Efficacy and Safety of Concurrent TACE and Sorafenib in Patients With HCC and Extrahepatic Metastasis (COTSOM Study)

A Phase II, Prospective, Open-label, Single Arm Study of the Efficacy and Safety of Concurrent Conventional TACE and Sorafenib in Patients With Hepatocellular Carcinoma and Extrahepatic Metastasis (COTSOM Study)

This study is a phase II, prospective, open-label, single arm, single center study of the efficacy and safety of concurrent conventional transarterial chemoembolization (TACE) and sorafenib in patients with hepatocellular carcinoma and extrahepatic metastasis. All of the 55 patients with hepatocellular carcinoma and newly diagnosed extrahepatic (lung, bone, lymph node, adrenal gland) metastasis will be included.

On demand conventional TACE will be performed in all the patients after enrollment and can be continued until intrahepatic CR, TACE failure or consent withdrawal. Sorafenib will be started 3-7 days after the first and each subsequent TACE and stopped one day before next TACE and will be continued until sorafenib failure, consent withdrawal or condition worsening by clinical decision. Repeated on-demand TACE and sorafenib should continue until the criteria for treatment discontinuation are met. After initiation of sorafenib combination treatment, patients will be seen and will perform routine examination at week 4 and, after then routine examination will be followed every 6 ± 2 weeks.

This is a single center, single arm, prospective, phase II study in patients with metastatic HCC. A total of 55 patients with HCC and newly diagnosed extrahepatic (lung, bone, lymph node, adrenal gland) metastasis will be enrolled.

On demand conventional TACE will be performed in all the patients after enrollment and can be continued until intrahepatic CR, TACE failure or consent withdrawal. Safety will be evaluated every 6 ± 2 weeks after initial TACE and closed monitoring at unscheduled visit will be done as well. The efficacy of TACE will be evaluated every 6 ± 2 weeks after each session of TACE using dynamic CT or MRI. Performance of repeated TACE will be decided based on the findings of follow-up CT, patients' liver function and performance status, within 6 ± 2 weeks of the previous TACE. Patients with no residual viable tumors after previous TACE who are not indicated for further TACE are evaluated with routine examination and imaging studies every 6 ± 2 weeks. Safety should be evaluated on an ongoing basis and within 3 days of next TACE. All eligible patients will be given sorafenib (initially 400mg po bid) on day 3-7 after the first or every session of TACE, and sorafenib will be stopped one day before each TACE. Sorafenib will be continued until sorafenib failure, consent withdrawal or condition worsening by clinical decision. Treatment failure will be judged by the evaluation of intra- or extrahepatic lesion separately. TACE failure is defined as when TACE/transarterial chemo-lipiodolization (TACL) has no more benefit by clinical assessment which is judged clinically by one investigator and/or the patient is not more eligible because of worsening of ECOG PS or liver function. Detailed criteria for stopping TACE will be clarified in below. Sorafenib failure will be evaluated by modified RECIST applied to the extrahepatic lesion, and sorafenib will be stopped when progressive disease (PD) by mRECIST for extrahepatic lesion is indicated and clinical benefit of TACE is not expected for intrahepatic lesion. As long as TACE is evaluated to be beneficial and planned to be performed by investigator, sorafenib could be continued if side effect is tolerable.

When any of the treatment discontinuation criteria is met, test treatment will be stopped. Survival and post-treatment information will be collected at 1-3 months intervals after the last study visit until the endpoint of death, or until the subject has become lost to follow-up or until study termination by Principal Investigator. Additional palliative anti-cancer therapies such as cytotoxic chemotherapy and TACL without gelfoam embolization and palliative radiation therapy will be allowed and recorded.

Inclusion Criteria:

• Patients with HCC and newly diagnosed extrahepatic metastasis meeting of following criteria

  1. Clinical or histological diagnosis of HCC based on the guidelines: Early enhancement followed by late wash-out on dynamic liver imaging (CT or MRI) Or Pathological examination of liver biopsy
  2. Evidence of extrahepatic metastasis with any of following methods; CT, MRI, bone scan, positron emission tomography with FDG-PET, biopsy of metastatic lesion
  3. Preserved liver function classified as Child-Pugh A
  4. ECOG PS of 0-1
  5. Age of at least 20 years
  6. Patients is able to comply with scheduled visits, evaluation plan, and other study procedures
  7. Patient is willing to provide written informed consent
  8. There is no limitation of prior TACE session number in case that further TACE is still considered to be beneficial
  9. Women of childbearing potential must have a negative pregnancy test performed within 14 days of the start of treatment. All patients of child-bearing potential must use adequate birth control measures during the course of the trial (barrier method of birth control) and up to at least 30 days of last dose.

Exclusion Criteria:

• Presence of any of following criteria

  1. Patients who are diagnosed as not eligible for further TACE before screening

  2. Patients with advanced liver disease as defined below:

     • Child Pugh B and C
     • Encephalopathy
     • Ascites

  3. Complete occlusion of main portal vein (PV) by HCC

  4. Patients with brain metastasis

  5. Inadequate liver function that could not perform TACE:

     • AST > 5 X ULN(upper limit normal) or ALT > 5 X ULN
     • Total bilirubin > 2.0 mg/dL
     • Prothrombin time INR > 1.7

  6. Inadequate bone marrow function (absolute neutrophil count < 1,500/μL, Hemoglobin (Hgb) < 8 g/dL, platelet count < 50,000/μL)

  7. Inadequate renal function (creatinine > 1.5 x ULN)

  8. Treatment with previous local therapy such as resection of HCC, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) < 4 weeks prior to the screening

  9. Prior sorafenib use

  10. Investigational drugs or other molecular target drugs ongoing or completed < 4 weeks prior to the screening

  11. Clinically significant gastrointestinal bleeding within 4 weeks prior to start of study drug

  12. Uncontrolled bleeding varices.

  13. History of cardiac disease:

      • Congestive heart failure >NYHA class 2
      • Active coronary artery disease (CAD) (myocardial infarction more than 6 months prior to study entry is allowed)
      • Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before screening
      • Cardiac arrhythmias which are poorly controlled with anti-arrhythmic therapy or requiring pace maker
      • Uncontrolled hypertension

  14. Active clinically serious infections except for HBV and HCV infection

  15. Patients with HIV

  16. Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) within 6 months before screening

  17. Recently treated or concurrent cancer that has a primary site or histology distinct from HCC except any cancer curatively treated more than 3 years prior to screening

  18. Pregnant or breast-feeding subjects

  19. Major surgery, open biopsy, or significant traumatic injury 4 weeks before screening

  20. Presence of a non-healing wound, non-healing ulcer, or bone fracture

  21. Subjects who have used strong CYP3A4 inducers within 4 weeks before screening

  22. Known or suspected allergy or hypersensitivity to any of the study drugs, study drug classes, or excipients of the formulations given during the course of this trial

  23. Any other condition which, in the opinion of the investigator, would make the patient unsuitable for enrollment or could interfere with the completing the study