HepaSphere/Quadrasphere Microspheres for Delivery of Doxorubicin for the Treatment of Hepatocellular Cancer

The purpose of this study is to evaluate overall survival in patients diagnosed with hepatocellular cancer (HCC) treated with HepaSphere/QuadraSphere Microspheres loaded with chemotherapeutic agent doxorubicin compared to conventional transarterial chemoembolization with particle PVA, lipiodol, and doxorubicin.

This phase three, interventional, and prospective study consists of a patient population that has advanced liver cancer (hepatocellular cancer \[HCC\]) that cannot be removed by standard therapies such as surgical removal, liver transplant, and/or ablation.

Embolics and drug eluting embolics are being used by interventional radiologists to try and shrink or kill the tumor area.

Patients that met eligibility criteria, wanted to participate in the study, and signed the informed consent form (ICF) made up the study subject population. Subjects were randomized on a 1:1 basis (subjects were blinded to arm they were randomized to).

Post randomization and within four weeks of the first chemoembolization procedure all subjects had a baseline MRI. Following, the first chemoembolization procedure (hqTACE or cTACE) or 'cycle' was completed. Subjects can (per protocol) receive up to 3 TACE cycles. Within 4 weeks after any TACE cycle, an MRI and labs should be conducted/collected to evaluate disease status (reduction vs progression) and measure treated lesions. Any residual disease that is present after after the first TACE will undergo the next TACE cycle (maximum of three). However, if the liver MRI shows a complete response (absence of HCC) then no additional TACE procedures are performed and the subject is followed for survival.

Eligibility Criteria:
Inclusion Criteria:

Patients must meet all of the following inclusion criteria in order to be entered into the study:

1. Age 18 or older
2. Patient has signed informed consent
3. Patient must have a diagnosis of hepatocellular cancer confirmed by at least one of the following:

i. Histological confirmation ii. Magnetic resonance imaging (MRI) result with early enhancement and delayed enhancement washout of at least one solid liver lesion \> 1 cm. Patient must also have evidence of cirrhosis or have chronic hepatitis B.

iii. Contrast enhanced computed tomography (CT) with early enhancement and delayed enhancement washout of at least one solid liver lesion \> 1cm. Patient must also have evidence of cirrhosis or have chronic hepatitis B.

d. Patient must not be suitable for treatment by resection or percutaneous ablation at time of study entry.

Patients not suitable for ablation due to lesion location may be enrolled

e. Patient MUST meet at least ONE of the following criteria:

i. Stage Child-Pugh B 7 ii. Recurrent HCC iii.Performance status ECOG 1

f. Patient has a life expectancy of at least 6 months

g. Absence of occlusive thrombus to the main portal trunk

Exclusion Criteria:

If patients meet any of the following criteria they may not be entered into the study:

1. Current or previous treatment with chemo- or radiation therapy or sorafenib
2. Previous treatment with any form of transarterial embolization for HCC
3. Patients with current or history of any other cancer except non-melanomatous skin cancer
4. Female patients who are pregnant, breastfeeding, or premenopausal and not using an effective method of contraceptive
5. Performance status ECOG \> 2
6. Child-Pugh scores \>7
7. Active gastrointestinal bleeding
8. Evidence of uncorrectable bleeding diathesis
9. Extra-hepatic spread of the HCC
10. Total Bilirubin \> 3 mg/dL
11. \>50% tumor involvement of the liver
12. Infiltrative or diffuse HCC
13. Encephalopathy not adequately controlled medically
14. Presence of ascites not controlled medically
15. Presence of medically relevant localized or systemic infection, other than hepatitis B, C, D, E or G
16. Any contraindication for MRI (eg. metallic implants)
17. Allergy to contrast media that cannot be managed with prophylaxis
18. Allergy to iodized oil
19. Any contraindication to arteriography
20. Any contraindication for doxorubicin administration, including the following:

i. White Blood Cell count (WBC) \<3000 cells/mm₃

ii. Absolute Neutrophil \<1500 cells/mm₃

iii. Cardiac ejection fraction \<50%

iv. Other condition deemed exclusionary by physician

u. Any contraindication for hepatic embolization, including the following:

i. Porto-systemic shunt, or an arteriovenous shunt that cannot be adequately closed prior to chemoembolization

ii. Hepatofugal blood flow

iii. Serum creatinine \> 2mg/dL

iv. Uncorrectable impaired clotting

1. Platelet \<50,000/mm₃
2. International Normalized Ratio (INR) \> 1.4
3. Activated Prothrombin Time (aPTT) less than 21 or greater than 40

   v. AST \> 5X upper limit of normal for lab

   vi. ALT \> 5X upper limit of normal for lab