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A Phase II Randomized Multicenter Placebo-Controlled Blinded Study of Sorafenib Adjuvant Therapy in High Risk Orthotopic Liver Transplant (OLT) Recipients With Hepatocellular Carcinoma (HCC)

Phase 2
19 Years
Open (Enrolling)
Adult Primary Hepatocellular Carcinoma, Localized Resectable Adult Primary Liver Cancer, Localized Unresectable Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer

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Trial Information

A Phase II Randomized Multicenter Placebo-Controlled Blinded Study of Sorafenib Adjuvant Therapy in High Risk Orthotopic Liver Transplant (OLT) Recipients With Hepatocellular Carcinoma (HCC)


I. Two-year recurrence free survival (RFS).


I. One-year recurrence free survival. II. Overall survival (OS). III. Safety. IV. Impact of
drug-drug interactions (i.e. immunosuppression agents). V. Impact of biomarkers
(alpha-fetoprotein [AFP], protein-induced by vitamin K absence or antagonist II [PIVKA II]).

VI. Effects of therapy on wound healing. VII. Impact of hepatitis C viral recurrence.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive sorafenib tosylate orally (PO) twice daily (BID).

ARM II: Patients receive placebo PO BID.

In both arms treatment continues for 24 months in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 2 years.

Inclusion Criteria:

- Patients must have hepatocellular carcinoma (HCC) with one of the following on
explant: microvascular/macrovascular invasion, tumor outside of Milan criteria, poor
tumor differentiation; patients with macrovascular invasion on explant pathology will
be stratified

* Additionally, the following will be included

** Patients with elevated surrogate markers (AFP > 500 or PIVKA > 400) pre transplant
and with biopsy proven HCC prior to orthotopic liver transplantation (OLT) or on

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

- Patients with a life expectancy > 12 weeks

- Patients must have completed prednisone taper within 6 weeks post OLT

- Patients must be enrolled between 6 to 12 weeks post OLT

- Cadaveric donors only (no living donor liver transplantation [LDLT] or donor after
cardiac death transplantation [DCDT])

- No sorafenib prior to inclusion in the study

- Platelet count > 50 x 10^9/L

- Hemoglobin >= 8.5 g/dL

- Total bilirubin =< 5 mg/dL

- Alanine transaminase (ALT) and aspartate aminotransferase (AST) =< 5 x upper limit of

- Amylase and lipase =< 1.5 x the upper limit of normal

- Serum creatinine < 2 x the upper limit of normal

- Prothrombin time (PT) =< 6 seconds or international normalized ratio (INR) =< 2.3

- AFP > 500 (pre-transplant)

- PIVKA > 400 (pre-transplant)

- Patient has not received prior anti-angiogenic therapy, systemic targeted agents or
systemic chemotherapy

* Prior surgical resection, chemoembolization or other local therapy prior to
transplant is permitted

- Women of childbearing potential must have a negative serum pregnancy test performed
within 7 days prior to the start of study drug; post-menopausal women (defined as no
menses for at least 1 year) and surgically sterilized women are not required to
undergo a pregnancy test

- Patients (men and women) of childbearing potential must agree to use adequate
contraception beginning at the signing of the informed consent form (ICF) until at
least 30 days after the last dose of study drug; the definition of adequate
contraception will be based on the judgment of the principal investigator or a
designated associate

- Patient must be able to swallow and retain oral medication

- Patient must exhibit the ability to understand and willingness to sign a written
informed consent regarding the study and alternative treatments

Exclusion Criteria:

- Significant ongoing immunologic rejection based on pathology and clinical diagnosis
(from time of transplant until randomization)

- Use of T cell depleting agents for prevention or treatment of rejection at any point
prior to or after enrollment in the study

- Patient with documented evidence of metastatic disease

- 100% tumor necrosis on explant pathology

- Use of mammalian target of rapamycin (mTOR) inhibitors prior to transplant and as
post-transplant immunosuppression

- Use of alemtuzumab

- Living donor liver transplant (LDLT) or donation after cardiac death transplant

- Human immunodeficiency virus (HIV) positive patients

- Hepatitis C virus (HCV) recurrence at the time of randomization

- Use of direct acting antivirals for HCV recurrence

- Requirement of re-transplantation for primary non function

- Uncontrolled hypertension, defined as systolic blood pressure > 140 mmHg or diastolic
pressure > 90 mmHg, despite optimal medical management

- Active or clinically significant cardiac disease including:

- Congestive heart failure - New York Heart Association (NYHA) > class II

- Coronary artery disease

- Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers
or digoxin

- Unstable angina or new-onset angina within 3 months before randomization, or
myocardial infarction (MI) within 6 months before randomization

- Clinically active serious infection documented by positive cultures or an incomplete
course of treatment for bacteremia or fungemia

- Evidence or history of bleeding diathesis or coagulopathy

- Patients with any pulmonary hemorrhage/bleeding event grade 2 or higher within 4
weeks before randomization

- Patients with thrombotic, embolic, venous, or arterial events, such as
cerebrovascular accident (including transient ischemic attacks [TIAs]) within 6
months before randomization

- Prior use of raf-kinase inhibitors (sorafenib), vascular endothelial growth factor
(VEGF) inhibitors, mitogen-activated protein kinase
(MAPK)/extracellular-signal-related kinase (ERK) kinase (MEK) inhibitors, or farnesyl
transferase inhibitors

- Patients using cytochrome P450 3A4 (CYP3A4) inducers (eg, phenytoin, carbamazepine,
phenobarbital, St. John's Wort dexamethasone) at a dose of greater than 16 mg daily,
or rifampin and/or rifabutin within 28 days before randomization

- Patients with non-HCC malignancy except those with DCIS (ductal carcinoma in situ),
cervical cancer in-situ, basal cell or superficial bladder tumor; patients surviving
a cancer that was curatively treated and without evidence of recurrence for more than
3 years before randomization are allowed

- Presence of a non-healing wound, non-healing ulcer, or bone fracture

- Known or suspected allergy or hypersensitivity to any of the study drugs, study drug
classes, or excipients of the formulations given during the course of this trial

- Any malabsorption condition

- Women who are pregnant or breast-feeding

- Inability to comply with the protocol and/or not willing or not available for
follow-up assessments

- Patients with fibrolamellar HCC, cholangiocarcinoma, and combined

- Any condition which, in the investigator's opinion, makes the patient unsuitable for
trial participation

- Prior use of any systemic chemotherapy for HCC

- Prior use of systemic investigational agents for HCC

- Prior use of raf-kinase inhibitors (sorafenib), VEGF inhibitors, MEK inhibitors or
farnesyl transferase inhibitors

- Use of biologic response modifiers, such as granulocyte colony-stimulating factor
(G-CSF), will not be permitted within 3 weeks prior to study entry; G-CSF and other
hematopoietic growth factors may be used in the management of acute toxicity, such as
febrile neutropenia, when clinically indicated or at the discretion of the
investigator; however, they may not be administered to prevent a dose reduction;
patients taking chronic erythropoietin are permitted, provided no dose adjustment is
undertaken within 1 month prior to randomization or during the study

- Autologous bone marrow transplant or stem cell rescue within four months of start of
study drug

- Concomitant treatment with rifampin and St. John's wort

- Concomitant oral mTOR inhibitor treatment

- Use of direct acting antivirals for HCV recurrence

- Use of T-cell depleting agents

- Use of alemtuzumab

- Anticoagulation, as described below, is allowed:

- Vitamin-K antagonists (e.g., warfarin)

** Low dose warfarin (1 mg orally, once daily) with PT-INR =< 1.5 x ULN is
permitted; patients taking concomitant warfarin should be monitored regularly
for changes in PT, PT-INR or clinical bleeding episodes

- Low dose aspirin (=< 100 mg daily).

- Heparins and heparinoids Use of any other investigational drug

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Outcome Measure:

Recurrence-free survival, evaluated using the new international criteria proposed by the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Committee

Outcome Description:

Estimated using the Kaplan-Meier method. Compared between the drug verses placebo groups using the unstratified log rank test. Hazard rates, hazard rate ratios and median times to recurrence (or 25 percentiles if median time is not reached) and their corresponding 95% confidence bounds will be reported. A secondary analysis will also be presented stratified by macro versus non-macro status, the most important potential covariate.

Outcome Time Frame:

Defined as the time from randomization to the first documented disease recurrence by radiological assessment or death due to any cause whichever occurs first, assessed at 2 years

Safety Issue:


Principal Investigator

Ronald Busuttil

Investigator Role:

Principal Investigator

Investigator Affiliation:

Jonsson Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

July 2012

Completion Date:

Related Keywords:

  • Adult Primary Hepatocellular Carcinoma
  • Localized Resectable Adult Primary Liver Cancer
  • Localized Unresectable Adult Primary Liver Cancer
  • Recurrent Adult Primary Liver Cancer
  • Carcinoma
  • Liver Neoplasms
  • Carcinoma, Hepatocellular



Baylor College of Medicine Houston, Texas  77030
Johns Hopkins University Baltimore, Maryland  21205
Cleveland Clinic Foundation Cleveland, Ohio  44195
University of Nebraska Medical Center Omaha, Nebraska  68198-3330
Ochsner Clinic Foundation New Orleans, Louisiana  70121
University of Colorado Denver, Colorado  80217
University of Pittsburgh Pittsburgh, Pennsylvania  15261
Vanderbilt University Nashville, Tennessee  37232-6305
Northwestern University Chicago, Illinois  60611
Emory University Atlanta, Georgia  30322
Lombardi Comprehensive Cancer Center at Georgetown University Washington, District of Columbia  20057
New York University Langone Medical Center New York, New York  10016
The Methodist Hospital Research Institute Houston, Texas  77030
Lahey Clinic Medical Center Burlington, Massachusetts  01805
University of Michigan University Hospital Ann Arbor, Michigan  48109
Jonsson Comprehensive Cancer Center Los Angeles, California  90095
Mount Sinai Hospital Hartford, Connecticut  06112
University of Pennsylvania Health System Cherry Hill, New Jersey  08034
New York Presbyterian-The University Hospital of Columbia and Cornell New York, New York  10065
Integris-Baptist Medical Oklahoma City, Oklahoma  73112