LC Drug Eluting Bead for Treatment of Liver Cancer Which Cannot be Surgically Removed

LC BeadTM is a new product specifically designed for TACE. LC BeadTM microspheres can be
loaded with doxorubicin (Trade name: adriamycin), a chemotherapeutic anthracycline glycolide
agent widely accepted for treatment of HCC. This novel bead slowly releases the ionically
bound chemotherapeutic agent rather than administering a bolus of chemotherapy as is the
case with many alternative methods of TACE. Thus, the LC BeadTM offers the potential
advantage of less toxicity and prolonged tumor exposure.

This study offers local regional therapy to a defined population of patients beyond
transplant criteria as an attempt to downstage them to eligibility for liver
transplantation. This study will make an important contribution to understanding the beads'
local effect as seen in the explanted livers of those patients who go on to receive a liver
transplant. Additionally, we will examine the impact of this novel treatment tool on
patients' quality of life.

- Adults patients (≥ 18 years of age) with a diagnosis of HCC that is not amenable to
surgical resection or local ablative therapy

- Histological confirmed HCC or clinical/laboratory diagnosis of HCC or nodules larger
than 2cm with typical vascular features or AFP > 200

- Patient must have one lesion < 8cm or up to five lesions with total diameter < 8cm

- Quantifiable disease limited to the liver; 40% of liver must be free of tumor burden

- Patient must have at least one tumor lesion that meets both of the following
criteria:

- Lesion can be accurately measured in at least one dimension according to RECIST
criteria

- Lesion has not been previously treated with surgery, radiation therapy,
radiofrequency ablation, percutaneous ethanol or acetic acid injection, or
cryoablation.

- ECOG performance status ≤ 2

- No prior systemic chemotherapy

- At least 4 weeks since prior TACE or interferon

- Not pregnant

- No significant baseline liver dysfunction. Child-Pugh class A and B 7-8 (in abscence
of ascites)

- No significant renal impairment (creatinine clearance < 30mL/minute) or patients on
dialysis

- No current infections requiring antibiotic therapy

- Not on anticoagulation or suffering from a known bleeding disorder

- No unstable coronary artery disease or recent MI

- The following laboratory parameters

- Hemoglobin ≥ 8.5g/dL

- Total bilirubin ≤ 3.0mg/dL

- ALT and AST ≤ 5x upper limit of normal

- Serum creatinine ≤ 1.5x upper limit of normal

- INR ≤ 1.5 or a PT/PTT within normal limits

- Platelet count ≥ 50,000/uL

- Ability to understand the protocol and to agree to and sign a written informed
consent document

Exclusion Criteria:

- HCC with gross vascular invasion or extrahepatic disease

- Previous or concurrent cancer that is distinct in primary site or histology from HCC
except cervical carcinoma in situ, treated basal-cell carcinoma of the skin,
superficial bladder tumors (Ta, Tis & T1), and any cancer curatively treated > 3
years prior to entry is permitted

- Renal failure requiring dialysis

- Child-Pugh B9 or C hepatic impairment

- History of cardiac disease: NYHA class 2 congestive heart failure, active coronary
artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other than beta
blockers or digoxin, and uncontrolled hypertension. Myocardial infarction more than 6
months prior to study entry is permitted.

- Active clinically serious infections (> CTCAEv3 grade 2)

- Known history of HIV

- Known central nervous system tumors including metastatic brain disease

- History of organ allograft

- Substance abuse (current), psychological, or social conditions that may interfere
with the patient's participation in the study or evaluation of the study results.

- Allergy to the investigational agents or any agent given in association with this
trial.

- Pregnant or breast-feeding patients. Both men and women enrolled in this trial must
use adequate barrier birth control measures during the course of the trial.

- Uncontrolled hypertension defined as systolic blood pressure > 150mmHg or diastolic
blood pressure > 90mmHg

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of
study drug

- Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of
study drug

- Serious non-healing wound, ulcer, or bone fracture

- Any contraindication for doxorubicin administration:

- serum bilirubin > 3mg/dL

- WBC < 3000 cells/mm3

- neutrophil < 1500 cells/mm3

- cardiac ejection fraction < 50 percent assessed by isotopic ventriculography,
echocardiography or MRI

- MUGA scan < 40% ejection fraction

- Any contraindication for hepatic embolization procedures

Excluded therapies and medications, previous and concomitant:

- Prior use of any systemic anti-cancer chemotherapy for HCC

- Prior use of any systemic investigational agents for HCC

- Major surgery within 6 weeks of start of study drug

- Radiotherapy during study or within 3 weeks prior to start of study drug

- Use of biological response modifiers such as granulocyte colony-stimulating factor
(G-CSF)within 3 weeks prio to study entry

- Autologous bone marrow transplant or stem cell rescue within four months of study
drug initiation

- Concomitant treatment with rifampin or St. John's wort