A Randomized, Double Blind, Placebo Controlled, Multicenter Phase III Study of Regorafenib in Patients With Hepatocellular Carcinoma (HCC) After Sorafenib
- 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, liver
transplantation, 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 8 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 (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
- 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 m2 according to the Modification of
diet in renal disease abbreviated formula.
- 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 .
- Sorafenib treatment within 2 weeks of randomization.
- Prior systemic treatment for HCC, except sorafenib.
- Permanent discontinuation of prior sorafenib therapy due to sorafenib related
- 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
- 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
- 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.