Study of Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma
Condition: Carcinoma, Hepatocellular
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Regorafenib (Stivarga, BAY73-4506); Placebo
Intervention description: Regorafenib, 40 mg tablets; Placebo tablets matching in appearance
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 573.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Regorafenib; BAY73-4506

Summary:

      The objective of this study was to evaluate efficacy and safety of regorafenib in patients
      with advanced liver cancer who had progressed after sorafenib treatment. Patients were
      treated with regorafenib or placebo using a 2:1 randomization scheme.
    

Eligibility criteria:

        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.