Sorafenib Dose Ramp-Up in Hepatocellular Carcinoma (HCC)
Condition: Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Sorafenib Standard Dosing Regimen; Sorafenib Ramp-Up Regimen
Intervention description: Sorafenib 400 mg twice daily until wk 24 or end of treatment; 200 mg daily, Day 0-Day 13 200 mg twice daily, Day 14-Day 20 600 mg daily, Day 21-Day 27 400 mg twice daily, Day 28 until end of treatment400 mg twice daily
Intervention MeSH terms: Sorafenib
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 120.0
Sex: All
Minimum age: 20 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Hepatocellular Carcinoma; HCC; Liver Cancer

Summary:

      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.
    

Eligibility criteria:

        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.