Refametinib in Combination With Sorafenib in RAS Mutant Hepatocellular Carcinoma (HCC)

Inclusion Criteria:

Eligibility criteria for RAS mutation testing

- Unresectable or metastatic HCC, confirmed either by histology or clinically according
to the American Association for the Study of Liver Disease (AASLD) criteria for
cirrhotic patients. For non-cirrhotic patients, histological confirmation is
mandatory.

- Male or female ≥18 years of age.

- Eastern Cooperative Oncology Group (ECOG) performance state 0 or 1.

- Life expectancy of at least 12 weeks.

- No prior use of targeted agents, experimental therapy or systemic anti-cancer
treatment.

- No previous treatment with sorafenib or refametinib. Criteria for study treatment
eligibility

- Patient must harbor GTPase Kirsten rat sarcoma viral oncogene homolog (KRAS) or
Neuroblastoma RAS viral oncogene homolog (NRAS) mutation based on Beads, emulsions,
amplification, and magnetic technology, sensitive mutation detection (BEAMing) plasma
test.

- Patients must have at least one uni-dimensional measurable lesion by Computed
tomography (CT) or Magnetic resonance (MR) according to Response Evaluation Criteria
in Solid Tumors (RECIST) 1.1 and Modified Response Evaluation Criteria in Solid
Tumors (mRECIST) which is either naïve (not previously treated by local therapy such
as surgery, radiation therapy, hepatic arterial therapy, chemoembolization,
radiofrequency ablation, percutaneous ethanol injection or cryoablation) or
previously treated and has progressed until baseline (both measureable lesion and/or
progressed lesion have to be confirmed by central image review of baseline and
progression scan).

- ECOG performance status of 0 or 1.

- Liver function status of Child-Pugh Class A.

- Adequate bone morrow, liver, and renal function

- Patient has within normal range cardiac function confirmed by the enrolling clinical
institute as measured by echocardiogram or multiple gated acquisition (MUGA) scan.

- Patients who are therapeutically anti-coagulated with an agent such as warfarin or
heparin are allowed to participate provided that no prior evidence of underlying
abnormality in these parameters exists. Close monitoring of at least weekly
evaluations will be performed until International normalized ratio (INR) is stable
(within Child Pugh class A threshold) based on a measurement at pre-dose, as defined
by the local standard of care.

Exclusion Criteria:

- Any Cancer curatively treated < 3 years prior to study entry, except cervical
carcinoma in situ (CIS), treated basal cell carcinoma, and superficial bladder tumors
[Staging: noninvasive papillary tumor (Ta), CIS carcinoma (Tis) and tumor invades
lamina propria (T1)].

- Patients who are eligible for surgery, liver transplantation, ablation or
transarterial chemoembolization for HCC.

History of cardiac disease:

- Congestive heart failure New York Heart Association (NYHA) > class 2.

- Unstable angina (angina symptoms at rest, new-onset angina i.e. within the last 3
months) or myocardial infarction (MI) within the past 6 months prior to start of
screening.

- Cardiac arrhythmias requiring anti-arrhythmic therapy.

- QTc (corrected QT interval) > 480 ms

- Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic blood
pressure >90 mmHg despite optimal medical management).

- Ongoing infection > Grade 2 according to National Cancer Institute - Common Toxicity
Criteria for Adverse Events version 4.03 (NCI-CTCAE version 4.03) Hepatitis B is
allowed if no active replication (defined as abnormal Alanine aminotransferase [ALT]
>2x Upper limit normal [ULN] associated with Hepatitis B virus [HBV] DNA >20,000
IU/mL) is present. Hepatitis C is allowed if no antiviral treatment is required.

- Known history of, or symptomatic metastatic brain or meningeal tumors (head CT or MR
at Screening to confirm the absence of central nervous system [CNS] disease if
patient had symptoms suggestive or consistent with CNS disease).

- History of interstitial lung disease (ILD).

- History of hepatic encephalopathy.

- History of organ allograft, cornea transplantation will be allowed.

- History or current evidence of retinal vein occlusion (RVO) or central serous
retinopathy (CSR).

- Visible retinal pathology as assessed by ophthalmologic exam that is considered a
risk factor for RVO or CSR.