Study of Sorafenib and Transarterial Chemoembolization (TACE) to Treat Hepatocellular Carcinoma
Condition: Hepatocellular Carcinoma; Hepatoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: sorafenib; LC Bead-TACE
Intervention description: sorafenib: given 400 mg twice per day for as long as it is beneficial; LC Beads loaded with doxorubicin
Doxorubicin loaded LC Beads: given intra-arterially into the liver, up to fours times in a 6 month period
Intervention MeSH terms: Sorafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: primary liver cancer; sorafenib; Nexavar; doxorubicin; drug eluting beads; transarterial chemoembolization

Summary:

      This study will combine two therapies to treat patients with unresectable hepatocellular
      carcinoma; sorafenib, and drug eluting beads delivered intra-arterially. The purpose of the
      study is to establish the safety and the effectiveness of the combination therapy. The
      investigators hypothesize that the combination of the two therapies will not result in
      greater toxicities to patients than that expected for either therapy given alone.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Unresectable hepatocellular carcinoma (HCC) patients with liver-predominant disease as
             described in section 5.1, or patients with hepatocellular carcinoma who refuse
             surgery. No more than 30% of the cohort should have macrovascular invasion and/or
             asymptomatic extrahepatic disease. Multifocal HCC is acceptable, no diffuse HCC.

          2. Age > 18 years old

          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          4. Childs class of A or B (up to 7) (see Table 5.0)

          5. Adequate end-organ function as manifested by:

               -  Absolute neutrophil count of > 1500/mm3 and platelets > 50,000/mm3

               -  Creatinine ≤ 2.0

               -  Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) < 5 x upper
                  limit of normal (ULN)

               -  Total bilirubin of ≤ 3

               -  Albumin > 2.0

               -  International normalized ratio (INR) < 2.0

               -  Leukocyte count >3000 cells/mm3

          6. Amylase and lipase ≤ 1.5 the upper limit of normal

          7. Patients who have received previous hepatic surgery , radiofrequency ablation (RFA),
             percutaneous ethanol injection (PEI), or cryoablation are eligible if target lesion(s)
             have not been treated and local therapy completed > 6 weeks prior to entry.

          8. Left ventricular ejection fraction ≥ 45%

          9. Patients with asymptomatic HIV infection are not eligible

         10. Willingness of male and female subjects, who are not surgically sterile or post
             menopausal, to use reliable methods of birth control for the duration of the study and
             for 30 days after the last dose of study medication.

         11. Patient must have signed informed consent prior to registration on study.

         12. Resolution of all acute toxic effects of any prior local treatment to Common
             Terminology Criteria for Adverse Events (CTCEA) Grade 1 or 0.

         13. At least one tumor lesion can be accurately measured in at least one dimension
             according to RECIST. The lesion has not been previously treated with local therapy
             (such as surgery, radiation therapy, RFA, PEI, or cryoablation) unless it has shown
             progression in the interim.

        Exclusion Criteria:

          1. Patients unable to swallow oral medications

          2. Prior embolization, systemic or radiation therapy for HCC (liver)

          3. Tumor burden in the liver exceeding 70%.

          4. Complete occlusion of the entire portal venous system

          5. Ascites refractory to diuretic therapy (minimal or trace on imaging is acceptable)

          6. Previous or concurrent cancer that is distinct in primary site or histology from HCC,
             except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder
             tumors (Ta, Tis, and T1). Any cancer curatively treated > 3 years prior is permitted.

          7. Patients with clinically significant gastrointestinal bleeding within 30 days prior to
             study entry

          8. History of bleeding within the past 4 weeks (unless deemed by PI as clinically
             insignificant, for ex., a brief episode of epistaxis)

          9. Any contraindication to doxorubicin administration

         10. Evidence of severe or uncontrolled systemic diseases,

         11. Congestive cardiac failure > New York Heart Association (NYHA) class 2, myocardial
             ischemia within 6 months, active coronary artery disease, cardiac arrhythmias
             requiring anti-arrhythmic therapy other than beta blockers or digoxin, unstable
             angina, or laboratory finding that in the view of the investigator makes it
             undesirable for the patient to participate in the trial

         12. Any prior history of hypertensive crisis or hypertensive encephalopathy

         13. History of stroke or transient ischemic attack within 6 months prior to study
             enrollment

         14. Inadequately controlled hypertension (defined as systolic blood pressure of 150/100
             mmHg on antihypertensive medications) (patients with treated hypertension are
             eligible)

         15. Significant vascular disease (e.g., aortic aneurysm, aortic dissection, peripheral
             vascular disease)

         16. History of organ allograft

         17. Presence of grade > 2 hepatic encephalopathy (see Appendix D)

         18. Current, recent (within 4 weeks of the first infusion of this study), or planned
             participation in an additional experimental drug

         19. Evidence of bleeding diathesis or coagulopathy or on warfarin. Note: If a patient has
             been on coumadin for a period of 1 month and has been stable, they may be accepted
             into the protocol.

         20. Presence of clinically evident central nervous system or brain metastases

         21. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 1, anticipation of need for major surgical procedure during the course of
             the study

         22. Vascular anatomy that precludes catheter placement or injection of LC Bead
             microspheres

         23. Presence of collateral vessel pathways potentially endangering normal territories
             during embolization

         24. Pregnant (positive pregnancy test) or lactating

         25. Inability to comply with study and/or follow-up procedures

         26. Life expectancy of less than 12 weeks

         27. Child B8, B9 and C

         28. ECOG ≥ 2

         29. Patients with concomitant HIV infection or AIDS-related or serious acute or chronic
             illness

         30. Presence of porto-systemic shunt

         31. Severe atheromatosis

         32. Substance abuse, medical, psychological or social conditions that may interfere with
             the patient's participation in the study or evaluation of study results

         33. Active clinically serious infections (>grade 2)

         34. Patients receiving therapy for hepatitis A, B, or C.

         35. Patients with obvious and/or symptomatic extrahepatic disease. Findings of uncertain
             significance, such as lung lesions less than 10 mm in diameter or enlarged periportal
             lymph nodes will not exclude patients, however, findings highly suspicious for
             metastatic HCC will exclude patients from this study.

         36. Any contraindication for an arterial procedure such as impaired clotting tests
             (platelet count < 50.000/mm3 or prothrombin activity < 50 percent)

         37. Any contraindication for systemic chemotherapy administration (serum bilirubin >
             3mg/dL, leukocyte count < 3.000 cells/mm3)

         38. Any contraindication for sorafenib administration