To Evaluate Safety and Efficacy of FB-1603 in Hepatocellular Carcinoma Patient Receiving Transarterial Chemoembolization

I. Objectives:

• Primary objective: To assess the efficacy of FB-1603 on improving liver function impairment after transarterial chemoembolization (TACE) in subjects
• Secondary objective:

• To evaluate the safety of FB-1603 in subjects
• To evaluate selected parameters indicative of clinical efficacy
• To assess postembolization syndrome improvement of FB-1603 compared with placebo
• To evaluate virologic test level of FB-1603 compared with placebo
• To assess liver stiffness change of FB-1603 compared with placebo
• Exploratory objective:

• To assess the antioxidation activity of FB-1603 in hepatocellular carcinoma (HCC) subjects after TACE

II. Investigational product:

• Name: FB-1603 oral capsule (FB-1603)
• Dosage form: 165 mg oral capsule
• Dose(s): Each arm consisted of 40 subjects.

• Arm 1: 4*Placebo each time, TID (three times a Day), two weeks before and eight weeks after TACE
• Arm 2: 2*FB-1603 165 mg oral capsule and 2*Placebo each time, TID (990 mg/day), two weeks before and eight weeks after TACE
• Arm 3: 4*FB-1603 165 mg oral capsule each time, TID (1980 mg/day), two weeks before and eight weeks after TACE
• Dosing schedule:

All enrolled subjects will be randomly assigned (1:1:1) to receive low dose (990 mg/day), high dose (1980 mg/day) of FB-1603 165 mg oral capsule or placebo capsule three times a day for 10 weeks. Each subject starts receiving FB-1603 165 mg oral capsule or placebo capsule on two weeks before and eight weeks after TACE. The investigational drugs should be taken orally about 10 minutes before the breakfast, lunch, and dinner

• Mechanism of action:

The proposed mechanism is that FB-1603 can improve liver function via decrease of oxidative stress. In previous study conducted in diethylnitrosamine (DEN) induced liver cirrhosis and cancer rat model (Report #: FENTU30SEP2009) shown that the extent of oxidative stress determined by NBT (Nitro blue tetrazolium) staining was significant decreased in treatment group orally administrated with 0.8, 1 or 2 g/kg/day of FB-1603 compared with the control group.

III. Developmental phase: phase I and II

IV. Study design:

• placebo control study
• Blinding: double blind
• Randomized: yes
• Parallel
• Duration of treatment: days 10 weeks months years
• Titration: forced
• Single center

VI. Study procedures:

This is a randomized, double-blind, 10-week dose-finding study in 3 parallel arms.

The study is conducted as follows: eligible subjects are randomized parallelly into 3 arms. Each arm comprises 40 subjects orally receive active (FB-1603 165 mg oral capsule) or placebo (placebo capsule) two weeks before and eight weeks after TACE. Each subject will begin receiving FB-1603 oral capsule or placebo two weeks before TACE. As the appearance of the placebo capsule is identical to the FB-1603 165 mg oral capsule, study blinding will be maintained during the administration procedure. Other than staff involved in randomization, the sponsor, participants, and staff involved in the preparation of the study drug are blinded. Each subject is assigned to either active (FB-1603 165 mg oral capsule) or placebo treatment using a block randomization algorithm. Three times a day (TID) doses of FB-1603 165 mg oral capsule are escalated capsule low dose (990 mg/day) and high dose (1980 mg/day).

Inclusion criteria

• Aged 18-85 years (inclusive) of either gender
• Willing and able to provide signed informed consent
• Confirmed diagnosis of hepatocellular carcinoma by radiology, histology, or cytology
• Subject has the willingness to undergo TACE
• ECOG performance Status of 0-1
• The patient is expected to survive more than 3 months
• Laboratory values should meet all the following standards at the screening visit:

A. AST, ALP and ALT are ≤ 5x ULN. B. International Normalized Ratio (INR) ≤ 1.5 C. Prothrombin time < 4 sec above upper limit of normal D. Absolute neutrophil count ≥ 1.5×10^9/L; Hemoglobin ≥ 9 g/dL; platelet ≥ 50×10^9/L.

E. Total bilirubin < 2.5 mg/dL F. Serum creatinine < 2 mg/dL

• With liver stiffness measurement >7 kPa (assessed by FibroScan®) or > 1.5 m/sec (assessed by acoustic radiation force impulse elastography (ARFI))

Exclusion criteria

• Patients with evidence of macrovascular invasion
• Patients with evidence of extrahepatic spread
• Any condition representing a contraindication to TACE as determined by the investigators
• Acute liver failure or liver function decompensation patient perform, such as hepatic encephalopathy, and ascites
• Patients with acute or chronic active hepatitis B or C infection and are recommended to receive HBV or HCV treatment, e.g., Patient with HBV DNA ≥ 20,000 IU/ml or with detectable HCV RNA
• Patients who have severe organic diseases on heart, lungs, brain, kidney, and gastrointestinal tract by the judgment of investigators
• Patients with chronic pancreatitis
• Patients who are taking any prohibited drugs that might interfere the trial
• Patients who are not able to express the chief complaint, for example, the patients with psychosis and severe neurosis
• Patients with active infections (infection requiring the use systemic antibiotics) within 4 weeks prior to the screening visit