Study in the Treatment of HCC With a Radiopaque (RO) Bead (LC Bead LUMI™) Loaded With Doxorubicin

A Prospective, US Multicenter Open Label Study in the Treatment of Hepatocellular Carcinoma (HCC) With a Radiopaque (RO) Bead (LC Bead LUMI™) Loaded With Doxorubicin

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. This type of cancer may be "hypervascular". Hypervascular means there is an increased number or concentration of blood vessels. These blood vessels get their blood supply from the hepatic artery, while the non-tumor liver tissue gets blood supply from the portal vein. Therefore, blockage of the hepatic artery to cut off the blood supply to the tumor is possible without affecting the normal liver.

This research protocol will study chemoembolization using radiopaque beads loaded with a chemotherapy drug called doxorubicin. Chemoembolization is a procedure in which the blood supply to a tumor is blocked after anticancer drugs are given in blood vessels near the tumor. In this study, the anticancer drug, doxorubicin, is attached to small beads that are injected into an artery that feeds the tumor. The radiopaque beads (RO beads) are visible on imagining scans (X-rays) so that the Interventional Radiologist performing the chemoembolization procedure can see the location of the beads in the tumor during and after the procedure. The visibility of the beads allows the interventional radiologist to confirm where the beads loaded with doxorubicin have been delivered in the tumor; this in theory could help to improve the efficiency of embolization and plan the next course of treatment. In addition to the embolization, the beads elute a sustained dose of doxorubicin locally to the tumor site as a second effect.

The usual treatment for HCC is to perform a procedure to the tumor known as Transarterial Chemo-Embolization (TACE). TACE has been approved and used worldwide for over 10 years.

Transarterial means that the treatment is delivered using a catheter inserted into the hepatic artery. Embolization is a treatment that blocks or slows down the blood supply to tissues. This procedure is performed to block the flow of blood to a tumor, so the cancer cells die because the oxygen supply is interrupted. When the material used to block the blood supply also delivers a chemotherapy drug to the tumor, it is called chemoembolization. The most commonly used material for chemoembolization are drug-eluting beads (DEBs) that are loaded with a chemotherapy drug (doxorubicin). These beads are not visible, during the procedure, on the imaging (scanner, ultrasonography or MRI) while injected into the tumor. The consequences of the blood flow interruption are visible on imaging (CT, MRI) in the weeks following treatment (tissue infarction/tumor necrosis).

This study uses the LC Bead LUMI™ radiopaque beads (RO beads). The difference is that RO Beads are visible with X-Ray imaging (scanner, fluoroscopy). This is important because it means that the Interventional Radiologist is able to verify, during the procedure, where the beads have been delivered to the tumor. The Interventional Radiologist will identify the blood supply to the tumor, and then inject the LC Bead LUMI™ loaded with doxorubicin and a compatible contrast agent into the blood vessels that supply the liver tumor. These RO beads block the blood vessel, starve the tumor of nutrients and deliver a slow release of the doxorubicin.

Many of the tests, investigations and procedures that will be requested as a part of the study may be the same as what is routinely done in the diagnosis and treatment of HCC. These tests will be used to determine if you are eligible to participate in this study and receive the LC Bead LUMI™ loaded with doxorubicin. Some of the study assessments are done to evaluate the safety and efficacy of the treatment procedure and others will be done for research purposes.

During the study, the tests and evaluations will be scheduled with normally occurring appointments, when possible; to reduce the number of visits the patient needs to make to the study center. Study visits for tumor response evaluation occur at one month after the first treatment then every 3 months for 2 years then every 6 months.

The information obtained during your visits will help your study doctor determine what choices you have for the next best course of action in treating your cancer. Options may include; repeat the study treatment, propose another alternative treatment or to continue the follow-up.

Inclusion Criteria:

1. Patient with HCC, diagnosed by at least one of the following:

   1. Imaging according to the American Association for the Study of Liver Disease (AASLD) guidelines
   2. Histology

2. Adults (18 years of age or older)

3. Tumor not suitable for resection, ablation or transplantation at the time of study entry

4. Patient is a candidate for TACE after multidisciplinary team (MDT) decision

5. HCC Barcelona Clinic Liver Cancer (BCLC) B or BCLC A not eligible for or refuses curative treatment, or BCLC C (Performance Status 1 only)

6. At least one measurable disease according to mRECIST

7. Preserved liver function (Child Pugh Score A and B7)

8. Performance Status: Eastern Cooperative Oncology Group score of 0 or 1 or Karnofsky Performance Status 80 -100 at study entry

9. TACE of all lesions can be achieved within a single cycle (2 sessions in 21 days +/- 7 days for the first cycle only)

10. Life expectancy of at least 6 months at study entry

11. Women and men of child bearing potential must agree to use adequate contraception prior, during and post therapy according to the standard instructions at the study site

12. Negative serum or urine pregnancy test at study entry for woman of childbearing potential according to institutional policy

13. Patient is willing and able to provide written signed and dated informed consent

Exclusion Criteria:

1. Extrahepatic metastases

2. Portal vein tumor thrombosis (any type I to IV, refer to appendix 12.6)

3. Patient on waiting list for transplantation

4. Hematology:

   1. Hemoglobin <9g/dL, or
   2. White Blood Cell (WBC) <2,500 cells/mm3, or
   3. Absolute Neutrophil Count (ANC) <1,500 cells/mm3, or
   4. Platelets <50,000/mm3, or
   5. International Normalized Ratio (INR) > 1.8

5. Renal

   1. Glomerular Filtration Rate (GFR) <30 mL/min/1.73m2
   2. Creatinine >2 mg/dL

6. Hepatic

   1. Any single tumor nodule > 7cm (Multiple lesions can be included but not one >7cm)
   2. Estimated tumor burden >50%
   3. Clinically detectable ascites on physical exam (ascites detected by imaging only and is deemed not clinically significant is acceptable)
   4. Bleeding diathesis; history of hemorrhage / bleeding events
   5. Variceal bleeding of grade 3 or worse within 3 months of study entry
   6. Bilirubin >3mg/dL,
   7. Significant impairment of liver function tests defined as AST/ALT >5X Upper Limit Normal or 250 units/L
   8. Albumin <30g/L

7. Cardiovascular

   a. Significant cardiovascular disease; e.g., myocardial infarction within 6 months of inclusion, chronic heart failure (New York Heart Association class III or IV), Left Ventricular Ejection Fraction <50%, unstable coronary artery disease

8. Other serious concurrent medical conditions

   1. Previous malignancy other than carcinoma in situ of the skin, the cervix or uterus within 5 years prior to inclusion
   2. HIV, congenital immune defect, any immunosuppressive therapy for autoimmune disease (rheumatoid arthritis) or inflammatory bowel disease
   3. History of organ transplant
   4. Serious or chronic infection (Active, clinically severe bacteria or fungal infection of >grade 2 NCI-CTCAE_ v4.0)
   5. In case of Hepatitis B or C, viral disease must be under control (antiviral treatment not needed or completed or if hepatitis B with no interaction with cancer treatment).
   6. Other uncontrolled intercurrent underlying medical condition that in judgement of the investigator could impact the ability of the subject to participate in the trial

9. Prior or concurrent cancer therapy

   1. Target lesions previously treated by a loco regional therapy (TACE, Y90, RFA, MWA, PEI, SBRT)
   2. Any systemic treatment within the past 3 months or any plan to administer systemic treatments during the study
   3. Endocrine therapy - any prior hormonal therapy for HCC
   4. Radiotherapy - any prior radiotherapy for HCC or any concurrent anticancer radiotherapy
   5. Surgery - major surgery/laparoscopy within 30 days before screening
   6. Investigational therapy - Patients who have participated in another clinical study within 12 weeks prior to the Screening/Baseline visit
   7. TACE therapy - Prior TACE on the same lesions

10. Performance Status: ECOG ≥ 2 or KPS < 80 at study entry

11. Contraindication for both enhanced Magnetic Resonance Imaging (MRI) and Computerized Tomography (CT) imaging (according to patient characteristics and investigator decision).

12. Any condition that would result in biliary ductal colonization including Whipple procedure, biliary stenting, a sphincterotomy within 3 month, hepatojejunostomy, etc.

13. Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial

14. Any absolute contra-indication to TACE, contraindication to angiography

15. Any absolute contra-indication to doxorubicin according to its label

16. Contraindication or known allergic reactions to contrast media agents, Radiopaque Beads or with known sensitivity to iodine/iodine containing substances.