. liver transplant and BMT

Total body irradiation RADIATION

200 cGy total body irradiation (TBI) on Day -1.

part. liver transplant and BMT

Bone marrow transplant from same donor PROCEDURE

BMT using cells from the same Human Leukocyte Antigen (HLA)-matched or -haploidentical living related donor will be performed on Day 0

Also known as: BMT

part. liver transplant and BMT

Cyclophosphamide DRUG

Pre-transplantation low dose cyclophosphamide given day -6 and -5 Post-transplantation high dose cyclophosphamide (PTCy; 50 mg/kg/day) will be administered on Days 3 and 4 with hydration

Also known as: Cytoxan

part. liver transplant and BMT

Mesna DRUG

administered on Days 3 and 4 with PTCy

Also known as: sodium-2-mercaptoethane sulfonate

part. liver transplant and BMT

Filgrastim DRUG

administered daily starting on Day 5 until absolute neutrophil count (ANC) recovery

part. liver transplant and BMT

Tacrolimus DRUG

Given after liver transplant for through day -7, stopped on day -6 and restarted on day 5 post BMT

part. liver transplant and BMT

mycophenolate mofetil DRUG

Given after liver transplant for through day -7, stopped on day -6 and restarted on day 5 post BMT

Also known as: MMF

part. liver transplant and BMT

Prednisone DRUG

Given after liver transplant for through day -7, stopped on day -6 and restarted on day 5 post BMT

part. liver transplant and BMT

Antithymocyte globulin DRUG

Given from Day -16 to Day -14 prior to bone marrow transplantation on day 0

Also known as: ATG

part. liver transplant and BMT

fludarabine DRUG

fludarabine given from Days -6 to Day -2 before BMT

part. liver transplant and BMT

Eligibility Criteria

• Age: 16 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• RECIPIENT
• 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:
• Single viable tumor ≤5 cm in size or ≤3 tumors each ≤3 cm in size based on CT or Magnetic resonance (MR) imaging
• Pretransplant alpha fetoprotein (AFP) level of ≤400.
• 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.
• Age 16 to 65 years.
• 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.
• Forced expiratory volume (FEV1) and forced vital capacity (FVC) \> 40% of predicted at the screening visit.
• Serum creatinine \<2.0 mg/dl
• 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 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.
• Ability to receive oral medication.
• Ability to understand and provide informed consent.
• Must meet all other criteria for listing for liver transplantation
• DONOR:

You may not qualify if:

• RECIPIENT
• Extrahepatic disease at the time of enrollment.
• Macrovascular invasion by tumor as seen on imaging
• Anti-donor HLA antibody with a level that produces a positive test on flow cytometric crossmatch. \[Note: patients with a positive flow cytometric crossmatch may undergo desensitization and may become eligible, at the discretion of the protocol investigators, if desensitization decreases the antibody concentration to a level that produces a negative flow cytometric crossmatch.\]
• Ineligible for liver transplantation per institutional criteria (see Appendix 1)
• Women who are breastfeeding.
• History of positive HIV-1 or HIV-2 serologies or nucleic acid test.
• Active hepatitis B infection as documented by positive Hepatitis B assay
• Any active, severe local or systemic infection at the screening visit.
• 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
• Age: less than age 18 or older than age 60
• BMI \>35

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• Fibrolamellar Cancer Foundation: collaborator

Study Sites (1)

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21205, United States

Location

MeSH Terms

Conditions

Fibrolamellar hepatocellular carcinoma; Carcinoma, Hepatocellular

Interventions

Whole-Body Irradiation; Cyclophosphamide; Mesna; Filgrastim; Tacrolimus; Mycophenolic Acid; Prednisone; Antilymphocyte Serum; fludarabine

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2016
• First Posted: March 9, 2016
• Study Start: March 1, 2016
• Primary Completion: January 3, 2018
• Study Completion: January 3, 2018
• Last Updated: June 15, 2018

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will share

Locations

US (1)