TACE Using Doxorubicin-eluting Beads for Patients With HCC and Marginal Hepatic Reserve

Prospective Phase II Study of Chemoembolization With Doxorubicin-Eluting Microspheres for Liver Transplantation Candidates With Hepatocellular Carcinoma and Marginal Hepatic Reserve

TACE is frequently offered to patients with baseline hepatic dysfunction with the purpose of diminishing hepatic tumor burden while patients await transplantation. Without this therapeutic measure, disease may progress beyond UNOS T2 criteria required for organ allocation.

The purpose of the study is to determine whether transarterial chemoembolization using doxorubicin-eluting beads (DEB-TACE) can be used safely and effectively to treat patients with liver-only hepatocellular carcinoma (HCC) and baseline hepatic dysfunction.

Inclusion Criteria:

1. Adult male or female patients, age 18 years of age or older

2. Diagnosis of liver-only HCC based on European Association for the Study of the Liver (EASL) criteria (radiographic lesion appearance on contrast-enhanced CT or MRI, i.e. enhancement on early arterial phase, washout on portal venous phase with or without associated elevation of serum alpha-fetoprotein (AFP) level >200 Units Per Millilitre (U/ml)) or histologic confirmation of HCC diagnosis, whichever is applicable.

3. UNOS stage T1, T2, or T3 disease.

4. Candidates for liver transplantation (listed or screened) according to one of the following criteria:

   1. Milan criteria (one lesion < 5cm or 3 or fewer lesions each < 3cm),
   2. UCSF Downstaging criteria (one lesion less than 8 cm or 2-3 lesions each less than 5 cm with sum of maximum dimensions less than 8 cm, or 4-5 lesions each less than 3 cm with sum of maximum dimensions less than 8 cm)
   3. University of California, San Francisco (UCSF) All-Comers criteria (UNOS stage T3 disease beyond UCSF Downstaging Criteria).

5. At least one measurable site of disease in the liver according to RECIST version 1.1 and odified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.

6. At least one of the following clinical, laboratory, or imaging parameters:

   1. Mild or moderate ascites
   2. Serum bilirubin ≥ 3 mg/dl but less than 6 mg/dl
   3. Aspartate aminotransferase (AST) > 5 times upper limit of normal (ULN) but < 10 times ULN
   4. Alanine aminotransferase (ALT) > 5 times upper limit of normal (ULN) but < 10 times ULN
   5. International normalized ratio for prothrombin time (INR) >1.5 but ≤ 2.5
   6. Portal vein thrombosis (branch or main)
   7. Functioning transjugular intrahepatic portosystemic shunt (TIPS) or surgical portosystemic shunt

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

Exclusion Criteria:

1. Liver-directed therapy (chemoembolization, radioembolization, bland embolization, ablative therapy) within 4 weeks of DEB-TACE.
2. Previous liver transplantation.
3. Serum bilirubin ≥ 6 mg/dl
4. AST > 10 times upper normal limit
5. ALT > 10 times upper normal limit
6. INR > 2.5
7. Serum creatinine > 1.5 mg/dl
8. Macrovascular tumor invasion of portal and/or hepatic vein(s)
9. Extracapsular tumor extension
10. Extrahepatic disease
11. Hepatic encephalopathy refractory to medical therapy
12. Active uncontrolled infection
13. Imaging evidence of common bile duct obstruction
14. Previous sphincterotomy or bilio-enteric anastomosis
15. Significant hepatic arterial to portal vein shunting in the area to be treated.
16. Symptomatic congestive heart failure (CHF)
17. Allergy to or intolerance of prior doxorubicin-based TACE
18. Allergy to or intolerance to iodinated contrast media despite standard of care pre-medication
19. Any contraindications to treatment with LC Bead™ device (e.g. patients with large diameter arteriovenous shunts or patients with a right-to-left shunt).
20. Systemic therapy with sorafenib or other systemic chemotherapeutic agent(s) less than 1 week prior to first planned DEB-TACE.
21. Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ. (Patients with history of malignancy are not considered to have a "currently active" malignancy if they have completed therapy and are now considered by their physician to be at less than 30% risk for relapse.)
22. Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled peripheral vascular disease, myocardial infarction within preceding 12 months, cerebrovascular accident within preceding 12 months, pulmonary disease impairing functional status or requiring oxygen, impairment in gastrointestinal function that may affect or alter absorption of oral medications (such as malabsorption or history of gastrectomy or bowel resection).
23. Pregnant or lactating women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DEB-TACE, breastfeeding must be discontinued for eligibility.
24. Psychiatric illness, other significant medical illness, or social situation which, in the investigator's opinion, would limit compliance or ability to comply with study requirements.