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Trial record 4 of 6 for:    fibrolamellar

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

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2016 by Sidney Kimmel Comprehensive Cancer Center
Sponsor:
Collaborator:
Fibrolamellar Cancer Foundation
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT02702960
First received: February 26, 2016
Last updated: May 17, 2016
Last verified: May 2016
  Purpose

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.


Condition Intervention Phase
Fibrolamellar Hepatocellular Carcinoma Hepatocellular Carcinoma (Fibrolamellar Variant) Hepatocellular Carcinoma 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 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Sequential, Related Donor Partial Liver Transplantation Followed by Bone Marrow Transplantation for Fibrolamellar or Non-fibrolamellar Hepatocellular Carcinoma (HCC) Including Fibrolamellar HCC

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

Primary Outcome Measures:
  • 1 year disease-free survival (at 1 year after BMT) [ Time Frame: 1 year ]
    Disease-free is defined as the lack of radiographic evidence of recurrence by computed tomography or MRI.


Secondary Outcome Measures:
  • Occurrence of Graft versus Host Disease [ Time Frame: 1 year ]
    Determine the cumulative incidences of acute grades II-IV, III-IV and chronic graft-versus-host disease

  • Death [ Time Frame: 1 year ]
    Proportion of transplanted participants who die

  • Liver allograft failure [ Time Frame: 1 year ]
    Determine the proportion of transplanted participants with liver allograft rejection demonstrated by a biopsy or clinically if a biopsy cannot be performed.


Other Outcome Measures:
  • Efficacy measure - proportion disease free [ Time Frame: 1 year ]
    The proportion of transplanted participants who remain free of disease recurrence for 1 year post bone marrow transplantation

  • Efficacy measure- proportion off immunosuppression without graft versus host disease (GVHD) or liver rejection [ Time Frame: 1 year ]
    The proportion of participants who are off immunosuppression without GVHD or liver rejection at 1 year after bone marrow transplantation.


Estimated Enrollment: 6
Study Start Date: March 2016
Estimated Study Completion Date: January 2020
Estimated Primary Completion Date: July 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: part. liver transplant and BMT

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
HLA matched or haploidentical related living donor partial liver transplant followed by tacrolimus, prednisone, and MMF immunosuppression for >3 wks
Radiation: Total body irradiation
200 cGy total body irradiation (TBI) on Day -1.
Procedure: Bone marrow transplant from same donor
BMT using cells from the same Human Leukocyte Antigen (HLA)-matched or -haploidentical living related donor will be performed on Day 0
Other Name: BMT
Drug: Cyclophosphamide
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
Other Name: Cytoxan
Drug: Mesna
administered on Days 3 and 4 with PTCy
Other Name: sodium-2-mercaptoethane sulfonate
Drug: Filgrastim
administered daily starting on Day 5 until absolute neutrophil count (ANC) recovery
Drug: Tacrolimus
Given after liver transplant for through day -7, stopped on day -6 and restarted on day 5 post BMT
Drug: mycophenolate mofetil
Given after liver transplant for through day -7, stopped on day -6 and restarted on day 5 post BMT
Other Name: MMF
Drug: Prednisone
Given after liver transplant for through day -7, stopped on day -6 and restarted on day 5 post BMT
Drug: Antithymocyte globulin
Given from Day -16 to Day -14 prior to bone marrow transplantation on day 0
Other Name: ATG
Drug: fludarabine
fludarabine given from Days -6 to Day -2 before BMT

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.

  Eligibility

Ages Eligible for Study:   16 Years to 65 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02702960

Contacts
Contact: Ephraim Fuchs, MD 410-955-8781 fuchsep@jhmi.edu

Locations
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21205
Contact: Ephraim Fuchs, MD    410-955-8781    fuchsep@jhmi.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Fibrolamellar Cancer Foundation
  More Information

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT02702960     History of Changes
Other Study ID Numbers: J15171
IRB00080373 ( Other Identifier: JHU IRB )
Study First Received: February 26, 2016
Last Updated: May 17, 2016
Individual Participant Data  
Plan to Share IPD: Yes

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
FL-HCC
living donor liver transplant
HLA matched first degree relative
Milan Criteria
Ephraim Fuchs
Fibrolamellar Cancer Foundation
fibrolamellar
non-fibrolamellar

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Liver Extracts
Prednisone
Fludarabine
Fludarabine phosphate
Cyclophosphamide
Mycophenolic Acid
Tacrolimus
Antilymphocyte Serum
Mycophenolate mofetil
Lenograstim
Mesna
Hematinics
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents

ClinicalTrials.gov processed this record on June 23, 2017