A randomized, double blind, placebo-controlled, multicenter phase III study of regorafenib in patients with hepatocellular carcinoma (HCC) after sorafenib

• Signed informed consent (IC) obtained before any study specific procedure. Patients must be able to understand and willing to sign the written informed consent.
• Male or female patients >=18 years of age.
• Histological or cytological confirmation of HCC or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in patients with a confirmed diagnosis of cirrhosis.
• Barcelona Clinic Liver Cancer (BCLC) 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 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 intraaterial chemotherapy, without lipiodol or embolizing agents are not eligible.
• Eastern Cooperative Oncology Group (ECOG) 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:
o Hemoglobin > 8.5 g/dl
o Absolute neutrophil count (ANC) >= 1500/mm3
o Platelet count >= 60.000/mm3
o Total bilirubin <= 2 mg/dl. Mildly elevated total bilirubin (<6 mg/dL) is allowed if Gilbert*s syndrome is documented.
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 5 x upper limit of normal (ULN)
o Prothrombin time-international normalized ratio (PT-INR) < 2.3. x (ULN) and PTT < 1.5 (ULN). Patients who are therapeutically anticoagulated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in this parameter exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care.
o Serum creatinine <= 1.5 x ULN
o Amylase and lipase <= 2 x ULN
• Glomerular filtration rate (GFR) >= 30 ml/min/1.73 m2 according to the Modification of diet in renal disease (MDRD) study equation.
• At least one naïve (not previously treated by locoregional therapy such as surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation) 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.
• Life expectancy of at least 3 months.
• Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months for men and 12 months for woman after the last study drug administration. The investigator or a designated associate is requested to advise the subject how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.

• Prior liver transplantation or candidates for liver transplantation
• Prior treatment with regorafenib. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
• Prior and/or concomitant participation in a clinical study other than with sorafenib during or within 4 weeks of randomization.
• Sorafenib treatment within 2 weeks of randomization.
• Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention: beta blockers or endoscopic treatment. Assessment of esophageal varices should be performed by endoscopy within 6 months of study start, and within 12 months for patients in whom conventional medical intervention for known esophageal varices is already in place.
• Prior systemic treatment for HCC, except sorafenib.
• Permanent discontinuation of prior sorafenib therapy due to sorafenib related toxicity.
• Permanent discontinuation of prior sorafenib therapy due to any cause more than 8 weeks prior to randomization.
• Past or concurrent history of neoplasm other than HCC, except for in situ carcinoma of the cervix uteri and/or basal cell epithelioma. Any cancer curatively treated > 3 years prior to study entry is permitted.
• 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).
• Major surgical procedure or significant traumatic injury within 28 days before randomization.
• 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 before randomization.
• Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
• Uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
• Patients with phaeochromocytoma.
• Uncontrolled ascites (defined as not easily controlled with diuretic or paracentesis treatment).
• Pleural effusion or ascites that causes respiratory compromise (NCI-CTCAE version 4.0 Grade >=2 dyspnea).
• Persistent proteinuria of NCI-CTCAE version 4.0 Grade 3 or higher. Urine dipstick result of 3+ is allowed if protein excretion (estimated by urine protein/creatinine ratio on a random urine sample) is < 3.5 g/24 hours.
• Ongoing infection > Grade 2 according to NCI-CTCAE version 4.0. Hepatitis B and Hepatitis C are allowed if no active replication is present.
• 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.
• Unresolved toxicity higher than NCI-CTCAE version 4.0 Grade 1 (excluding alopecia or anemia) attributed to any prior therapy/procedure.
• Any illness or medical condition that is unstable or could jeopardize the safety of the patient and his/her compliance in the study.
• Known history of human immunodeficiency virus (HIV) infection.
• Seizure disorder requiring medication.
• History or organ allograft.
• Non-healing wound, ulcer, or bone fracture.
• Renal failure requiring hemo-or peritoneal dialysis.
• Substance abuse, medical, psychological or social conditions that may interfere with the patient*s participation in the study or evaluation of the study results.
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation.
• Patients unable to swallow oral medications.
• Interstitial lung disease with ongoing signs and symptoms at the time of screening.
• Any malabsorption condition.
• Breast feeding
• Pregnancy
• Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site that would have access to study records and electronic case report form (eCRF) data).