Phase I/II Comparison of Efficacy and Safety of BIBF 1120 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

• MTD for phase I [ Time Frame: Phase I (endpoint MTD): 4 weeks, Phase II (endpoints TTP, OS): minimum 4 weeks, maximum n/a ] [ Designated as safety issue: Yes ]
• TTP (Time to Progression) for phase II [ Time Frame: Phase I (endpoint MTD): 4 weeks, Phase II (endpoints TTP, OS): minimum 4 weeks, maximum n/a ] [ Designated as safety issue: No ]

• TTP (Time to Progression) for phase II [ Time Frame: Phase II (endpoints TTP, OS): minimum 4 weeks, maximum n/a ]
• MTD for phase I [ Time Frame: Phase I (endpoint MTD): 4 weeks ]

• Drug concentration measurements (PK) [ Time Frame: minimum 4 weeks, maximum n/a ] [ Designated as safety issue: No ]
• Response Rate by RECIST [ Time Frame: minimum 4 weeks, maximum n/a ] [ Designated as safety issue: No ]
• PFS (Progression Free Survival) [ Time Frame: minimum 4 weeks, maximum n/a ] [ Designated as safety issue: No ]
• OS (Overall Survival) [ Time Frame: minimum 4 weeks, maximum n/a ] [ Designated as safety issue: Yes ]
• Incidence and Intensity AE [ Time Frame: minimum 4 weeks, maximum n/a ] [ Designated as safety issue: Yes ]

• Drug concentration measurements (PK) [ Time Frame: minimum 4 weeks, maximum n/a ]
• Response Rate by Response Evaluation Criteria In Solid Tumors (RECIST) [ Time Frame: minimum 4 weeks, maximum n/a ]
• PFS (Progression Free Survival) [ Time Frame: minimum 4 weeks, maximum n/a ]
• OS (Overall Survival) [ Time Frame: minimum 4 weeks, maximum n/a ]
• Incidence and Intensivity adverse event (AE) [ Time Frame: minimum 4 weeks, maximum n/a ]

The study aim is to determine maximally tolerated dose (MTD) of BIBF 1220 in HCC (hepatocellular cancer) and compare efficacy of BIBF 1120 to Sorafenib in HCC patients

• Drug: Sorafenib
  Twice daily dosing
• Drug: BIBF 1120
  MTD defined in phase I, phase II vs. Sorafenib comparison

• Experimental: BIBF 1120
  Phase I dose escalation and phase II using dose determined in phase I ( 200 mg BID)
  Interventions:

  • Drug: Sorafenib
  • Drug: BIBF 1120
• Active Comparator: Sorafenib
  Twice daily dosing in phase II
  Interventions:

  • Drug: BIBF 1120
  • Drug: Sorafenib

Inclusion criteria:

• Histologically confirmed diagnosis of hepatocellular cancer (HCC) not amenable to local therapy
• Age 18 years or older
• Eastern Cooperative Oncology Group performance score of 2 or less
• at least one untreated measurable lesion according to Response Evaluation Criteria In Solid Tumors (RECIST); lesion previously treated by local therapy - radiofrequency ablation, percutaneous ethanol injection, radiotherapy, transarterial chemoembolization - must have documented progression according to Response Evaluation Criteria In Solid Tumors (RECIST) by computed tomography (CT) or magnetic resonance imaging (MRI) (this criterion is limited to phase II only and, patients with non-measurable tumors are allowed in phase I)
• Time interval from last local therapy (radiofrequency ablation, percutaneous ethanol injection, radiotherapy, transarterial chemoembolization) more than 4 weeks prior to registration
• Written informed consent consistent with International Conference on Harmonisation/ Good Clinical Practice (ICH-GCP) and local legislation

Exclusion criteria:

• Fibrolamellar hepatocellular cancer (HCC)
• Uncontrolled or refractory ascites
• Barcelona Clinic Liver Cancer (BCLC) stage D
• Hepatic encephalopathy grade II or higher
• Prothrombin time international normalized ratio greater than 2.3, or prothrombin time more than 6 seconds prolonged than control
• Absolute neutrophil count less than 1000 /mL
• Platelet count less than 60000 /mL
• Hemoglobin less than 9 g/dL
• Serum creatinine greater than 1.5 times Upper Limit of Normal (ULN)
• Proteinuria of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater
• Variceal bleeding within last 3 months prior to registration
• History of major thrombotic (except portal vein thrombosis) or clinically relevant major bleeding event in the past 6 months
• Known inherited predisposition to bleeding or thrombosis
• Significant cardiovascular diseases (i.e. hypertension not controlled by medical therapy, blood pressure > 150/90 mmHg), unstable angina, history of myocardial infarction within the past 6 months, congestive heart failure > class II according to New York Heart Association (NYHA), serious cardiac arrhythmia, pericardial effusion)
• Therapeutic anticoagulation (except low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy (except for chronic low-dose therapy with acetylsalicylic acid =< 325mg per day)
• Major surgery within 4 weeks prior to registration
• Treatment with other investigational drugs or participation in another clinical trial within the past four weeks before start of therapy or concomitantly with this trial (except for present trial drug)
• Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study
• Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial and for at least twelve months after end of active therapy
• Current alcohol abuse or drug abuse that would limit pt ability to comply with protocol
• Symptomatic central nervous system (CNS) metastasis
• Life expectancy less than 12 weeks
• Patient unable to take oral medication