A Study of the Effectiveness and Safety of AMG 386 and Sorafenib to Treat Advanced or Inoperable Hepatocellular Cancer

• Incidence of adverse events and significant laboratory abnormalities [ Time Frame: Adverse events at every visit, significant laboratory abnormalities at least every 4 weeks ] [ Designated as safety issue: Yes ]
• Objective response rate, Disease control rate, Progression free survival, Overall survival, Time to progression [ Time Frame: Radiologic imaging every 8 weeks ] [ Designated as safety issue: No ]
• Pharmacokinetic parameters for AMG 386 when used in combination with Sorafenib [ Time Frame: Weeks 1, 2, 5, 9, and every 16 weeks thereafter ] [ Designated as safety issue: No ]
• Pharmacokinetic parameter for Sorafenib when used in combination with AMG 386 [ Time Frame: Weeks 2, 5, 9, and every 16 weeks thereafter ] [ Designated as safety issue: No ]
• Incidence of the occurrence of anti-AMG 386 antibody formation [ Time Frame: Weeks 1, 5, 9, and every 16 weeks thereafter ] [ Designated as safety issue: No ]
• Baseline values of and changes from baseline in pharmacodynamic, immunologic, biochemical, transcriptional, pharmacogenetic and angiogenic markers [ Time Frame: Weeks 1, 2, 5, and every 16 weeks thereafter ] [ Designated as safety issue: No ]

• Incidence of adverse events and significant laboratory abnormalities [ Time Frame: 48 months after date of last subject enrolled ] [ Designated as safety issue: Yes ]
• Objective response rate, Disease control rate, Progression free survival, Overall survival, Time to progression [ Time Frame: 48 months after date of last subject enrolled ] [ Designated as safety issue: No ]
• Pharmacokinetic parameters for AMG 386 when used in combination with Sorafenib [ Time Frame: 48 months after date of last subject enrolled ] [ Designated as safety issue: No ]
• Pharmacokinetic parameter for Sorafenib when used in combination with AMG 386 [ Time Frame: 48 months after date of last subject enrolled ] [ Designated as safety issue: No ]
• Incidence of the occurrence of anti-AMG 386 antibody formation [ Time Frame: 48 months after date of last subject enrolled ] [ Designated as safety issue: No ]
• Baseline values of and changes from baseline in pharmacodynamic, immunologic, biochemical, transcriptional, pharmacogenetic and angiogenic markers [ Time Frame: 48 months after date of last subject enrolled ] [ Designated as safety issue: No ]

The purpose of this study is to determine whether AMG 386, in combination with Sorafenib, is effective in the treatment of advanced or inoperable Hepatocellular cancer in subjects who have not received any prior systemic therapy except surgery or locoregional therapy.

Disease status and disease progression will be assessed every 8 weeks. Subjects will remain on treatment until: progressive disease by RECIST criteria; clinical progression; death or loss to follow-up; or withdrawal of informed consent.

• Drug: Sorafenib
  AMG 386 is the investigational product administered in this study. Sorafenib will be administered 400mg orally twice daily and indicated for the treatment of advanced or inoperable Hepatocellular Carcinoma. Sorafenib will be administered to all subjects until disease progression, clinical progression, withdrawal of informed consent, unacceptable toxicity or death, whichever comes first.
• Drug: AMG 386
  AMG 386 will be administered 10mg/kg intravenously once weekly until disease progression, clinical progression, withdrawal of informed consent, unacceptable toxicity or death, whichever comes first.
  Other Name: AMG 386 will be administered 15mg/kg intravenously once weekly until disease progression, clinical progression, withdrawal of informed consent, unacceptable tox

• Experimental: 15mg/ kg cohort
  AMG 386 15mg/kg intravenously once weekly and Sorafenib 400mg orally twice daily in an every 4 weeks dosing schedule.
  Interventions:

  • Drug: Sorafenib
  • Drug: AMG 386
• Experimental: 10 mg/kg cohort
  AMG 386 10mg/kg intravenously once weekly and Sorafenib 400mg orally twice daily in an every 4 weeks dosing schedule.
  Interventions:

  • Drug: Sorafenib
  • Drug: AMG 386

Inclusion Criteria:

• Subjects must have histologically confirmed advanced or inoperable HCC
• Child-Pugh liver function class A
• Measurable disease with at least one unidimensionally measurable lesion per RECIST 1.0 guidelines with modifications
• Adequate organ and hematological function
• Men or women greater than or equal to 18 years old
• Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
• Able to tolerate infusions and self-administer oral medications

Exclusion Criteria:

• Any previous systemic chemotherapy for HCC (chemotherapy or targeted therapies)
• Previous surgical resections are allowed if ≥ 30 days elapsed prior to enrollment
• Locoregional therapies (e.g. TACE) are allowed if ≥ 30 days elapsed prior to enrollment provided that subjects either have a target lesion which has not been subjected to local therapy and/or the target lesions(s) within the field of the local therapy has shown an increase of ≥ 20% in size
• History of arterial or venous thromboembolism within 12 months prior to enrollment
• History of clinically significant bleeding within 6 months prior to enrollment including pulmonary hemorrhage, gastroesophageal varices or gross hemoptysis (greater than or equal to ½ teaspoon or 2.5 mL of bright red blood)
• Anticoagulation therapy must be stopped 1 week prior to enrollment except:
• aspirin and anti-platelet agents
• low dose warfarin (i.e. ≤ 1mg daily)
• Concomitant anti-viral therapy is allowed with the exception of interferon alfa or pegylated interferon alfa therapy
• Known ongoing pancreatitis
• Known history of central nervous system metastases
• Clinically significant cardiovascular disease within 12 months prior to enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent
• Uncontrolled hypertension as defined as diastolic > 90 mmHg OR systolic > 150 mmHg. The use of anti-hypertensive medications to control hypertension is permitted
• Exclude subjects with a history of prior malignancy, except:
• Malignancy treated with curative intent and with no known active disease present for greater than or equal to 3 years before enrollment and felt to be at low risk for recurrence by treating physician
• Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease
• Adequately treated cervical carcinoma in situ without evidence of disease
• Prostatic intraepithelial neoplasia without evidence of prostate cancer
• Other primary solid tumor with no known active disease present that in the opinion of the investigator will not affect patient outcome in the setting of current hepatocellular carcinoma diagnosis
• Non-healing wound, ulcer (including gastrointestinal) or fracture