Clinical trial NCT01258608 (phase 1/phase 2, status: completed)
Conditions: carcinoma, hepatocellular
ICD codes: C22.0, C4A.9, C7B.1, C4A.0, C4A.31, C4A.51, C4A.8
Drugs: mapatumumab, placebo, sorafenib
SMILES: CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C=CC=C2)C#N)C1=O, CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1
Eligibility criteria:

        Inclusion Criteria:

          -  Child-Pugh Class A.

          -  Barcelona Clinic Liver Cancer (BCLC) advanced stage (C) hepatocellular carcinoma, or
             BCLC intermediate stage (B) hepatocellular carcinoma if treatment with transarterial
             chemoembolization is not considered appropriate

          -  Measurable disease demonstrating intratumoral arterial enhancement by contrast
             enhanced computerized tomography (CT), with use of multislice scanners, or contrast
             enhanced dynamic magnetic resonance imaging (MRI), with at least 1 tumor lesion that
             meets the following criteria: located in the liver; can be accurately measured in at
             least 1 dimension; well delineated area of viable, hypervascular (contrast enhancement
             in the arterial phase) tumor that is >2 centimeter (cm) in the axial plane; suitable
             for repeat measurement; OR not previously treated with locoregional or systemic
             treatment unless the lesion shows a well-delineated area of viable (contrast
             enhancement in the arterial phase) tumor that is >2 cm in the axial plane. (If the
             lesion is poorly demarcated or exhibits atypical enhancement as a result of the
             previous intervention, then it cannot be selected as a target lesion)

          -  Radiologic eligibility (measurable disease) must be must be confirmed by the BICR
             prior to randomization.

          -  Adequate bone marrow, renal and liver function as defined in the protocol.

          -  Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale

          -  Age 18 years or older

          -  Have the ability to understand the requirements of the study, provide written informed
             consent (including consent for the use and disclosure of research-related health
             information), and comply with the study and follow-up procedures.

        Exclusion Criteria:

          -  Any co-morbid condition that in the judgment of the investigator renders the subject
             at high risk of treatment complications or reduces the possibility of assessing
             clinical effect.

          -  Received prior investigational or non-investigational cytotoxic chemotherapy, hormonal
             therapy, biological therapy (including but not limited to monoclonal antibodies, small
             molecules or other immunotherapy) to treat hepatocellular carcinoma.

          -  History of organ allograft.

          -  Previously received mapatumumab or sorafenib.

          -  Underwent resection, radiofrequency ablation, radiation or chemoembolization within 4
             weeks before enrollment or not recovered from such treatments.

          -  Need for concomitant anticancer therapy (surgery, radiation therapy, chemotherapy,
             immunotherapy, radiofrequency ablation) or other investigational agents during the
             study treatment period.

          -  Major surgery (i.e., the opening of a major body cavity, requiring the use of general
             anesthesia) within 4 weeks before enrollment; minor surgery (except for insertion of
             vascular access device) within 2 weeks before enrollment; or not yet recovered from
             the effects of the surgery.

          -  Systemic steroids within 1 week before enrollment except steroids used as part of an
             antiemetic regimen or maintenance-dose steroids for non-cancerous disease.

          -  Hepatic encephalopathy, per the investigator's evaluation.

          -  History of clinically significant gastrointestinal bleeding requiring procedural
             intervention (e.g., variceal banding, transjugular intrahepatic portosystemic shunt
             procedure, arterial embolization, topical coagulation therapy) within 4 weeks before
             enrollment.

          -  Gastrointestinal disease resulting in an inability to take oral medication or a
             requirement for intravenous hyperalimentation.

          -  History of any infection requiring hospitalization or intravenous antibiotics within 2
             weeks before enrollment.

          -  Known brain or spinal cord metastases unless adequately treated (surgery or
             radiotherapy) with no evidence of progression and neurologically stable off
             anticonvulsants and steroids.

          -  Known human immunodeficiency virus infection.

          -  Unstable angina, myocardial infarction, cerebrovascular accident, >= Class II
             congestive heart failure according to the New York Heart Association Classification
             for Congestive Heart Failure within 6 months before enrollment.

          -  Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
             digoxin.

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

          -  Using and unable to discontinue use of concomitant strong CYP3A4 inducers (e.g.,
             including but not limited to St. John's Wort, dexamethasone, phenytoin, carbamazepine,
             rifampin, rifabutin, phenobarbital)

          -  Pregnant female or nursing mother. All females with an intact uterus (unless
             amenorrheic for the 24 months before enrollment) must have a negative serum pregnancy
             test at screening. All non-sterile or non-postmenopausal females must practice a
             medically accepted method of contraception over the course of the study and for 60
             days after the last dose of study agent.

          -  Males who do not agree to use effective contraception during the study and for a
             period of 60 days following the final dose of study agent.

          -  Subject is currently enrolled in or has not yet completed at least 30 days since
             ending other investigational device or drug study(s) or subject is receiving other
             investigational agents.

          -  Acute or chronic severe renal insufficiency (glomoerular filtration rate <30
             milliliters [mL]/minute/1.73 square meters) or acute renal insufficiency of any
             severity due to the hepato-renal syndrome.

          -  Hepatitis B virus deoxyribonucleic acid (DNA) levels >2,000 international units/mL.