Clinical trial NCT01624285: Sorafenib Tosylate Following a Liver Transplant in Treating Patients With Liver Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adult Primary Hepatocellular Carcinoma
Localized Resectable Adult Primary Liver Cancer
Localized Unresectable Adult Primary Liver Cancer
Recurrent Adult Primary Liver Cancer
Lead sponsor: Jonsson Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2012-06-20
Enrollment: 20
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine if sorafenib (sorafenib tosylate) is a safe and effective treatment option for preventing liver cancer in high risk patients following liver transplantation. Liver transplantation is a treatment option for liver cancer patients, but despite transplantation, the liver cancer can recur in the new, transplanted liver. It is not known whether sorafenib is effective in preventing cancer recurrence in high risk patients following liver transplantation

Detailed description: PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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.

Eligibility criteria: 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 explant
* 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 normal
* 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 (DCDT)
* 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 HCC-cholangiocarcinoma
* 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

Primary outcomes:
measure: Recurrence-free survival, evaluated using the new international criteria proposed by the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Committee
timeFrame: 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
Secondary outcomes:
measure: Overall survival
timeFrame: From randomization to the date of death or the last date the subject was known to be alive, assessed up to 2 years after completion of study treatment
measure: Recurrence-free survival, evaluated using the new international criteria proposed by the mRECIST Committee
timeFrame: 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 1 year
measure: Adverse events assessed in terms of seriousness, severity, and relationship to the study material according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
timeFrame: Assessed up to 2 years
measure: Impact of drug-drug interactions
timeFrame: Assessed up to 2 years after completion of study treatment
measure: Impact of biomarkers (AFP and PIVKA II)
timeFrame: Assessed up to 2 years after completion of study treatment
measure: Time to wound healing
timeFrame: Assessed up to 2 years after completion of study treatment
measure: Time to first HCV viral recurrence
timeFrame: Assessed up to 2 years after completion of study treatment
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Hartford
country: United States
facility: Mount Sinai Hospital
state: Connecticut
city: Washington
country: United States
facility: Lombardi Comprehensive Cancer Center at Georgetown University
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Burlington
country: United States
facility: Lahey Clinic Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan University Hospital
state: Michigan
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Cherry Hill
country: United States
facility: University of Pennsylvania Health System
state: New Jersey
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian-The University Hospital of Columbia and Cornell
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Oklahoma City
country: United States
facility: Integris-Baptist Medical
state: Oklahoma
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital Research Institute
state: Texas
Study officials:
affiliation: Jonsson Comprehensive Cancer Center
name: Ronald Busuttil
role: PRINCIPAL_INVESTIGATOR
References: