Sorafenib Tosylate in Treating Patients With Liver Cancer Who Have Undergone a Liver Transplant

PRIMARY OBJECTIVES:

I. Establish the safety and toxicity profile of sorafenib administered daily to hepatocellular carcinoma (HCC) patients who have undergone orthotopic liver transplantation.

SECONDARY OBJECTIVES:

I. Determine explant and allograft expression of vascular endothelial growth factor (VEGF), platelet derived growth factor receptor (PDGFR), microvessel density (CD34) and Ki67 (proliferation marker).

OUTLINE: Patients receive sorafenib tosylate orally (PO) twice daily on days 1-28. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, and then every 6 months for 3 years.

Inclusion criteria

• Patients with HCC on explant, who have not received prior systemic anti-cancer treatment for HCC
• HCC patients who have undergone orthotopic liver transplantation, are at high risk for tumor recurrence or who have high suspicion or documentation of tumor recurrence
• Patients who have a life expectancy of at least 12 weeks
• Patients must have one of the following disease states:

• Patients are 4 weeks beyond and less than 60 days from liver transplant surgery (to first study treatment) who have no residual hepatocellular carcinoma following liver transplantation;
• Patients with post transplant recurrent hepatocellular carcinoma within the liver or at an extra hepatic site, diagnosed by radiographic imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) consistent with hepatocellular carcinoma or proved by biopsy, within 24 months of transplantation;
• Post-transplant patients with rising alpha-feta protein level > 500ng/mL, even in the absence of confirmed disease within 24 months of transplant
• Patients must have one of the following explant histological features of HCC:bilobar tumor; macrovascular invasion; or multifocality; if patients have well-differentiated HCC, they must have all three features
• Patients who have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• Platelet count >= 60 x 10^9/L
• Hemoglobin >= 8.5 g/dL
• Total bilirubin =< 3 mg/dL
• Alanine transaminase (ALT) and aspartate transaminase (AST) =< 5 x upper limit of normal
• Amylase and lipase =< 1.5 x the upper limit of normal
• Serum creatinine =< 1.5 x the upper limit of normal
• Prothrombin time (PT)-international normalized ratio (INR) =< 2.3 or PT 6seconds above control
• Patients who give written informed consent

Exclusion criteria

• Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma,superficial bladder tumors (Ta, Tis & T1); any cancer curatively treated > 3 years prior to entry is permitted
• Renal failure requiring hemo- or peritoneal dialysis
• History of cardiac disease: congestive heart failure > New York Heart Association (NYHA) class 2; active coronary artery disease (CAD); cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers ordigoxin; or uncontrolled hypertension; myocardial infarction more than 6months prior to study entry is permitted
• Active clinically serious infections > grade 2 (National Cancer Institute -Common Terminology Criteria for Adverse Events version 3.0)
• Known history of human immunodeficiency virus (HIV) infection
• Known central nervous system tumors including metastatic brain disease
• Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
• Known or suspected allergy to the investigational agent or any agent given in association with this trial
• Patients unable to swallow oral medications
• Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study
• Pregnant or breast-feeding patients; women of childbearing potential must have a negative pregnancy test performed within seven days prior to the start of study drug; both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial
• Prior use of any systemic anti-cancer chemotherapy for HCC
• Prior use of systemic investigational agents for HCC
• Prior use of Raf-kinase inhibitors (RKI), VEGF inhibitors, MEK inhibitors or Farnesyl transferase inhibitors
• Use of biologic response modifiers, such as granulocyte colony-stimulating factor (G-CSF), 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 substituted for a required dose reduction)
• Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 1 month prior to the study 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 anti-coagulation therapy with warfarin