Open-label study to evaluate the safety and tolerability of Sorafenib dose ramp-up (starting at a lower dose and then gradually increasing the dose) versus standard Sorafenib dosing in subjects with unresectable and/or metastatic hepatocellular carcinoma.

This is an open-label study that investigates the impact of a dose ramp-up strategy for sorafenib in patients with HCC. Clinical trial and post-marketing data suggest that sorafenib dose reductions and discontinuations due to adverse events are common and limit the drug's effectiveness. It is our hypothesis that a dose escalation strategy for sorafenib will improve the tolerability and allow a greater percentage of patients to remain on drug. The primary end-point of the study is the total accumulated and median daily dose of sorafenib delivered at month 2 and 4.

Inclusion Criteria:

• HCC must be unresectable and/or metastatic

• CPT score <9 at the time of screening (that is all Child A and Child B with a score of 7 or 8)

• Age 20-75 years

• Signed informed consent

• EGD for variceal screening performed as per standard of care prophylaxis with non-selective beta-blockers or ligation

• ECOG Performance Status ≤ 2.

• Adequate bone marrow, liver and renal function as assessed by the following:

  1. Hemoglobin > 8.5 g/dl
  2. Absolute neutrophil count (ANC) > 1,500/mm3
  3. Platelet count > 50,000/mm3
  4. Total bilirubin < 3 mg/dl
  5. ALT and AST ( < 5 x ULN)
  6. Creatinine < 1.5 times ULN

• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment

• Women of childbearing potential and non-surgically sterile men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib.

• Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.

• INR< 2.3. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.

• Life expectancy of at least 24 weeks

Exclusion Criteria:

• Absence of informed consent

• Child-Pugh score >9

• ECOG PS >2

• Active alcohol dependence per PI discretion

• History of organ or bone marrow transplant

• Plans to relocate from the study center within the period of the trial

• Pregnancy or breastfeeding

• Contraindications to sorafenib

  1. Cardiac disease: Congestive heart failure > class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.
  2. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
  3. Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis.
  4. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.

• Known human immunodeficiency virus (HIV) infection

• Active clinically serious infection > CTCAE Grade 2.

• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.

• Bleeding

  1. Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug.
  2. Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug.
  3. Evidence or history of bleeding diathesis or coagulopathy

• Serious non-healing wound, ulcer, or bone fracture.

• Major surgery, open biopsy or significant traumatic injury within 4 weeks prior to first study drug.

• Use of St. John's Wort or rifampin (rifampicin).

• Known or suspected allergy to sorafenib or any agent given in the course of this trial.

• Any condition that impairs patient's ability to swallow whole pills.

• Any malabsorption problem.

Adverse events were collected during 6 months of treatment. First subject randomized 8/29/2011 and last subject completed 6 months of treatment on 3/10/14.