Study of TAC-101 as Second Line Treatment in Patients With Advanced Hepatocellular Carcinoma Who Received Sorafenib as First Line Therapy

The purpose of this study is to determine whether TAC-101 as a second line therapy for participants who received Sorafenib as first line therapy is effective in slowing tumor activity in patients with advanced hepatocellular carcinoma. The study is also looking at the safety of TAC-101 following treatment with Sorafenib.

Advanced metastatic hepatocellular carcinoma (HCC) is not treatable by surgical approaches or locoregional therapies such as hepatic artery hemoembolization or radiofrequency ablation (RFA) which are effective in controlling localized tumors. Currently marketed systemic chemotherapy agents, with the exception of sorafenib, provide marginal benefit. Despite the demonstrated survival benefit from sorafenib, it is still imperative to improve to the effectiveness of systemic therapy in this patient population. Studies of TAC-101, a synthetic retinoid, indicate that although TAC-101 may not induce tumor regression, it appears to have a stabilizing effect, prolonging survival over what was expected historically. This Phase 2, randomized, double-blind, placebo-controlled international, multicenter study is designed to evaluate the efficacy and safety of TAC 101 as second line treatment in patients with advanced HCC following treatment with sorafenib as first-line therapy. Sorafenib has recently been approved as first line treatment for HCC in the EU and the US and is expected to become the standard of care for the first-line treatment of advanced HCC. Aside from best supportive care, there is no second line therapy available for HCC. It is hypothesized that TAC 101 treatment can extend Overall Survival (OS) after discontinuation of sorafenib.

Eligibility Criteria:
Inclusion Criteria:

* Provide written informed consent prior to performance of any study procedures.
* Is at least 18 years of age.
* Have a diagnosis of advanced unresectable histologically confirmed HCC (excluding fibrolamellar carcinoma).
* Have discontinued from first line treatment with sorafenib monotherapy for any reason (ie, tumor disease progression, intolerance) at least 14 days prior to planned randomization but have not received any second line treatment for HCC.
* Have recovered from any significant sorafenib-related treatment toxicities prior to randomization (Grade 1).
* Have at least 1 target lesion that is viable (has vascularization) and can be accurately measured according to RECIST.
* Patients who have received local therapy prior to sorafenib administration (radiation, surgery, hepatic arterial embolization, chemoembolization, RFA, percutaneous ethanol injection \[PEI\] or cryoablation) are eligible. Local therapy must be completed at least 4 weeks prior to the baseline scan.
* Have ECOG score of 0, 1, or 2.
* Child-Pugh score \<8.
* Have adequate organ function defined as:

  * Platelet count great than 50, less than 109/L;
  * Hemoglobin 8.0 g/dL;
  * Total bilirubin 3 mg/dL;
  * Alanine transaminase (ALT) and aspartate aminotransferase (AST) less than or equal to 5 X ULN;
  * Serum creatinine 1.5 X ULN;
  * PT-international normalized ratio (INR) 2.3 or PT 6 seconds above control
  * Total white blood cell (WBC) count 2.0 109/L
* Is able to take medications orally (eg, no feeding tube).
* Women of childbearing potential must have a negative pregnancy test (urine or serum) prior to randomization and within 2 days prior to starting the study drug. Females must agree to adequate non-estrogenic birth control if conception is possible during the study; and males must agree to adequate birth control during the study and up to 6 months after the discontinuation of study medication.

Exclusion Criteria:

* History of DVT, PE, myocardial infarction (MI), CVA, transitory ischemic attack (TIA), or any other significant TE during the last 3 years.
* Have clinically significant symptoms of hepatic encephalopathy or known brain metastasis.
* Patients who have had clinically significant acute gastrointestinal bleeding as a result of portal vein hypertension within 4 weeks prior to randomization are excluded; however, patients with a history of acute gastrointestinal bleeding that have received appropriate treatment, ie, ligation of varices, are eligible.
* Are receiving therapeutic regimens of anticoagulants, with the exception of prophylaxis care of indwelling venous access devices.
* Have received a liver transplant.
* Are taking prohibited medication.
* Have received a previous systemic therapy (including investigational agents) other than sorafenib (see Inclusion Criterion 4) for treatment of HCC. Patients participating in surveys or observational studies are eligible to participate in this study.
* Have had treatment with any of the following within the specified timeframe prior to randomization:

  * Any sorafenib within the 14 days prior to randomization.
  * Major surgery within the 4 weeks prior to randomization.
  * Any transfusion, treatment with blood component preparation, received. erythropoietin , albumin preparation, and granulocyte colony-stimulating factor (G CSF) within the 2 weeks prior to randomization.
* Has a serious illness or medical condition(s) including, but not limited to the following:

  * Known gastrointestinal disorder, including malabsorption, chronic nausea, vomiting, or diarrhea present to the extent that it might interfere with oral intake and absorption of the study medication.
  * Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
  * Previous or concurrent malignancy except for basal cell carcinoma and/or in situ carcinoma of the cervix, or other solid tumor treated curatively and without evidence of recurrence for at least 3 years prior to the study.
  * Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induce a high medical risk and/or make assessment of survival uncertain.
  * Has active or uncontrolled clinically serious infection excluding chronic hepatitis.
  * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study (eg, active urinary tract infection).
  * Known allergy or hypersensitivity of TAC 101 and any other components used in the TAC 101 tablet.