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

Study Overview
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Brief Summary
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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.

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

Conditions
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Hepatocellular Carcinoma, Chemoembolization

Intervention / Treatment
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* Device: LC Bead


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female patients, age 18 years of age or older 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. UNOS stage T1, T2, or T3 disease. Candidates for liver transplantation (listed or screened) according to one of the following criteria: Milan criteria (one lesion < 5cm or 3 or fewer lesions each < 3cm), 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) University of California, San Francisco (UCSF) All-Comers criteria (UNOS stage T3 disease beyond UCSF Downstaging Criteria). 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. At least one of the following clinical, laboratory, or imaging parameters: Mild or moderate ascites Serum bilirubin ≥ 3 mg/dl but less than 6 mg/dl Aspartate aminotransferase (AST) > 5 times upper limit of normal (ULN) but < 10 times ULN Alanine aminotransferase (ALT) > 5 times upper limit of normal (ULN) but < 10 times ULN International normalized ratio for prothrombin time (INR) >1.5 but ≤ 2.5 Portal vein thrombosis (branch or main) Functioning transjugular intrahepatic portosystemic shunt (TIPS) or surgical portosystemic shunt Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. Exclusion Criteria: Liver-directed therapy (chemoembolization, radioembolization, bland embolization, ablative therapy) within 4 weeks of DEB-TACE. Previous liver transplantation. Serum bilirubin ≥ 6 mg/dl AST > 10 times upper normal limit ALT > 10 times upper normal limit INR > 2.5 Serum creatinine > 1.5 mg/dl Macrovascular tumor invasion of portal and/or hepatic vein(s) Extracapsular tumor extension Extrahepatic disease Hepatic encephalopathy refractory to medical therapy Active uncontrolled infection Imaging evidence of common bile duct obstruction Previous sphincterotomy or bilio-enteric anastomosis Significant hepatic arterial to portal vein shunting in the area to be treated. Symptomatic congestive heart failure (CHF) Allergy to or intolerance of prior doxorubicin-based TACE Allergy to or intolerance to iodinated contrast media despite standard of care pre-medication Any contraindications to treatment with LC Bead™ device (e.g. patients with large diameter arteriovenous shunts or patients with a right-to-left shunt). Systemic therapy with sorafenib or other systemic chemotherapeutic agent(s) less than 1 week prior to first planned DEB-TACE. 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.) 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). 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DEB-TACE<br>Doxorubicin Eluting Bead Transarterial Chemoembolization (DEB-TACE): Doxorubicin-loaded LC Beads® are administered via a co-axially placed commercially available hepatic artery catheter into hepatic arteries targeted for treatment. Procedure is performed under direct fluoroscopic visualization until stasis of arterial flow is achieved or until a total of 4 ml of microspheres have been administered, whichever occurs first | Device: LC Bead<br>* Doxorubicin Eluting Bead Transarterial Chemoembolization (DEB-TACE): Doxorubicin-loaded LC Beads® are administered via a co-axially placed commercially available hepatic artery catheter into hepatic arteries targeted for treatment. Procedure is performed under direct fluoroscopic visualization until stasis of arterial flow is achieved or until a total of 4 ml of microspheres have been administered, whichever occurs first.<br>* Other names: DC Bead;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Observed Radiographic Response Rate (Measured by mRECIST) | Best observed radiographic response rate to Doxorubicin Eluting Bead Transarterial Chemoembolization (DEB-TACE) by modified Response Evaluation Criteria in Solid Tumors (mRECIST) was defined as number of patients who had CR, PR, or SD as their best observed response divided by total number of patients with at least one available CT or MRI. Definition of mRECIST for Hepatocellular Carcinoma (HCC). Complete response (CR) = Disappearance of any intratumoral arterial enhancement in all target lesions. Partial response (PR)=At least a 30% decrease in sum of diameters of viable (enhancement in arterial phase) target lesions, taking as reference baseline sum of diameters of target lesions. Stable disease (SD)=Any cases that do not qualify for either partial response or progressive disease. Progressive disease (PD)=An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enh | 1 year | 
| Number of Patients Who Developed New Severe Adverse Events | Number of patients who developed new severe adverse events according to NCI CTCAE version 4.0 | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Observed Objective Radiographic Response by mRECIST | Best observed objective radiographic response was defined as the number of patients who had a complete response or partial response divided by total number of evaluable patients. Measured by mRECIST (see mRECIST definition in the description of the primary objective). | 6 months | 
| Time to Untreatable Progression (TTUP) | TTUP is defined as time (months) from the first on-study DEB-TACE to development of radiographic disease progression untreatable by liver-directed percutaneous or surgical methods (by mRECIST). | 1 year | 
| Time to Progression (TTP) | Time to progression was defined as the period of time from the first on-study DEB-TACE to radiographic disease progression at any site by mRECIST. | 1 year | 
| Time to Hepatic Progression (TTHP) | Time to hepatic progression (TTHP) was defined as a period of time from the first on-study DEB-TACE till development of radiographic evidence of disease progression in the liver by mRECIST. | 1 year | 
| Progression Free Survival (PFS) Rate | Progression free survival rate was defined as the number of patients who were alive and free from radiographic progression by mRECIST at pre-defined time periods. PFS rate was calculated at 3 months, 6 months, 12 months, and 24 months | 3 months, 6 months, 12 Months, and 24 months | 
| Proportion of Patients With Alpha-fetoprotein (AFP) Response With ≥ 50% Decline From Baseline | This measure was defined as the number of patients with alpha-fetoprotein (AFP) response with ≥ 50% decline from baseline (in patients with baseline level ≥ 20) after DEB-TACE. | 1 year | 
| Left Ventricular Ejection Fraction (LVEF) | Left ventricular ejection fraction (LVEF) was measured as percent contraction prior to the first DEB-TACE and 1 month following last planned DEB-TACE. Median LVEF and full range were reported. | Baseline, 1 month following last planned DEB-TACE | 
| Median Area Under Curve (AUC) | Area under curve for doxorubicin concentration in the serum over 7 days was measured by obtaining serum doxorubicin concentration samples at predose, 5 min, 20 min, 40 min, 60 min, 120 min, 6 hours, 24 hours, 7 days time points. A graph of serum doxorubicin concentration over time was then plotted for each of the 17 patients, and the area under the curve for each of the 17 patients was calculated. Pharmacokinetic sampling was performed only during each of the first planned DEB-TACE procedures. | 7 days |