Study of Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma

Regorafenib BAY73-4506

Inclusion Criteria:

- Histological or cytological confirmation of HCC (hepatocellular carcinoma) or
non-invasive diagnosis of HCC as per American Association for the Study of Liver
Diseases criteria in patients with a confirmed diagnosis of cirrhosis

- Barcelona Clinic Liver Cancer stage Category B or C that cannot benefit from
treatments of established efficacy with higher priority such as resection, local
ablation, chemoembolization or systemic sorafenib.

- Failure to prior treatment with sorafenib (defined as documented radiological
progression according to the radiology charter). Randomization needs to be performed
within 10 weeks after the last treatment with sorafenib.

- Tolerability of prior treatment with sorafenib defined as not less than 20 days at a
minimum daily dose of 400 mg QD within the last 28 days prior to withdrawal.

- Liver function status Child-Pugh Class A. Child Pugh status should be calculated based
on clinical findings and laboratory results during the screening period.

Local or loco-regional therapy of intrahepatic tumor lesions (e.g. surgery, radiation
therapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation,
percutaneous ethanol injection, or cryoablation) must have been completed >/=4 weeks before
first dose of study medication. Note: patients who received sole intrahepatic intraarterial
chemotherapy, without lipiodol or embolizing agents are not eligible.

- Eastern Cooperative Oncology Group Performance Status of 0 or 1.

- Adequate bone marrow, liver and renal function as assessed by the following laboratory
tests conducted within 7 days before randomization.

- Glomerular filtration rate >/= 30 ml/min/1.73 m^2 according to the Modification of
diet in renal disease study equation.

- At least one uni-dimensional measurable lesion by computed tomography (CT) scan or
magnetic resonance imaging (MRI) according to RECIST (RECIST version 1.1), and
modified RECIST for HCC. Tumor lesions situated in a previously irradiated area, or in
an area subjected to other loco-regional therapy, may be considered measurable if
there has been demonstrated progression in the lesion.

- Life expectancy of at least 3 months.

- Women of childbearing potential and men must agree to use adequate contraception .

Exclusion Criteria :

- Sorafenib treatment within 2 weeks of randomization.

- Prior systemic treatment for HCC, except sorafenib.

- Permanent discontinuation of prior sorafenib therapy due to sorafenib related
toxicity.

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

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

- Uncontrolled ascites (defined as not easily controlled with diuretic or paracentesis
treatment).

- Ongoing infection > Grade 2 according to NCI-CTCAE (National Cancer Institute - Common
Terminology Criteria for Adverse Events) v. 4.0. Hepatitis B is allowed if no active
replication is present. Hepatitis C is allowed if no antiviral treatment is required.

- Clinically significant bleeding NCI-CTCAE version 4.0 Grade 3 or higher within 30 days
before randomization.

- Arterial or venous thrombotic or embolic events such as cerebrovascular accident
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism
within 6 months before the start of study medication.

- Patients unable to swallow oral medications.

- Interstitial lung disease with ongoing signs and symptoms at the time of screening.