A Research Study to Treat Patients With Advanced Hepatocellular Carcinoma

• Overall Survival [ Time Frame: from date of randomization of the first patient until 3 years later ] [ Designated as safety issue: No ]
  The time from date of randomization to date of death
• Progression Free Survival (PFS) [ Time Frame: from date of randomization of the first patient until 3 years later ] [ Designated as safety issue: No ]
  Time from the date of randomization to the date of the first documented radiological progression (as defined per independent central radiological assessment) or death, whichever occurs first
• Percentage of Participants in Each Category of Best Tumor Response [ Time Frame: achieved during treatment or within 30 days after termination of active therapy ] [ Designated as safety issue: No ]
  Percentage of participants with complete or partial response (CR or PR) confirmed according to Response Evaluation Criteria in Solid Tumors (RECIST) and achieved during treatment or 30 days after end of treatment. CR: disappearance of all clinical and radiological tumor lesions. PR: at least 30% decrease in sum of the longest diameters of tumor lesions. Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease.
• Time to Symptomatic Progression (TTSP) [ Time Frame: from date of randomization of the first patient until 3 years later ] [ Designated as safety issue: No ]
  Time from date of randomization to date of first documented symptomatic progression defined by Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index-8 (FHSI-8) assessment
• Duration of Response [ Time Frame: from date of randomization of the first patient until 3 years later ] [ Designated as safety issue: No ]
  Time from date of first objective response (complete response [CR] or partial response [PR]) to date progression is first documented (as defined per independent central radiological assessment) or death, whichever occurs first
• Time to Response (TTR) [ Time Frame: from date of randomization until 3 years later at end of study ] [ Designated as safety issue: No ]
  Time from date of randomization to date of first objective response (complete response [CR] or partial response [PR]) is documented and confirmed according to RECIST criteria
• Percentage of Participants for Whom Disease Control Was Achieved [ Time Frame: from date of randomization to end of treatment plus 30 days ] [ Designated as safety issue: No ]
  Participants with disease control: those who have as best response complete response (CR), partial response (PR) or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease) according to Response Evaluation Criteria in Solid Tumors (RECIST)

The purpose of this study is to evaluate the safety and efficacy of doxorubicin plus sorafenib versus doxorubicin plus placebo in patients with advanced hepatocellular carcinoma (HCC).

In addition to the key secondary outcome parameters the following parameters will be assessed in an exploratory manner: relative time to progression (TTP), time to symptomatic progression (TTSP), response rate (RR) and overall survival between the 2 study populations.

The possible and potential predictive assays of clinical benefit through an assessment of the correlation between the defined baseline characteristics and key clinical endpoints.

The safety and tolerability will be assessed in the adverse event section. Doxorubicin pharmacokinetics in HCC patients treated with sorafenib versus placebo will be compared and the pharmacokinetic data will be correlated with doxorubicin-related adverse events (i.e., cardiotoxicity).

• Drug: Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
  Multi kinase inhibitor plus Chemotherapy
• Drug: Doxorubicin/Placebo
  Chemotherapy plus Placebo

• Experimental: Sorafenib + Doxorubicin
  "Sorafenib + Doxorubicin" -- combination therapy: Sorafenib (Nexavar, BAY43-9006) 200 mg tablets by mouth (orally) twice daily + doxorubicin 60 mg/m2 intravenous infusion every 21 days for 6 cycles (18 weeks)
  Intervention: Drug: Sorafenib (Nexavar, BAY43-9006) plus Doxorubicin
• Active Comparator: Placebo + Doxorubicin
  "Placebo + Doxorubicin" -- monotherapy: Sorafenib (Nexavar, BAY43-9006) matching placebo tablets by mouth (orally) twice daily + doxorubicin 60 mg/m2 intravenous infusion every 21 days for 6 cycles (18 weeks)
  Intervention: Drug: Doxorubicin/Placebo

• Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006 Sep 10;24(26):4293-300. Epub 2006 Aug 14.
• Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010 Nov 17;304(19):2154-60. doi: 10.1001/jama.2010.1672.

Inclusion Criteria:

• Patients who have a life expectancy of at least 12 weeks
• Patients with advanced HCC (unresectable, and/or metastatic) which has been histologically or cytologically documented

• Patients must have at least one tumor lesion that meets both of the following criteria:

  • can be accurately measured in at least one dimension according to Response Evaluation Criteria in Solid Tumors (RECIST)
  • has not been previously treated with local therapy
• Patients who have received local therapy except chemoembolization, such as surgery, radiation therapy, hepatic arterial embolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible, provided that they either have a target lesion which has not been subjected to local therapy and/or the target lesion(s) within the field of the local therapy has shown an increase of 25% in the size. Local therapy must be completed at least 4 weeks prior to the baseline scan
• Patients who have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

• Previous or concurrent cancer that is distinct in primary site or histology from HCC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, and superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated > 3 years prior to entry is permitted
• History of cardiac disease
• Serious myocardial dysfunction
• Active, clinically serious infections
• Known history of Human Immunodeficiency Virus (HIV) infection
• Known Central Nervous System (CNS) tumors including metastatic brain disease
• Patients with clinically significant gastrointestinal bleeding within 30 days prior to study entry