Prospective Phase II Study of Chemoembolization With Doxorubicin-Eluting Microspheres for Liver Transplantation Candidates With Hepatocellular Carcinoma and Marginal Hepatic Reserve
Phase: NA
Conditions: Hepatocellular Carcinoma, Chemoembolization
Sponsor: University of California, San Francisco

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CC# 124520: Prospective Phase II Study of Chemoembolization with 
Doxorubicin-Eluting Microspheres for Liver Transplantation Candidates 
with Hepatocellular Carcinoma and Marginal Hepatic Reserve 
 
 
Protocol Number: 124520 
Version Number:  2.5 
Version Date:  13 JAN 2015 
Investigational Agent(s): Doxorubicin-Eluting LC Beads® 
 
Principal Investigator 
Nicholas Fidelman, M.D. 
University of California San Francisco 
Box 0628 
San Francisco, CA  94143 
Phone: 415-353-1300 
Nicholas.Fidelman@ucsf.edu 
 
Co-Investigators 
Robin Kate Kelley, M.D. 
Francis Y. Yao, M.D. 
Alan P. Venook, M.D. 
Chloe E. Atreya, M.D., Ph.D. 
Emily K. Bergsland, M.D. 
D. Montgomery Bissell, M.D. 
Danielle Brandman, M.D. 
Bilal Hameed, M.D. 
 
Robert K. Kerlan Jr, M.D. 
Andrew Ko, M.D. 
Maureen P. Kohi, M.D. 
K. Pallav Kolli, M.D. 
W. Michael Korn, M.D. 
Jeanne M. LaBerge, M.D 
Jennifer Lai, M.D. 
Neil Mehta, MD 
 
 
Jennifer Price, M.D. 
Marion G. Peters, M.D. 
Andrew G. Taylor, M.D. 
Norah Terrault, M.D. 
Monika Sarkar, MD 
Katherine Van Loon, MD 
Marissa Espejo, RNP 
Yawen Yeh, RNP 
 
Revision History 
Version #2.5  01/13/2015 
Version #2.4   11/06/2014 
Version #2.3 02/20/2014 
Version #2.2 10/08/2013 
Version #2.1 03/27/2013 
Version #2.0 01/22/2013 
Version #1.5 12/12/2012 
 
Version #1.4 10/16/2012 
Version #1.3 09/18/2012 
Version #1.2 08/21/2012 
Version #1.1 05/08/2012 
Version #1.0 04/24/2012 
 
 
 
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others 
except to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by 
Federal and State laws.  Persons to whom this information is disclosed should be informed that this information is 
privileged and confidential and that it should not be further disclosed. 

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Protocol Signature Page 
Protocol No.:  124520 
Version & Date:  2.4 06-Nov-2014 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee (PRC), 
Committee on Human Research (CHR), and Data Safety Monitoring Committee (DSMC).  
2. I will conduct the study in accordance with applicable CHR requirements, Federal regulations, and 
state and local laws to maintain the protection of the rights and welfare of study participants.  
3. I certify that I, and the study staff, have received the requisite training to conduct this research 
protocol.  
4. I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in accordance 
with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the Statement of 
Investigator (Form FDA 1572), and with local regulatory requirements. In accordance with the FDA 
Modernization Act, I will ensure the registration of the trial on the www.clinicaltrials.gov website.  
5. I agree to maintain adequate and accurate records in accordance with CHR policies, Federal, state and 
local laws and regulations. 
UCSF Principal Investigator 
 
 
Printed Name 
 
 
Signature 
 
Date 
 

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Abstract 
Title 
Prospective Phase II Study of Chemoembolization with Doxorubicin-Eluting 
Microspheres for Liver Transplantation Candidates with Hepatocellular Carcinoma and 
Marginal Hepatic Reserve 
Patient 
population 
Intermediate stage, unresectable hepatocellular carcinoma (HCC) confined to the liver, 
without significant hepatic synthetic dysfunction 
Rationale 
for Study 
To determine whether DEB-TACE can be used safely and effectively to treat patients 
with liver-only HCC and baseline hepatic dysfunction, 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. 
Primary 
Objectives 
• To determine the safety of DEB-TACE in patients with HCC confined to liver who 
are being considered for liver transplantation 
• To determine the response rate to DEB-TACE by conventional and modified 
Response Evaluation Criteria in Solid Tumors (RECIST version 1.1, mRECIST) for 
treated lesions in patients with liver-only HCC who are being considered for liver 
transplantation 
Secondary 
Objectives 
• 
To measure overall radiographic response (by RECIST v1.1 and mRECIST) 6 
months after the date of the first planned DEB-TACE procedure.  
• 
To measure time to untreatable progression (TTUP). TTUP is defined as time to 
disease progression untreatable by liver-directed percutaneous or surgical 
methods.  
• 
To measure median time to progression (TTP)  
• 
To measure hepatic progression free survival (HPFS) 
• 
To measure progression free survival (PFS)  
• 
To measure overall survival (OS) 
• To determine the proportion of patients who remain active on the wait 
list for a liver transplant and eventually are transplanted. 
• To determine the proportion of patients who are inactivated or drop out 
from the wait list for any reason but transplantation. 
• To determine the proportions of patients who are successfully down-
staged and achieve active waitlist status and eventually are 
transplanted. 
• 
To measure proportion with alpha-fetoprotein (AFP) response with ≥ 50% 
decline from baseline (in patients with baseline level ≥ 20) post DEB-
TACE and test for association with hepatic and overall response rate, PFS, 
and OS  
• 
To determine whether cardiac function changes occur as a result of DEB-TACE 
with doxorubicin 
• 
To obtain pharmacokinetic data for doxorubicin administered as a part of DEB-
TACE procedures 

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Abstract 
Study 
Design 
Prospective open-label two-stage phase II clinical trial to evaluate the safety and 
efficacy of DEB-TACE in patients with liver-only HCC and significant hepatic 
dysfunction who are being considered for a liver transplant. 
Number of 
patients 
17 patients will be enrolled into the first stage of the study for safety and efficacy 
34 patients will be enrolled into the second stage of the study  
Duration of 
Therapy 
Most patients will need only one DEB-TACE treatment, performed within 60 days of 
Screening procedures 
For patients that have more than one treatment, the procedure will be done about 4 
weeks after the first, or previous treatment, up to 4 treatments total  
Duration of 
Follow up 
Post Treatment Evaluation will last 1 year 
Duration of 
study 
The study will reach completion 5 years from the time the study opens to accrual 
Study 
Procedure 
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.  

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Abstract 
Safety 
Assessments 
• Laboratory tests (Day 1 and Day 7±3 after every DEB-TACE, then 30±7, 90±14, 
180±14, 270±14, and 360±14 days after last planned DEB-TACE) 
• Physical exam/AE assessment (Day 1and Day 7 after every DEB-TACE, then 30±7, 
90±14, 180±14, 270±14, and 360±14 days after last planned DEB-TACE) 
• MELD score (30±7, 90±14, 180±14, 270±14, and 360±14 days after last planned 
DEB-TACE)) 
• Imaging procedures to assess tumor burden (30±7, 90±14, 180±14, 270±14, and 
360±14 days after last planned DEB-TACE) 
• Cardiac function monitoring by echocardiography (at baseline and approximately 30 
days after last planned DEB-TACE procedure). 
 
Safety data will be routinely monitored and sequential safety assessments will be 
conducted as subjects are enrolling to the study. The study will be stopped due to 
safety/toxicity concern prior to interim efficacy analysis if any of the following 3 
stopping rules are met: 
 
1. Liver dysfunction (clinical or laboratory [total serum bilirubin], grade 4) 
that does not improve to baseline or </= grade 3 within 1 month 
following DEB-TACE in ≥ 7 patients (12% of 51 patients). 
 
OR 
2. Renal dysfunction (clinical or laboratory [serum creatinine], grade 3 or 4) 
that does not improve to baseline or </= grade 2 within 1 month 
following DEB-TACE in ≥ 2 patients (1.2% of 51 patients). 
 
 
OR 
 
3. Any grade 5 AE (death) attributed as at least possibly-related to study 
intervention in ≥ 3 patients (4.8% of 51 patients). 
Stopping Rules for Efficacy after 17 patients have completed last planned DEB-TACE 
1. If four (4) or fewer responses (complete, partial, or stable disease response 
according to mRECIST in treated lesion(s) approximately 1 month after last planned 
DEB-TACE) are observed among first stage of 17 patients. 
Efficacy 
Assessments 
Evaluation of treatment response will be based on contrast-enhanced cross-sectional 
imaging of the abdomen (CT or MRI) performed one month following last planned 
DEB-TACE procedure within six months of the first DEB-TACE procedure. Treatment 
response will be evaluated according to both the RECIST version 1.1 and mRECIST 
criteria. 
Unique 
Aspects of 
this Study 
This is the first prospective study to evaluate safety and efficacy of DEB-TACE for 
patients with marginal hepatic function. 
 

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Table of Contents 
Protocol Signature Page ....................................................................................................... 2 
Table of Contents ................................................................................................................. 6 
1.0 
BACKGROUND AND RATIONALE .................................................................. 10 
1.1 
Background/Standard Therapies ............................................................................ 10 
1.2 
TACE Toxicity ....................................................................................................... 11 
1.6 
Rationale ................................................................................................................. 13 
2.0 
OBJECTIVES ......................................................................................................... 13 
3.0 
STUDY DESIGN ................................................................................................... 14 
3.1 
Single DEB-TACE procedure algorithm ................................................................ 14 
3.2 
Treatment Algorithm for Multiple DEB-TACE infusions ..................................... 14 
4.0 
ELIGIBILITY CRITERIA ..................................................................................... 15 
4.1 
Subject Population .................................................................................................. 15 
4.2 
Inclusion Criteria .................................................................................................... 16 
4.3 
Exclusion Criteria ................................................................................................... 16 
4.4 
Subject Selection .................................................................................................... 17 
5.0 
SUBJECT REGISTRATION ................................................................................. 18 
6.0 
TREATMENT PLAN ............................................................................................ 18 
7.0 
TOXICITY MANAGEMENT ............................................................................... 18 
7.1 
Liver toxicity .......................................................................................................... 18 
7.2 
Renal toxicity .......................................................................................................... 19 
7.3 
Postembolization syndrome .................................................................................... 19 
7.4 
Side effects of angiography and embolization ....................................................... 19 
8.0 
EVALUATIONS AND PROCEDURES ............................................................... 19 
8.1 
Screening/Baseline ................................................................................................. 21 
8.2 
Treatment ................................................................................................................ 22 
8.3 
Multiple DEB-TACE Infusions Targeting Different Vascular Territories ............ 23 
8.4 
Follow-Up Assessments ......................................................................................... 23 
8.4.1 Patients with Single DEB-TACE Infusion ....................................................... 24 
8.4.2 Patients with Multiple DEB-TACE Infusions .................................................. 24 
8.5 
Ancillary Therapy ................................................................................................... 22 
9.0 
CRITERIA FOR EVALUATION .......................................................................... 26 
9.1 
Safety ...................................................................................................................... 26 
9.2 
Efficacy ................................................................................................................... 26 
9.2.1 RECIST Definitions ......................................................................................... 26 

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Table of Contents 
9.2.2 RECIST Guidelines .......................................................................................... 27 
9.2.3 mRECIST Definitions ...................................................................................... 27 
9.2.4 mRECIST Guidelines ....................................................................................... 28 
10.0 
CRITERIA FOR STUDY TERMINATION .......................................................... 28 
10. 1 
CRITERIA FOR PATIENT REMOVAL FROM STUDY ............................... 31 
11.0 
DEVICE INFORMATION .................................................................................... 31 
11.1 Classification ......................................................................................................... 31 
11.2 Mode of Action ..................................................................................................... 31 
11.3 Storage and Stability ............................................................................................. 32 
11.4 Metabolism ............................................................................................................ 32 
11.5 Preparation ............................................................................................................ 32 
11.6 Procedure ............................................................................................................... 33 
11.7 Incompatibilities/Contraindications ...................................................................... 33 
11.8 Side Effects ........................................................................................................... 33 
11.9 Availability ............................................................................................................ 34 
11.11 
Accountability .................................................................................................... 34 
12.0 
STATISTICAL CONSIDERATIONS ................................................................... 34 
12.1 Basis for Sample Size ............................................................................................ 34 
12.2 Interim Analysis .................................................................................................... 34 
12.3 Analysis Plan ......................................................................................................... 35 
13.0 
ETHICAL AND REGULATORY CONSIDERATIONS ...................................... 37 
13.1 Pre-study Documentation ...................................................................................... 37 
13.2 Protocol Review/Changes ..................................................................................... 37 
13.2.1 
Protocol Review Committee .......................................................................... 37 
13.2.2 
Institutional Review Board / Independent Ethics Committee ....................... 37 
13.3 Investigational Device Exemption (IDE) .............................................................. 38 
13.4 Data Safety Monitoring ......................................................................................... 38 
13.5 CCC Data Safety Monitoring Committee ............................................................. 38 
13.5.1 
Oversight and Monitoring Plan ..................................................................... 38 
13.5.2 
Monitoring and Reporting Guidelines ........................................................... 38 
13.5.3 
Review and Oversight Requirements ............................................................ 38 
14.0 
ADVERSE EVENT REPORTING ........................................................................ 40 
14.1 Adverse Event Definitions .................................................................................... 40 
14.1.1 
Adverse Events .............................................................................................. 40 
14.1.2 
Unanticipated Adverse Events ...................................................................... 40 
14.1.3 
Serious Adverse Events ................................................................................. 41 

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14.1.4 
Laboratory Adverse Events ........................................................................... 41 
14.2 Adverse Event Grading ......................................................................................... 41 
14.3 Adverse Event Reporting Period ........................................................................... 42 
14.4 Reporting Procedures ............................................................................................ 42 
15.0 
Protection of Human Subjects ................................................................................ 43 
15.1 Protection from Unnecessary Harm ...................................................................... 43 
15.2 Protection of Privacy ............................................................................................. 43 
16.0 
FINANCIAL CONSIDERATIONS ....................................................................... 43 
16.0 
REFERENCES ....................................................................................................... 44 
 
Appendices 
Appendix 1 
ECOG Performance Status Criteria ........................................................ 48 
Appendix 2 
Child-Pugh Score .................................................................................... 49 
Appendix 3 
MELD Score .......................................................................................... 50 
Appendix 4 
Modified RECIST .................................................................................. 51 
 
List of Tables 
Table 1 
Schedule of Events: Single Deb-TACE ............................................................. 20 
Table 2 
Schedule of Events: Multiple DEB-TACE infusions ........................................ 21 
Table 3 
Number of complications reported in the literature and overall incidence for  
DEB-TACE ........................................................ Error! Bookmark not defined. 
 
 

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LIST OF ABBREVIATIONS 
 
AE 
 
Adverse Event 
AFP 
 
Alpha-FetoProtein 
ALT 
 
Alanine Aminotransferase 
AST 
 
Aspartate Aminotransferase 
BUN  
Blood urea nitrogen 
CBC  
Complete Blood Cell (count) 
CCC  
Comprehensive Cancer Center (UCSF) 
CFR 
 
Code of Federal Regulations 
CHR  
Committee on Human Research 
CT 
 
Computerized Tomography 
cTACE 
Conventional Transarterial Chemoembolization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DEB-TACE 
Doxorubicin Eluting Bead Transarterial Chemoembolization 
DSMC  
Data Safety Monitoring Committee 
ECOG  
Eastern Cooperative Oncology Group 
EASL  
European Association for the Study of Liver Disease 
FDA  
Food and Drug Administration 
HCC  
Hepatocellular Carcinoma 
HIPAA 
Health Insurance Portability and Accountability Act 
INR 
 
International Normalized Ratio for prothrombin time 
IRB 
 
Institutional Review Board 
IV 
 
Intravenous 
LFT 
 
Liver Function Test 
LT 
 
Liver transplant 
MELD  
Model for End-stage Liver Disease 
mRECIST 
Modified Response Evaluation Criteria In Solid Tumors 
MRI 
 
Magnetic Resonance Imaging 
NCI 
 
National Cancer Institute 
OS 
 
Overall Survival 
PEI 
 
Percutaneous Ethanol Injection 
PFS 
 
Progression Free Survival 
PRC 
 
Protocol Review Committee 
PT 
 
Prothrombin Time 
PTT 
 
Partial Thromboplastin Time 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RFA 
 
Radiofrequency Ablation 
SAE 
 
Serious Adverse Event 
SIRT  
Selective Internal Radiation Therapy 
TACE  
Transarterial Chemoembolization 
TTP 
 
Time To Progression 
TTUP  
Time To Untreatable Progression 
UCSF  
University of California San Francisco 
ULN  
Upper Limit of Normal 
UNOS  
United Network for Organ Sharing 

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1.0 
BACKGROUND AND RATIONALE 
1.1 
Background/Standard Therapies 
Tumor resection or liver transplant (LT) represent the best options for cure in patients with 
hepatocellular carcinoma (HCC). Unfortunately, most patients are candidates for neither at the 
time of diagnosis (1). Depending on the extent of tumor and the overall health of the patient, 
those who are not able to undergo resection or transplantation may be referred for liver-directed 
treatments, supportive care or rarely, experimental medical protocols (2). 
 
Liver-directed therapies have been shown to extend survival compared with supportive care (3, 
4, 5), and in optimal cases may be effective in allowing “downstaging” (6, 7, 8) of the tumor to 
allow resection or transplantation. Moreover, liver-directed therapies have been found to 
diminish drop-out from the liver transplant wait list (7). 
 
Many liver-directed therapies take advantage of the liver’s unique blood supply. Two sets of 
vessels bring blood to the liver: the portal vein and the hepatic artery. The portal vein brings the 
majority of the blood and the great majority of the nutrients to normal liver. While the hepatic 
artery supplies a far smaller percentage of blood to normal liver, it provides nearly all of the 
vascular supply to liver tumors. Hepatocellular carcinoma characteristically has a very rich 
arterial blood supply, providing an excellent opportunity for minimally invasive, arterially 
directed targeted therapies. The hepatic artery is routinely accessed using standard angiographic 
techniques and fluoroscopic guidance. 
 
Liver-directed therapies may be used alone or in combination. These therapies include: 
percutaneous ablation (a needle-like device called an applicator is inserted into the tumor(s) 
under imaging guidance, energy is applied through the applicator, and tumor destruction is 
induced around the “needle”), arterial embolization (the blood vessels supplying the tumor are 
occluded with tiny particles to induce ischemia), chemoembolization (chemotherapy is delivered 
directly to the tumor blood vessels immediately before they are occluded), intra-arterial 
chemotherapy (chemotherapy is delivered directly to the liver artery supplying the tumor(s) and 
radioembolization (selective internal radiation therapy, SIRT) (2). 
 
At UCSF and other transplant centers, patients with HCC confined to the liver may be offered a 
spot on the liver transplant list. Expected 5-year survival in patients with HCC who make it to 
liver transplant is 70-90%, which is better than that for surgery (50%) or liver-directed therapy 
alone (20-50%) (1). A chief requirement for listing is tumor burden within United Network for 
Organ Sharing (UNOS) T2 stage (one lesion less than 5 cm or up to 3 lesions each less than 3 cm 
in size). Patients with UNOS T3 stage (disease confined to the liver without evidence imaging 
evidence of portal or hepatic vein invasion or extracapsular extension) may also be listed if they 
undergo successful “down-staging” to UNOS T2 or T1 using liver-directed therapy (7, 8). Liver-
directed therapy choices include transarterial chemoembolization (TACE), SIRT, radiofrequency 
ablation (RFA), and percutaneous ethanol injection (PEI). Typical wait for an organ in UNOS 
region 5, which includes California, is 1.5-2 years depending on the patient’s blood type. If 
untreated, HCC is likely to progress during this long waiting period beyond UNOS T2 stage. 
Therefore, various liver-directed treatment approaches including TACE, RFA, and PEI are 

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employed to maintain patients active on the transplant list. 
 
TACE is a standard treatment option for patients with intermediate stage, unresectable 
hepatocellular carcinoma (HCC) without significant hepatic synthetic dysfunction (2).  TACE 
produces an objective tumor response rate of 35%-40% and confers a significant survival 
advantage as compared to best supportive care (9, 3, 4).  Improved quality of life and reduced 
pain following initiation of chemoembolization are reported among patients undergoing 
sequential TACE (10). Current indications for TACE include first line treatment for unresectable 
intermediate stage HCC, as “bridging” therapy to prevent disease progression and drop-out on 
the liver transplant waiting list, as a method to “down-stage” patients to qualify them for liver 
transplantation, or enable liver resection through the reduction of disease burden (2, 7). 
 
TACE for HCC can be performed in a variety of ways. Conventional TACE (cTACE) is 
performed by dissolving one or more cytotoxic drugs including doxorubicin, cisplatin, and/or 
mitomycin C in iodinated contrast and adding ethiodized oil to the dissolved drugs to make a 1:1 
emulsion. Following infusion of the emulsion into the hepatic artery, embolization is performed 
to stasis of arterial flow with a variety of permanent or dissolvable embolic agents (11). 
 
During the past 5 years, it has been recognized that two commercially available particulate 
embolic agents (LC Beads®, Biocompatibles Inc., Farnham, Surrey, UK; Hepasphere®, Merit 
Medical, South Jordan, UT, USA) can be used as drug carriers by forming an ionic bond 
between the drug and the microsphere (12, 13). The two drugs that are currently being delivered 
in this fashion are doxorubicin for patients with HCC and irinotecan for patients with colorectal 
liver metastases. The process of performing TACE using drug-eluting beads (DEB) has become 
known as DEB-TACE. Pharmacokinetic studies have shown that during cTACE a substantial 
amount of drug is present in the systemic circulation, whereas during DEB-TACE the amount of 
drug in the systemic circulation is negligible (12, 13). A recently published randomized clinical 
trial (PRECISION V) showed that DEB-TACE using doxorubicin-eluting microspheres had 
similar efficacy to cTACE performed with doxorubicin and ethiodized oil emulsion (14). 
1.2 
TACE Toxicity 
Complication rates following TACE are high (25-45%) with the majority being reversible 
elevations of hepatic transaminases and serum bilirubin without an impact on long-term 
prognosis, however, for a small proportion of patients, irreversible hepatic decompensation 
occurs (15).  TACE-related irreversible hepatic decompensation is described as significant and 
acute elevation of liver function tests, evidence of new ascites, new encephalopathy, or 
worsening of either.  These serious complications, frequently accompanied by deterioration in 
clinical status, may lead to the requirement of urgent liver transplantation in eligible patients, 
ineligibility for and/or risk of increased toxicity from systemic therapy with sorafenib or 
investigational systemic therapies for HCC, or death (16). Rates of complications following 
conventional TACE performed for patients with marginal hepatic reserve or portal vein 
thrombosis have been described (16-23). 
 
We have recently completed a retrospective record review of 252 patients with HCC and hepatic 
dysfunction who underwent 446 cTACE procedures at our institution between 2005 and 2009 
(24). Patients were eligible for inclusion if they had one of the following criteria:  pre-TACE 

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bilirubin >2mg/dl, aspartate aminotransferase (AST) or alanine aminotransferase (ALT)>5 times 
upper normal limit, international normalized ratio (INR) >1.5, creatinine >1.2 mg/dL, platelet 
count <60,000/µL, Model for End-Stage Liver Disease (MELD) score >15, Childs-Pugh class B 
or C, ascites, or portal venous thrombus. Hepatotoxicity was defined as one of the following:  
new or worsening ascites, encephalopathy, or NCI Common Terminology Criteria for Adverse 
Events grade 3 or 4 toxicity of bilirubin, AST, ALT, creatinine or INR. Rate and risk factors for 
persistent hepatotoxicity were determined using generalized estimating equation analysis.  
 
Reversible hepatotoxicity developed after 90 TACE procedures (20%) in 78 patients (31%).  
Reversible abnormalities resolved in under 30 days after 63 procedures, in 1-3 months after 19 
procedures, and in 3-6 months after 6 procedures. Irreversible hepatotoxicity developed after 41 
procedures (9%) in 37 patients (15%). Six patients (2%) received urgent liver transplants, and 
ﬁve (2%) died within 30 days of TACE. Patients at increased risk for procedure-related mortality 
or urgent need for a liver transplant had baseline elevated serum bilirubin (p<0.0001), elevated 
INR (p<0.0001), hypoalbuminemia (p=0.002), thrombocytopenia (p=0.011), elevated serum 
creatinine (p<0.0001), large ascites (p=0.0002), encephalopathy (p=0.0002), or MELD >15 
(p=0.0005).  
 
PRECISION V trial (14) showed that DEB-TACE was better tolerated than cTACE and led to 
better radiographic responses in patients with more advanced liver disease than cTACE. On the 
basis of this observation, DEB-TACE may, in fact be the preferred modality for treating patients 
with hepatic dysfunction. All studies performed on safety of DEB-TACE to date included 
patients with serum bilirubin <3 mg/dl, and AST and ALT levels under 5X upper normal limit 
14, 26-52). Patients with baseline liver dysfunction at bilirubin and transaminase levels above 
those included in trials are routinely treated in clinical practice. However, there have been no 
published studies to date to support safety and efficacy of DEB-TACE in patients with marginal 
hepatic reserve. A total of 37 patients with hepatic dysfuncation (who met the inclusion criteria 
proposed for this study) have been treated between at UCSF between 2011 and 2013. Their 
records were retrospectively reviewed. Preliminary results on adverse events following DEB-
TACE are summarized in Table 1. No treatment-related deaths and no events hepatic 
decompensation requiring an urgent liver transplant were encountered in this patient cohort. 
 
Table 1. Severe hepatic and renal adverse events in 37 patients with marginal hepatic reserve 
who underwent DEB-TACE at UCSF. 
 
Toxicity 
Bilirubin 
N (%) 
AST 
N (%) 
ALT 
N (%) 
INR 
N (%) 
Creatinine 
N (%) 
Reversible* grade 3 
9 (24) 
5 (14) 
1 (2.7) 
0 (0) 
0 (0) 
Reversible* grade 4 
1 (2.7) 
1 (2.7) 
0 (0) 
N/A 
0 (0) 
Irreversible** grade 3 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
Irreversible** grade 4 
0 (0) 
0 (0) 
0 (0) 
N/A 
0 (0) 
  *Abnormality returned to baseline within 6 weeks of DEB-TACE 
  **Abnormality persisted for at least 6 weeks following DEB-TACE 

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1.6 
Rationale 
TACE is frequently offered to patients with 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. PRECISION V 
randomized controlled trial has suggested that DEB-TACE may be associated with fewer adverse 
events than conventional TACE. Therefore, the purpose of this study is to determine whether 
DEB-TACE can be used safely and effectively to treat patients with liver-only HCC and hepatic 
dysfunction. 
2.0 
OBJECTIVES 
Primary Objective 
• To determine the safety of DEB-TACE in patients with HCC confined to liver who are 
being considered for liver transplantation 
• To determine the response rate to DEB-TACE by conventional and modified Response 
Evaluation Criteria in Solid Tumors (RECIST version 1.1, mRECIST [22]) for treated 
lesions in patients with liver-only HCC who are being considered for liver transplantation. 
 
Secondary Objectives 
• To measure overall radiographic response (by RECIST v1.1 and mRECIST) 6 months after 
the date of the first planned DEB-TACE procedure. To measure time to untreatable 
progression (TTUP). TTUP is defined as time to disease progression untreatable by liver-
directed percutaneous or surgical methods.  
• To measure median time to progression (TTP)  
• To measure hepatic progression free survival (HPFS) 
• To measure progression free survival (PFS)  
• To measure overall survival (OS). 
• To determine the proportion of patients who remain active on the wait list for a liver 
transplant and eventually are transplanted. 
• To determine the proportion of patients who are inactivated or drop out from the wait list 
for any reason but transplantation. 
• To determine the proportions of patients who are successfully down-staged and achiev 
active waitlist status and eventually are transplanted. 
• To measure proportion with alpha-fetoprotein (AFP) response with ≥ 50% decline from 
baseline (in patients with baseline level ≥ 20) post DEB-TACE and test for association with 
hepatic and overall response rate, PFS, and OS.  
• To determine whether changes in cardiac function occur as a result of DEB-TACE with 
doxorubicin 
• To obtain pharmacokinetic data for doxorubicin administered as a part of DEB-TACE 
procedures 
 
Exploratory/Other Objectives 
• To describe treatment response by histopathology at the time of liver transplantation (in the 
subgroup of patients who undergo LT). 

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3.0 
STUDY DESIGN 
This is a prospective open-label two-stage phase II clinical trial to evaluate the safety and 
efficacy of DEB-TACE in patients with liver-only HCC and hepatic dysfunction who are being 
considered for a liver transplant. Seventeen patients will be enrolled during the first stage of the 
study for efficacy. Subsequently, 34 patients will be enrolled into the second stage of the study. 
Prior surgical resection or liver-directed therapy will be allowed. Patients will be followed for 
one year following DEB-TACE. This study will take up to five years to complete. 
3.1 
Single DEB-TACE procedure algorithm 
Patients who meet the eligibility criteria in Section 4.0 and present with HCC confined to one 
liver segment supplied entirely by one segmental branch of the hepatic artery the right or the left 
hepatic artery will be offered a single DEB-TACE treatment intended to target the entire tumor 
vasculature. The following algorithm will be adhered to for patients with disease confined to one 
liver lobe or segment: 
 
One to sixty days prior to treatment, patients will undergo imaging of the abdomen with contrast-
enhanced CT or MRI. Within one to six days prior to DEB-TACE, laboratory tests including 
CBC, BUN, creatinine, coagulation panel, liver function tests, and serum alpha-fetoprotein level 
(AFP) will be performed. A history and physical examination will be performed within six days 
prior to and the day of DEB-TACE (Table 1). 
 
For the purposes of DEB-TACE procedure, hepatic angiogram will be performed in the standard 
fashion via a common femoral artery approach. Coaxial microcatheter will be used for selective 
catheterization of a segmental or subsegmental hepatic artery branch. Up to two 2 ml vials of 
100-300µm LC-Beads™ impregnated per manufacturer-supplied protocol with 25mg of 
doxorubicin per ml of beads will be administered into the catheterized hepatic artery. Procedure 
will be stopped when arterial flow approaches stasis and/or when the entire DEB dose has been 
administered. 
 
Patients will be on bed rest for approximately 4-8 hours following removal of the femoral artery 
catheter. Per institutional standard, they will be admitted for planned overnight observation to the 
hospital and discharged once determined to be in stable condition.  Management after each DEB-
TACE procedure will be according to institutional standard of care. 
 
Patient follow-up is summarized in section 8.4 and section 8.4.1. 
3.2 
Treatment Algorithm for Multiple DEB-TACE procedures 
Patients who meet the eligibility criteria in Section 4.0 with a lesion or lesions supplied by more 
than one segmental hepatic artery branch will be considered for up to four sequential DEB-
TACE procedures intended to target the entire tumor vascular supply in a step-wise fashion. The 
number of procedures will be based on the number, location, and size of the lesions as well as on 
the hepatic arterial anatomy up to a maximum of 4 DEB-TACE procedures. This information 
will be obtained from the pre-procedure cross-sectional imaging (CT or MRI), hepatic artery 
angiography, and C-arm CT (when applicable). 
 

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Sequential DEB-TACE may be offered in the following settings: 
A. Multifocal HCC (UNOS T2 or T3 disease; no radiographic evidence of macrovascular 
invasion or extracapsular extension) 
B. Single HCC greater than 3 cm (UNOS T2 or T3 disease without radiographic evidence of 
macrovascular invasion or extracapsular extension). 
C. More than 1 segmental feeding hepatic artery branch to a lesion of any size. 
 
Pre-procedure evaluation will be the same as for patients undergoing one DEB-TACE procedure 
(Table 2). For each DEB-TACE procedure, up to two 2 ml vials of 100-300µm LC-Beads® 
impregnated per manufacturer-supplied protocol with 25mg of doxorubicin per ml of beads will 
be administered into the catheterized hepatic artery. Procedure will be stopped when arterial flow 
approaches stasis and/or when the entire DEB dose has been administered. 
 
Sequential DEB-TACE procedures will be performed approximately 1 month apart. Longer 
intervals between the procedures may be necessary. The timing of DEB-TACE will be 
determined by the treating interventional radiologist and hepatologist or medical oncologist. The 
number of procedures (up to 4 total) will be based on the number, location, and size of the 
lesions as well as on the hepatic arterial supply to the lesions. This information will be obtained 
from the pre-procedure cross-sectional imaging (CT or MRI) and hepatic artery angiography. 
This step-wise approach is intended to target the entire tumor vascular supply in a step-wise 
fashion prior to assessing response to therapy. 
  
The maximum administered doxorubicin dose per DEB-TACE procedure (session) will be 
100mg (50 mg per each 2 ml vial of 100-300µm LC beads). The maximum administered dose as 
a result of four DEB-TACE procedures will be 400 mg.  
 
Post-procedure follow-up for the first month after DEB-TACE will be as outlined in Table 2. 
Additional treatment will be offered if the following criteria are met: 
1. Patient is willing to undergo additional DEB-TACE treatment. 
2. Patient meets all of the inclusion criteria and none of the exclusion criteria (see sections 4.2 
and 4.3 below) at the time of 20-day follow-up. 
 
Patient follow-up is summarized in section 8.4 and section 8.4.2. 
4.0 
ELIGIBILITY CRITERIA 
4.1 
Subject Population 
Patients with liver-only HCC UNOS stage T1, T2, or T3 being considered for liver 
transplantation at UCSF will be eligible. Patients who have undergone prior resection, 
chemoembolization, radioembolization, bland embolization, ablative therapy or systemic therapy 
will be eligible to participate in the study. 
 
Treatment with DEB-TACE will be offered to patients being considered for liver transplantation 
under one of the following protocols: 
 

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1. Milan criteria: One lesion less than 5 cm or up to 3 lesions each less than 3 cm. 
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. UCSF All-Comers criteria: UNOS stage T3 disease beyond UCSF Downstaging Criteria. 
4.2 
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 AFP level >200U/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: 
a. Milan criteria (one lesion < 5cm or 3 or fewer lesions each < 3cm),  
b. 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)  
c. 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 
mRECIST criteria. 
6. At least one of the following clinical, laboratory, or imaging parameters:  
a. Mild or moderate ascites 
b. Serum bilirubin ≥ 3 mg/dl but less than 6 mg/dl 
c. Aspartate aminotransferase (AST) > 5 times upper limit of normal (ULN) but < 10 
times ULN 
d. Alanine aminotransferase (ALT) > 5 times upper limit of normal (ULN) but < 10 times 
ULN 
e. International normalized ratio for prothrombin time (INR) >1.5 but ≤ 2.5 
f. Bland portal vein thrombosis (branch or main) 
g. Functioning transjugular intrahepatic portosystemic shunt (TIPS) or surgical 
portosystemic shunt 
7. ECOG performance status of 0, 1, or 2. 
8. Ability to give written informed consent. 
 
Patients should meet the above study entry criteria at study enrollment as well as prior to 
undergoing each subsequent DEB-TACE procedure.  
 
4.3 
Exclusion Criteria 
1. Liver-directed therapy (chemoembolization, radioembolization, bland embolization, 
ablative therapy) within 4 weeks of DEB-TACE. 
2. Previous liver transplantation. 

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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. 
4.4 
Subject Selection 
Participants who meet the eligibility criteria above will be evaluated by the UCSF liver tumor 
board, which consists of Hepatology, Medical Oncology, Transplant Surgery, and Interventional 
Radiology services. The team will determine which patients should be offered this therapy. 
Patients who meet eligibility criteria will be referred for possible treatment. 

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5.0 
SUBJECT REGISTRATION 
All patients who are consented will be entered into the UCSF Cancer Center OnCore® database. 
The OnCore® database is password protected and meets HIPAA guidelines. 
 
To register patients on-study, study personnel will complete an eligibility form. Study ID 
numbers for each patient will be assigned serially. Pertinent information will be entered from the 
patient medical record. 
6.0 
TREATMENT PLAN 
Segmental hepatic artery catheterization will be performed via femoral artery approach using a 
combination of 3-French, 4-French, and 5-French angiographic catheters. Segmental DEB-
TACE will be performed using two 2ml vials of LC beads (Biocompatibles, Inc.) impregnated 
per standard manufacturer-supplied protocol with a total of 100 mg of doxorubicin (25 mg per 
milliliter of beads). Microspheres in the size range of 100-300µm will be used. Procedure will be 
stopped when arterial flow approaches stasis and/or when the entire DEB dose has been 
administered. 
 
Patients with multiple liver lesions, lesions >3 cm, or lesions with more than 1 feeding branch 
hepatic artery may receive additional DEB-TACE at approximately 1 month intervals. Cross-
sectional imaging (contrast-enhanced CT or MRI) will be performed approximately 1 month 
after targeting of all hepatic lesions in the course of 1-4 DEB-TACE procedures. Patients with 
residual or recurrent disease may receive up to 4 total DEB-TACE procedures. 
7.0 
TOXICITY MANAGEMENT 
Once they are enrolled in the study, patients will be discussed at the gastrointestinal oncology 
site committee meeting at bi-weekly intervals for the first month following each DEB-TACE 
treatment. Any adverse events grade ≥ 4 will be discussed by the interventional radiologist and 
medical oncologist or hepatologist within 24 hours of being informed of the event. 
7.1 
Liver toxicity 
Up to one half of the patients are expected to experience at least one liver-related side effect 
following DEB-TACE. Liver-related toxicities, for which all patients will be monitored include 
elevation the serum bilirubin level, increase in aspartate or alanine aminotransferase, 
development of ascites, hepatic encephalopathy, hepatorenal syndrome, liver failure, hemobilia, 
gastrointestinal hemorrhage, cholangitis, liver abscess, and bile duct stricture. Most of these 
toxicities (80%) are expected return to pre-treatment levels. However, some may persist and may 
be exacerbated by tumor progression and/or advancing cirrhosis. Risk of liver toxicity will be 
minimized by performing segmental or subsegmental DEB-TACE whenever possible. 
 
Patients will be screened for presence of laboratory liver function test abnormalities at 10-day 
intervals for the first month following each DEB-TACE treatment. Any abnormal lab values will 
be followed as clinically indicated. Patients with ascites will be followed clinically and will be 
treated if symptoms referable to ascites develop. Patients with hepatic encephalopathy, 

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hepatorenal syndrome, liver failure, hemobilia, gastrointestinal hemorrhage, cholangitis, liver 
abscess, and bile duct stricture will be treated according to the current standard of care. 
7.2 
Renal toxicity 
Renal toxicity may be related to administration of iodinated contrast at the time of DEB-TACE 
or to development or exacerbation of the hepatorenal syndrome. Renal toxicity is expected to 
occur in fewer than 10% of patients. If renal impairment occurs, patients will be treated 
medically. Renal replacement therapy will be initiated if clinically indicated. 
7.3 
Postembolization syndrome 
A combination of abdominal pain, nausea/vomiting, fever, fatigue, and anorexia constitutes the 
post-embolization syndrome. The risk of postembolization syndrome related to DEB-TACE is 
estimated at 50-70%. While the risk of post-embolization syndrome is high, the symptoms are 
usually self-limited after a period of 10-14 days. Symptoms are expected to be most severe 
within the first 24 hours of DEB-TACE. Therefore, all patients will be admitted for 23-hour 
inpatient observation as per standard of care at UCSF for intravenous fluids, analgesic, and 
antiemetic therapy. Upon discharge, patients will be given a prescription for oral opiate analgesic 
and antiemetic agents. 
7.4 
Side effects of angiography and embolization 
Side effects of angiography may include access site hematoma, arterial injury (dissection, 
thrombosis) related to catheter or wire manipulation, allergic reactions to iodinated contrast 
(rash, dyspnea, hypotension, cardiopulmonary arrest), and contrast-induced nephropathy. The 
risks of angiography are small, with access site hematoma being the most common side effect 
occurring in < 5% of patients. 
7.5 
Drug-drug interactions 
Patients who are receiving P-glycoprotein inhibitors and CYP2D6 substrates that have a narrow 
therapeutic index for the potential risk of increased adverse events. However this risk of a drug 
interaction with systemically administered drugs might be low following intra-arterial bead-
bound doxorubicin as compared to intravenous administration of doxorubicin.  
 
Because of possible hepatotoxic and nephrotoxic effect of TACE, concurrent use of hepatotoxic 
and nephrotoxic drugs will be avoided. 

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8.0 
EVALUATIONS AND PROCEDURES 
Table 2 
Schedule of Events: Single Deb-TACE 
 
Pre-treatment 
Screening 
Evaluation 
DEB-
TACE 
Post Treatment Evaluation 
 
-60 to 
0 days 
-6 ±6d 
 
Day 0 
1 
±0d 
7 
±4d 
30 
±7d 
90 
±14d 
180 
±14d 
270 
±14d 
360 
±14d 
Clinical/Administrative Activities 
  
  
 
  
  
  
  
  
  
  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
ECOG Performance Status (See Appendix 1) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Child Pugh Turcotte Score (See Appendix 2) 
X 
 
 
 
 
X 
X 
X 
X 
X 
MELD Score (See Appendix 3) 
X 
 
 
 
 
X 
X 
X 
X 
X 
Interim History + Physical Exam 
 
 
 
 
X* 
X 
X 
X 
X 
X 
Evaluation of Response 
 
 
 
 
 
X 
X 
X 
X 
X 
Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
CBC, Coagulation Panel, BUN, Creatinine, 
Liver Function Tests 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Alpha-fetoprotein 
 
X 
 
 
 
X 
X 
X 
X 
X 
Imaging Studies 
 
 
 
 
 
 
 
 
 
 
Contrast-Enhanced CT or MRI of the abdomen  
X 
 
 
 
 
X 
X 
X 
X 
X 
CT chest with and/or without contrast 
X 
 
 
 
 
 
X 
X 
X 
X 
Cardiac Function Assessment 
Echocardiogram 
X& 
 
 
 
 
X& 
 
 
 
 
DEB-TACE Procedure 
 
 
 
 
 
 
 
 
 
 
DEB-TACE 
 
 
X 
 
 
 
 
 
 
 
Pharmacokinetics Evaluation 
Pharmacokinetics sample acquisition** 
 
 
X 
X 
X 
 
 
 
 
 
Abbreviation: d = days 
* May be substituted by telephone follow-up by interventional radiology nurse practitioner for patients who are non-local study participants. 
 
&     Cardiac function will be assessed via echocardiogram at baseline and one month following last planned DEB-TACE. 
**    See plan for pharmacokinetic data acquisition in Sections 8.1 and 8.4

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Table 3 
Schedule of Events: Multiple DEB-TACE procedures* 
 
Pre-treatment 
Evaluation 
DEB-
TACE 
1 
Evaluation 
TACE 1 
DEB-
TACE 
2 
Evaluation 
TACE 2 
DEB-
TACE 
3 
Post Treatment 
Evaluation 
TACE 3 
DEB-
TACE 
4** 
 
-60 to 
0 days 
-6 ±6d 
Day 0 
1d 
 
7 
±4d 
30 
+30d 
(Reset 
to d0) 
1d 
 
7 
±4d 
30 
+30d 
(Reset 
to d0) 
1 
 
7 
±4d 
30 
+30d 
(Reset 
to d0) 
Clinical / Administrative 
Activities 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
Child Pugh Turcotte Score  
(See Appendix 2) 
X 
 
 
 
 
 
 
 
 
 
 
 
MELD Score (See Appendix 3) 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Interim History + Physical 
Exam 
 
 
 
 
X 
X 
 
X 
X 
 
X 
X 
Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
CBC, Coagulation Panel,  
BUN, Creatinine, Liver 
Function Tests 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alpha-fetoprotein 
 
X 
 
 
 
 
 
 
 
 
 
 
Imaging Studies 
 
 
 
 
 
 
 
 
 
 
 
 
Contrast-Enhanced CT or MRI 
of the abdomen  
X 
 
 
 
 
 
 
 
 
 
 
 
CT chest with and/or without 
contrast 
X 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Function Assessment 
Echocardiogram 
X& 
 
 
 
 
X& 
 
 
X& 
 
 
X& 
DEB-TACE Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
DEB-TACE** 
 
 
X 
 
 
X** 
 
 
X** 
 
 
X** 
Pharmacokinetics Evaluation 
Pharmacokinetics data 
acquisition*** 
 
 
X 
X 
X 
 
 
 
 
 
 
 
Abbreviation: d = days 
* 
See Table 2 for post-treatment evaluation after DEB-TACE 4. DEB-TACE 3 and 4 are optional for patients with disease extent limited to two liver 
segments. Patients may proceed to evaluation of response and long-term follow-up after fewer than 4 DEB-TACE treatments at the investigator’s 
discretion. 
 
&     Cardiac function will be assessed via echocardiogram at baseline and one month following last planned DEB-TACE. 
** Up to 4 DEB-TACE procedures may be performed at approximately 1 month intervals depending upon initial size, number, vascular supply of 
lesion(s) and interval treatment response on imaging. 
*** See plan for pharmacokinetic data acquisition in Sections 8.1 and 8.4 
 
8.1 
Screening/Baseline 
Prior to enrollment, patients will be seen by a hepatologist and/or a medical oncologist at UCSF 
and evaluated for all possible treatment options, one of which will include DEB-TACE. Prior to 
enrollment, all patients will be discussed in the multidisciplinary liver tumor board, which 

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includes hepalogists, medical and surgical oncologists, and interventional radiologists. If the 
patient is deemed a good candidate for the procedure, the patient will then be referred to the 
interventional radiologist for DEB-TACE.  Patients will be offered the opportunity to be 
screened for study participation.   After informed consent is obtained, pre-procedure assessment 
is summarized in Table 1. 
 
Approximately zero to sixty days prior to DEB-TACE, the following will be performed to 
determine eligibility: 
• cross sectional imaging of the abdomen using multi-phase CT or MRI with IV contrast 
• CT scan of chest (with and/or without contrast)  
• baseline laboratory tests  
• clinical history and physical examination  
 
Approximately zero to twelve days prior to DEB-TACE, the following additional procedures 
will be performed (if the initial screening is performed outside 12-day window): 
• Laboratory testing including liver function tests, CBC, BUN, creatinine, coagulation 
profile, and serum alpha-fetoprotein level 
• Medical history and physical examination 
• ECOG performance status 
 
Baseline cardiac function monitoring using echocardiogram will be performed approximately 
zero to 720 days prior to first planned DEB-TACE 
 
One day prior to DEB-TACE, the UCSF Inpatient Pharmacy will be instructed by the 
interventional radiologist to start incubation of two 2ml vials of 100-300 µmLC Beads® with 
100mg doxorubicin (25mg/ml of beads) per manufacturer-supplied instructions for use (currently 
not cleared by the FDA for use). 
8.2 
Treatment 
The patient will come directly to the Interventional Radiology on the day of the procedure after 
an overnight fast. Moderate sedation will be supervised by the interventional radiologist 
performing the procedure. The patients will be continuously monitored during the procedure by 
an IR nurse. Access to the hepatic artery will be achieved using an angiographic catheter placed 
in the femoral artery. An angiographic catheter will be directed under fluoroscopic guidance to 
the appropriate location in the hepatic artery. Doxorubicin-loaded LC bead™ will be mixed with 
non-ionic iodinated contrast (per manufacturer-supplied instructions for use) and administered 
into the target hepatic artery branch under continuous fluoroscopic guidance by the 
interventional radiologist until flow approaches stasis or until the entire DEB dose is 
administered. 
 
The investigators will estimate the total amount of doxorubicin administered for each DEB-
TACE procedure using the following formula: 
 
 
Doxorubicin dose = 0.98 * 50mg *[% of vial 1 delivered + % of vial 2 delivered]/100 
 

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In the formula, correction factor 0.98 accounts for incomplete absorption of doxorubicin to LC 
Bead™, while 50 mg is the doxorubicin dose to be mixed with each 2 ml vial of beads. 
 
Estimated doxorubicin dose will be recorded in patients’ study charts and will be recorded in the 
medical record. 
 
Pharmacokinetics data for doxorubicin will be collected by obtaining peripheral venous blood 
samples from the first 17 patients at the time of completion of the first planned DEB-TACE, and 
subsequently 5±1 min, 30±5 min, 60±5 min, 120±10 min, 6±0.5 hours, 20±2 hours, and 8±2 
days following administration of 100-300 mm doxorubicin-impregnated LC bead™. 
 
All patients will be admitted to the hospital for planned 23-hour observation upon completion of 
the procedure and will then be discharged home once determined to be in stable condition.  
Management after each DEB-TACE procedure will be according to institutional standard of care. 
8.3 
Multiple DEB-TACE Procedures Targeting Different Vascular Territories 
 
Sequential DEB-TACE procedures may be offered in the following settings: 
A. Multifocal HCC (UNOS T2 or T3 disease; no radiographic evidence of macrovascular 
invasion or extracapsular extension). 
B. Single HCC greater than 3 cm (UNOS T2 or T3 disease without radiographic evidence of 
macrovascular invasion or extracapsular extension). 
C. More than 1 segmental feeding hepatic artery branch to a lesion of any size. 
 
Patients with lesions that meet at least one of these criteria will be considered for up to four 
DEB-TACE procedures that will be performed approximately 1 month apart. Longer intervals 
between the procedures may be necessary in order to allow patients to regain pre-TACE liver 
function and performance status. Intervals between DEB-TACE procedures up to 90 days will be 
allowed. The timing of DEB-TACE will be determined by the treating interventional radiologist 
and hepatologist or medical oncologist. The number of procedures (up to 4 total) will be based 
on the number, location, and size of the lesions as well as on the hepatic arterial supply to the 
lesions. This information will be obtained from the pre-procedure cross-sectional imaging (CT or 
MRI) and hepatic artery angiography. This step-wise approach is intended to target the entire 
tumor vascular supply in a step-wise fashion prior to assessing response to therapy (Table 2).  
 
The maximum administered doxorubicin dose per DEB-TACE procedure will be 100mg (50 mg 
per each 2 ml vial). The maximum administered dose as a result of four DEB-TACE procedures 
will be 400 mg.  
8.4 
Follow-Up Assessments 
Vast majority of the adverse effects of DEB-TACE are expected to occur within 30 days of 
treatment. For the first month following each DEB-TACE, the patient’s progress will be 
monitored at bi-weekly intervals at the gastrointestinal oncology site committee by a team 
consisting of medical oncologists and interventional radiologists. 

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8.4.1 Patients with Single DEB-TACE Procedure 
The following laboratory testing will be performed 1, 7±4, 30±7, 90±14, 180±14, 270±14, and 
360±14 days following DEB-TACE: CBC, coagulation panel, BUN, creatinine, and liver 
function tests. Serum alpha-fetoprotein testing will start approximately 30 days following last 
planned DEB-TACE procedure. Any abnormal lab values will be followed up as clinically 
indicated. Laboratory tests may be performed at UCSF or at a local lab. 
 
Seven ±4 days following DEB-TACE patients will have clinic follow up in Interventional 
Radiology for toxicity monitoring including reviewing the laboratory results above. Any 
expected or unexpected AEs will be discussed with the study PI or a designated co-investigator. 
Further testing and/or treatment will be coordinated by the study PI or a designated co-
investigator if clinically appropriate (see section 7). 
 
Cardiac function assessment monitoring using echocardiogram will be obtained approximately 
30 days following the DEB-TACE procedure. 
 
Patients will be seen in clinic approximately one month after the DEB-TACE procedure. During 
this visit, interim medical history will be obtained, and a physical examination will be 
performed. This will include (but will not be limited to) cardiopulmonary evaluation and an 
abdominal exam. Subsequently, patients will be followed in clinic at approximately 3 month 
intervals until 360 days following DEB-TACE.  
 
Approximately one month after DEB-TACE procedure, patients will undergo repeat cross-
sectional imaging with multi-phase contrast-enhanced CT or MRI of the abdomen. Subsequent 
imaging will be performed at approximately 3 month-intervals until 360 days following DEB-
TACE. Standard clinical practices will be adhered to during the follow-up period. 
 
Response to treatment will be assessed according to the RECIST version 1.1 and mRECIST 
criteria (see section 9.2). 
 
Patients will be removed from study and follow-up assessments will stop prior to 360 days 
following DEB-TACE if a patient:  
a) requires > 4 DEB-TACE procedures 
b) requires another anti-cancer treatment modality such as ablation, surgery, or conventional 
TACE  
c) receives a liver transplant 
d) develops untreatable intrahepatic or extrahepatic disease progression 
e) experiences unacceptable toxicity (see section 10.0). All serious adverse events will be 
followed until the SAE has been resolved. 
 
Pathology report describing the extent of HCC in the liver explant will be reviewed for the subset 
of patients who undergo LT. 
8.4.2 Patients with Multiple DEB-TACE Procedures 
The following laboratory testing will be performed 1 and 7±4 days following each DEB-TACE: 
CBC, coagulation panel, BUN, creatinine, and liver function tests. Any abnormal lab values will 

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be followed up as clinically indicated. Laboratory tests may be performed at UCSF or at a local 
lab. 
 
Seven ±4 days following DEB-TACE patients will have clinic follow up in Interventional 
Radiology for toxicity monitoring including reviewing the laboratory results above. Any 
expected or unexpected AEs will be discussed with the study PI or a designated co-investigator.  
Further testing and/or treatment will be coordinated by the study PI or a designated co-
investigator if clinically appropriate (see section 7). 
 
Cardiac function assessment monitoring using echocardiogram will be obtained approximately 
30 days following last planned DEB-TACE procedure. 
 
Candidacy for repeat DEB-TACE (sessions 2-4) will be based on laboratory and clinical follow-
up on day 7 ± 4 and on the day of scheduled repeat DEB-TACE (sessions 2-4). The decision to 
delay or cancel subsequent planned DEB-TACE procedures would be at the discretion of the 
treating interventional radiologist, hepatologist, or medical oncologist. This decision will be 
based on currently used clinical practice standards at UCSF. 
 
Upon completion of 2-4 planned DEB-TACE treatment sessions, the following laboratory testing 
will be performed 1, 7±4, 30±7, 90±14, 180±14, 270±14, and 360 ±14 days following DEB-
TACE: CBC, coagulation panel, BUN, creatinine, and liver function tests. Serum Alpha-
fetoprotein testing will start 30 days following last planned DEB-TACE procedure. Any 
abnormal lab values will be followed up as clinically indicated. 
 
Patients will be seen in clinic approximately one month after the last planned DEB-TACE 
procedure. During this visit, interim medical history will be obtained, and a physical examination 
will be performed. This will include (but will not be limited to) cardiopulmonary evaluation and 
an abdominal exam. Subsequently, patients will be followed in clinic at approximately 3 month 
intervals until 360 days following DEB-TACE.  
 
Approximately one month after last planned DEB-TACE procedure, patients will undergo repeat 
cross-sectional imaging with multi-phase contrast-enhanced CT or MRI of the abdomen. First 
follow-up imaging study will be obtained no more than 6 months following the first DEB-TACE 
procedure. Subsequent imaging will be performed at approximately 3 month-intervals until 360 
days following DEB-TACE. Standard clinical practices will be adhered to during the follow-up 
period. 
 
Response to treatment will be assessed according to RECIST version 1.1 and mRECIST criteria 
(see section 9.2). 
 
Patients will be removed from study and follow-up assessments will stop prior to 360 days 
following DEB-TACE if a patient:  
 
a) requires > 4 DEB-TACE procedures 
b) requires another anti-cancer treatment modality such as ablation, surgery, or conventional 
TACE  

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c) receives a liver transplant 
d) develops untreatable intrahepatic or extrahepatic disease progression 
e) experiences unacceptable toxicity (see section 10.1). All serious adverse events will be 
followed until the SAE has been resolved. 
 
Pathology report describing the extent of HCC in the liver explant will be reviewed for the subset 
of patients who undergo LT. 
8.5 Ancillary Therapy 
Patients should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, analgesics, antiemetics, etc., when appropriate. 
 
Patients taking concomitant medications known to be metabolized by the liver should be closely 
observed for side effects. Patients taking narrow therapeutic index medications that are 
hepatically metabolized should be monitored proactively. These medications include warfarin, 
phenytoin, quinidine, carbamazepine, phenobarbital, cyclosporin and digoxin. No medication is 
specifically prohibited, and there are no specific dietary restrictions. 
 
9.0 
CRITERIA FOR EVALUATION 
The primary endpoints of this study are to evaluate the safety and efficacy of DEB-TACE in 
patients with marginal hepatic function. 
9.1 
Safety 
Safety data will be collected as a part of this clinical protocol. The assessments will be based on 
post-procedure clinical evaluations, laboratory tests, and imaging studies (see section 8 for more 
details). Six weeks after all 17 patients have been treated with at least one DEB-TACE, data on 
DEB-TACE safety profile will be analyzed. Final safety analysis will be performed 6 weeks after 
all 51 patients have been treated with at least one DEB-TACE.  
9.2 
Efficacy 
Evaluation of the treatment response will be based on contrast-enhanced cross-sectional imaging 
of the abdomen (CT or MRI) performed one month following last planned DEB-TACE 
procedure within six months of the first DEB-TACE procedure. Treatment response will be 
evaluated according to both the RECIST version 1.1 and mRECIST criteria. Whenever possible, 
the same imaging modality (CT or MRI) will be used for pre- and post-treatment assessments. 
9.2.1 RECIST Definitions 
Measurable Disease:  The presence of at least one measurable lesion. If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
Measurable Lesion:  The lesion can be accurately measured in at least one dimension [longest 
diameter to be recorded] as ≥10 mm with spiral CT scan. 
 
Nonmeasureable Lesion:  All other lesions, including small lesions [<10 mm with spiral CT 
scan] and truly nonmeasurable lesions. 

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Complete Response (CR):  Disappearance of all target lesions 
 
Partial Response (PR):  30% decrease in the sum of the longest diameter of target lesions 
 
Stable Disease (SD):  Small changes that do not meet the criteria for CR, PR, or PD 
 
Progressive Disease (PD):  20% increase in the sum of the longest diameter of target lesions 
9.2.2 RECIST Guidelines 
• All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. 
• All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
• Assessment will be performed using conventional imaging methods (CT, MRI). 
• The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
• Up to three measurable lesions will be identified as target lesions.  Target lesions will be 
selected on basis of size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (lesions can be located/identified during follow-up as well as 
baseline). 
• Target lesions will be measured in one dimension.  A sum of the longest diameter (LD) for 
all target lesions will be calculated and reported as the baseline sum LD. The baseline sum 
LD will be used as reference by which to characterize the objective tumor. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence or absence 
of each should be noted throughout follow-up. 
 
 
9.2.3 mRECIST Definitions (See Appendix 4) 
Measurable Disease:  The presence of at least one measurable lesion.  
 
Measurable Lesion:  The lesion can be accurately measured in at least one dimension [longest 
diameter to be recorded] as ≥10 mm with spiral CT or MRI scan. 
 
Nonmeasureable Lesion:  All other lesions, including small lesions [<10 mm with spiral CT scan 
or MRI] and truly nonmeasurable lesions (infiltrative lesions). 
 
Complete Response (CR):  Disappearance of any intratumoral arterial enhancement in all target 
lesions 
 
Partial Response (PR):  30% decrease in the sum of diameters of viable (enhancement in the 
arterial phase) target lesions, taking as reference the baseline sum of the diameters of target 
lesions 
 

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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 
(enhancing) target lesions recorded since treatment started 
 
9.2.4 mRECIST Guidelines (See Appendix 4) 
• All eligible patients with measurable disease at baseline will be included in the analysis for 
efficacy. 
• All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. 
• All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
• Assessment will be performed using conventional imaging methods (CT, MRI). 
• The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. 
• Up to three measurable lesions will be identified as target lesions.  Target lesions will be 
selected on basis of size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (lesions can be located/identified during follow-up as well as 
baseline). 
• Target lesions will be measured in one dimension.  A sum of the longest diameter (LD) for 
all target lesions will be calculated and reported as the baseline sum LD. The baseline sum 
LD will be used as reference by which to characterize the objective tumor. 
• All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
 
The measurement of the longest diameter of the viable tumor may be challenging in lesions 
showing partial internal necrosis. The following points should be taken into account in such 
cases: 
• The measurement of the viable tumor should be performed on CT or MRI obtained in the 
arterial phase, when the contrast between viable vascularized tumor tissue and 
nonenhancing necrotic tissue is the highest. 
• The longest diameter of the viable tumor is not necessarily located in the same scan plane 
in which the baseline diameter was measured: a thorough careful evaluation of the CT or 
MRI scans is required. 
• The measurement of the viable tumor diameter should not include any major intervening 
areas of necrosis. 
10.0 CRITERIA FOR STUDY TERMINATION 
10.1 STOPPING RULES FOR SAFETY. 
 
 
10.1.1 Rationale 

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A retrospective analysis of toxicity of conventional TACE method for UCSF patients with HCC 
and hepatic dysfunction, which included 252 patients and 446 TACE procedures was recently 
completed (24). This cohort included 166 patients who met the more stringent inclusion criteria 
for the current study. These patients underwent a total of 260 TACE procedures. In this patient 
cohort, 20 patients (12%) developed NCI CTCAE grade 4 hepatotoxicity that persisted 1 month 
following TACE. Of note, patients who had irreversible grade 4 hyperbilirubinemia with or 
without grade 4 transaminitis had a 27.7% rate of mortality or required an urgent liver transplant 
within 6 weeks of TACE. This rate was higher than that for patients who had grade 4 
transaminitis without grade 4 hyperbilirubinemia, 11.1% of whom died or required an urgent 
liver transplant within 6 weeks of TACE. These findings suggested that irreversible 
hyperbilirubinemia was a more robust predictor of mortality or TACE-induced liver failure 
requiring salvage transplantation than transaminitis. 
 
Based on the same retrospective study (24), a total of 2 patients (1.2%) had grade 4 renal toxicity 
that persisted 1 month following TACE.  
 
Based on the same retrospective study (24), mortality rate 6 weeks following TACE was 4.8% (8 
patients). 
 
No published comparable safety data is available for DEB-TACE with regards to the patient 
population to be studied. However, a total of 37 patients with marginal liver function (within 
proposed inclusion criteria for this study) have been treated between 2011 and 2013. Their 
records were retrospectively reviewed. Preliminary results on adverse events following DEB-
TACE are summarized in Table 1. No treatment-related deaths and no events hepatic 
decompensation requiring an urgent liver transplant were encountered in this patient cohort. 
 
Stopping rules for safety were determined based on the assumption that DEB-TACE may be 
associated with similar rates of morbidity as conventional TACE. 
 
 
10.1.2 Specific Stopping Rules for Safety 
 
Safety data will be routinely monitored and sequential safety assessments will be conducted as 
subjects are enrolling to the study. The study will be stopped due to safety/toxicity concern prior 
to interim efficacy analysis if any of the following 3 stopping rules are met: 
 
1. Liver dysfunction (clinical or laboratory [total serum bilirubin], grade 4) that does not 
improve to baseline or </= grade 3 within 1 month following DEB-TACE in ≥ 7 patients 
(12% of 51 patients). 
 
OR 
 
2. Renal dysfunction (clinical or laboratory [serum creatinine], grade 3 or 4) that does not 
improve to baseline or </= grade 2 within 1 month following DEB-TACE in ≥ 2 patients 
(1.2% of 51 patients). 
 

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OR 
 
3. Any grade 5 AE (death) attributed as at least possibly-related to study intervention in ≥ 3 
patients (4.8% of 51 patients). 
 
The stopping rules above were used to generate the following chart, which will be adhered to 
with regards to stopping enrollment for the reasons of severe toxicity. 
 
Table 4. Number of patients with defined safety/toxicity for the study to be stopped during 
sequential and continuous safety assessments (based on binomial distribution) 
 
Number patients enrolled in study 
3 
7 
11 
13 
17 
23 
Number of patients with grade 4 
liver dysfunction, grade 4 renal 
dysfunction, or study-related death 
2 
4 
6 
7 
8 
9 
% chance of stopping enrollment if 
true SAE rate is <15% 
94% 
99% 
99% 
99% 
99% 
99% 
% chance of stopping enrollment if 
true SAE rate is <20% 
90% 
97% 
99% 
99% 
99% 
97% 
% chance of stopping enrollment if 
true SAE rate is < 30% 
78% 
87% 
92% 
94% 
90% 
77% 
Note: the study will also be terminated early if any of the 3 stopping rules is observed. 
 
Adverse events grade ≥ 4 will be discussed by the interventional radiologist and medical 
oncologist and/or hepatologist within 1 business day of being informed of the event. If at any 
time a patient has a fatal complication at least possibly related to treatment, the study will 
immediately be put on hold.  At that time, the data will be reviewed by a multidisciplinary team 
as to the etiology.  If it is determined that the death was attributed as at least possibly-related to 
treatment, the study investigators will meet to discuss if the study should continue. 
 
The patients will also be monitored for development or worsening of other recognized 
complications of DEB-TACE including ascites, hepatic encephalopathy, hepatorenal syndrome, 
biliary injury (stricture or leak), cholangitis, cholecystitis, hepatic abscess, abdominal pain, 
nausea, vomiting, fatigue, and fever. The study may be placed on hold or terminated based on 
development of these adverse events in study participants. 
 
10.2 STOPPING RULES FOR EFFICACY 
 
When 17 evaluable patients have been treated with at least one DEB-TACE procedure and had 
potential for at least 1 month of follow up, efficacy profile will be analyzed. Accrual will 
continue during this interim analysis period. 
 
Stopping Rule for Efficacy after 17 patients have completed last planned DEB-TACE 

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1. If four (4) or fewer responses (complete, partial, or stable disease response according to 
mRECIST in treated lesion(s) approximately 1 month after last planned DEB-TACE) are 
observed among first stage of 17 patients.  
 
During the interim efficacy analysis of 17 patients, if four or fewer complete, partial, or stable 
disease responses are observed in treated lesions by mRECIST on imaging approximately 1 
month after last planned DEB-TACE during the first stage, the study will be stopped early; 
otherwise, additional 34 patients will be accrued. If fourteen or fewer responses are observed by 
the end of the study, then no further investigation is warranted for DEB-TACE. 
 
Under the study design, if the response rate is <20%, the probability of ending the study during 
the first stage is 76%. If the response rate is >40%, the probability that the study will be stopped 
in the first stage is 13%. 
10.3 
CRITERIA FOR PATIENT REMOVAL FROM STUDY 
Patients will be removed from study for any of the following events: 
• Unacceptable toxicity (listed above in section 10.1), 
• Other toxicity which investigator deems to place the patient at significant risk for toxicity 
• Withdrawal of consent 
• Noncompliance or inability to meet requirements of protocol 
• Requirement for >4 DEB-TACE procedures 
• Requirement for another anti-cancer treatment modality such as ablation, surgery, 
conventional TACE 
• Receives a liver transplant 
• Develops untreatable intrahepatic tumor progression 
• Develops extrahepatic tumor progression  
11.0 DEVICE INFORMATION 
For further information, please refer to the product insert. 
11.1 
Classification 
LC Bead™ is an FDA-approved permanent particulate embolic agent, which consists of a range 
of hydrogel microspheres that are biocompatible, hydrophilic, nonresorbable and precisely 
calibrated. Instructions for Use are included in Appendix 5 to the Protocol. LC Bead™ 
microspheres are intended to be used for the embolization of hypervascular tumors and 
Arteriovenous malformations. LC Bead™ microspheres carry negative ionic charge, while 
allows them to be ionically bound to positively-charged drug molecules, such as doxorubicin. LC 
Bead™ bound to doxorubicin is currently used for DEB-TACE in patients with HCC. 
11.2 
Mode of Action 
Following injection of doxorubicin-impregnated LC Bead™ microspheres, doxorubicin is eluted 
from the beads over a period of 12 days. Microspheres also cause terminal tumor vessel 
occlusion leading to tumor hypoxia. By reducing tumor perfusion, microspheres prevent washout 

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of doxorubicin from the embolized tumor lesions, markedly limiting systemic concentration of 
doxorubicin. 
11.3 
Storage and Stability 
Doxorubicin-loaded LC Bead™ may be stored up to 14 days at 2-8°C. After reconstitution with 
non-ionic contrast, doxorubicin-loaded LC Beads may be stored up to 7 days at 2-8°C.  
11.4 
Metabolism 
 
Pharmacokinetic data for doxorubicin-eluting beads has already been acquired in animal 
models (Hong, 2006; Lewis, 2006) and in a human phase I study (Poon, 2007). Data from 
Hong (2006) show the pharmacokinetics of drug-eluting beads are compared with systemic 
or intra-arterial administration of doxorubicin in animal models and in clinical use. 
 
11.5 
Preparation 
 
Loading instructions for 100-300µm LC Bead™ using powdered Doxorubicin 50mg vials are 
summarized in Appendix 6. LC Bead™ loading (steps 1-4) will be performed in a fume hood by 
a clinical pharmacist with experience with handling doxorubicin. Doxorubicin powder (Bedford 
Laboratories, Bedford, OH) will be used. National Drug Code number for the product, 50mg 
vials of doxorubicin powder, is 55390-233-01. Package insert for this product can be found in 
Appendix 7. 
 
Step 1. Reconstitute each 50mg doxorubicin vial with 2ml of sterile water for injection. Mix well 
to obtain a clear red solution.  
 
Step 2. Take flip cap off 2 100-300µm LC Bead™ vials, but do not remove metal around the 
bung. Remove as much saline as possible from LC Bead™ vials using a syringe and filter 
needle. Pierce bung with a second needle to eliminate vacuum. If a filter needle is not 
available, place flattened tip of needle against side of vial to prevent beads being drawn into 
the needle. 
 
Step 3. Using a syringe and needle add 2 ml of doxorubicin solution directly to each vial of 100-
300µm LC Bead™. 
 
Step 4. Agitate the LC Bead™ with doxorubicin solution gently to encourage mixing and allow 
to stand for 60 minutes. Gently agitate the mixture occasionally during loading time. 
 
Steps 5 and 6 will be performed by the treating interventional radiologist investigator 
immediately prior to and during administration of doxorubicin-loaded LC Bead™. 
 
Step 5. Transfer the loaded beads into a 20 ml syringe using an 18-gauge needle. Expel excess 
liquid through an 18-gauge 5-micron filter needle. 
 

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Step 6. To prepare the loaded LC Bead™ for injection, add 10 ml of Omnipaque-350 contrast 
(Amersham Health, NJ) per 2 ml of LC Bead™ and mix gently using a 3ml syringe attached to 
the 20 ml syringe via a 3-way stop-cock. Administer suspended LC Bead™ at a rate of 1 ml per 
minute 
 
11.6 
Procedure 
Doxorubicin-loaded LC Bead™ 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 near stasis of arterial flow is achieved or until a total of 4 
ml of microspheres have been administered, whichever occurs first. 
11.7 
Incompatibilities/Contraindications 
• Severe and untreatable hypersensitivity reaction to doxorubicin 
• Angiographic evidence of a large hepatic artery to pulmonary vein shunt 
• Angiographic evidence of a large hepatic artery to hepatic vein shunt 
• Occlusion of the common hepatic duct 
• Severe and refractory coagulopathy and/or thrombocytopenia 
• Previous history of congestive heart failure 
• Patients who are receiving P-glycoprotein inhibitors and CYP2D6 substrates that have a 
narrow therapeutic index for the potential risk of increased adverse events. However this 
risk of a drug interaction with systemically administered drugs might be low following 
intra-arterial bead-bound doxorubicin as compared to intravenous administration of 
doxorubicin.  
• Because of possible hepatotoxic and nephrotoxic effect of TACE, concurrent use of 
hepatotoxic and nephrotoxic drugs will be avoided for a period of 2 weeks following each 
DEB-TACE session. 
11.8 
Side Effects 
This section summarizes the reported complications and adverse events relating to LC Bead™ 
with doxorubicin used for the embolization of HCC. The literature search identified 41 articles 
containing safety data. A total 1584 patients have therefore been reviewed in papers reporting 
data on safety. (LC Bead™ 70-900µm). 
 
All serious adverse events reported in these articles have been included in the table below. The 
overall incidence of events is calculated by taking the number of reports of each type of event 
and dividing by the total number of patients documented in this safety review. 
 
Where articles specifically state the grade of event by CTCAE or other criteria, events stated to 
be of grade II or less have been excluded in this analysis; however the majority of reports do not 
state the grade of the event. 
 
DEB-TACE has also been associated with development of liver toxicity including transaminitis, 
hyperbilirubinemia, synthetic hepatic dysfunction (hypoalbuminemia, coagulopathy), clinical 

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hepatic function decompensation (encephalopathy, ascites), gastrointestinal hemorrhage, and 
infections (cholangitis, liver abscess formation). DEB-TACE may lead to renal dysfunction 
related to development of contrast nephropathy and/or hepatorenal syndrome. DEB-TACE may 
cause postembolization syndrome, the symptoms of which may include pain, nausea, vomiting, 
fever, night sweats, fatigue, and anorexia. 
 
Cumulative systemic levels of doxorubicin above 550mg/m2 have been associated with left 
ventricular failure. 
11.9 
Availability 
LC Bead™ is available in four ranges of microsphere size: 70-150 µm, (black and yellow label), 
100-300µm (yellow label), 300-500µm (blue label), and 500-700 µm (red label). Drug loading 
with up to 75 mg of doxorubicin per 2 ml vial may be performed. Two 2 ml vials are injected 
during a single DEB-TACE procedure. For the purpose of this study, only 100-300µm (yellow 
label) LC beads will be used. Drug loading with up to 50mg of doxorubicin per 2 ml vial will be 
performed. 
11.11 Accountability 
LC Bead™ ordering and storage, doxorubicin hydrochloride ordering and storage, and 
microsphere loading with doxorubicin will be performed at the UCSF Inpatient Pharmacy 
according to LC Bead™ manufacturer-supplied loading and storage instructions. 
12.0 STATISTICAL CONSIDERATIONS 
12.1 
Basis for Sample Size 
This is an open label single arm phase II study. The primary objective is to assess the safety and 
to estimate the objective response rate using mRECIST in treated lesions to the DEB-TACE 
treatment. The response rate is assumed to be >40% in treated lesions using mRECIST on 
imaging approximately 1 month after last planned DEB-TACE treatment; the response rate of 
<20% would be unacceptable for the study treatment. If the response rate is less than a pre-
specified minimum goal (i.e. 20%) then the study will be terminated due to inefficacy. Under 
binomial approximation with 5% type I error and 85% power, a total of 51 patients is required 
for the study; 17 patients will be accrued in the first stage and 34 patients will be accrued in the 
second stage. 
12.2 
Interim Analysis 
After 17 patients have received at least one DEB-TACE and had potential for at least 4 weeks of 
follow up, the safety profile will be analyzed. The study will be terminated if one of the 
termination criteria based on unacceptable toxicity listed in section 10.0 has occurred. Final 
review of the safety will be performed within approximately three months after the treatment of 
the 17th patient.  Stopping rules for lack of safety and efficacy after first stage are defined in 
Section 10.0.  Accrual will continue during these interim analyses.   
 
During the interim efficacy analysis of 17 patients, if four or fewer responses by mRECIST in 
treated lesions on imaging approximately 1 month after last planned DEB-TACE are observed 
during the first stage, the study will be stopped early; otherwise, additional 34 patients will be 

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accrued. If fourteen or fewer responses by mRECIST in treated lesions on imaging 
approximately 1 month after last planned DEB-TACE are observed by the end of the study, then 
no further investigation is warranted for the regimen. 
 
Under the study design, if the response rate is <20%, the probability of ending the study during 
the first stage is 76%. If the response rate is >40%, the probability that the study will be stopped 
in the first stage is 13%. 
12.3 
Analysis Plan 
Demographics and Baseline Characteristics 
Demographic and baseline laboratory results will be summarized using descriptive statistics. 
 
Safety Analysis 
Patients will be monitored for development of recognized complications of DEB-TACE 
including liver dysfunction, renal dysfunction, ascites, hepatic encephalopathy, hepatorenal 
syndrome, biliary injury (stricture or leak), cholangitis, cholecystitis, hepatic abscess, abdominal 
pain, nausea, vomiting, fatigue, and fever. Adverse events will be graded according to NCI 
CTCAE version 4.03. Prevalence of adverse events will be summarized using descriptive 
statistics. 
 
Efficacy Analyses 
Analyses will be performed using the intent to treat population with exceptions as defined below, 
which require patient replacement. 
 
Primary efficacy analysis 
Primary efficacy will be evaluated as 1-month radiographic response after last DEB-TACE 
procedure in treated HCC lesions according to 1) RECIST version 1.1 and 2) mRECIST. Patients 
who do not have any post-baseline tumor assessments will be counted as non-responders. Point 
estimates of response rate and confidence intervals will be provided. 
 
Secondary efficacy analyses  
1. Overall radiographic response by 1) RECIST 1.1 and 2) mRECIST 6 months after the date 
of the first planned DEB-TACE procedure. This analysis will take into account all 
measurable hepatic HCC lesions present on cross-sectional imaging 6 months after the date 
of the first planned DEB-TACE procedure. 
 
2. Time to untreatable progression (TTUP). TTUP is defined as time to disease progression 
untreatable by liver-directed percutaneous or surgical methods as assessed by treating 
investigator(s). Patient follow-up up to 1 year after last DEB-TACE will be allowed for this 
outcome variable. 
 
3. Time to progression (TTP). TTP is defined as the time interval between date of first DEB-
TACE procedure and date of imaging documenting development of intra- or extrahepatic 
disease progression by 1) RECIST 1.1 and 2) mRECIST. Patient follow-up up to 1 year 
after last DEB-TACE will be allowed for this outcome variable. 

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4. Hepatic progression-free survival (HPFS). Hepatic progression-free survival rate will be 
defined as the number of patients who neither progressed in the treated regions of the liver 
(using RECIST 1.1 and mRECIST) nor died before 1, 3, 6, 9, and 12 months after date of 
last DEB-TACE over the number of patients who entered the trial at these same timepoints. 
Estimates of the HPFS curves from the Kaplan-Meier method will be presented. Median 
progression event time and a 2-sided 95% confidence interval for the median will be 
provided using a normal approximation. For each stratum, the median, 25th and 75th 
percentile for HPFS will be provided. 
 
5. Progression-free survival (PFS). Progression-free survival rate will be defined as the 
number of patients who neither progressed (using RECIST 1.1 and mRECIST) nor died 
before 1, 3, 6, 9, and 12 months after date of last DEB-TACE over the number of patients 
who entered the trial at these same timepoints. Estimates of the PFS curves from the 
Kaplan-Meier method will be presented. Median progression event time and a 2-sided 95% 
confidence interval for the median will be provided using a normal approximation. For 
each stratum, the median, 25th and 75th percentile for PFS will be provided. 
 
6. Overall Survival (OS) is a secondary efficacy endpoint and will be analyzed 12 months 
after the last patient is enrolled. OS will be calculated from date of first DEB-TACE until 
date of death, using chart review and/or follow up phone calls to determine date of death in 
patients after removal from study. The survival of patients who are permanently lost to 
follow-up or still alive after 360 days of follow up post study discontinuation will be 
censored on the date the patient is last-contacted or last known to be alive. Estimates of the 
OS curves from the Kaplan-Meier method will be presented.  
 
7. Proportion of patients who remain active on the waitlist and are eventually transplanted is a 
secondary clinical endpoint. This data will be presented using Kaplan-Meier method 
 
8. Proportion of patients who are inactivated or drop out from the wait list for any reason 
but transplantation will be determined. Reasons for inactivation and/or removal from 
waitlist will be tabulated. 
 
9. Proportions of patients who are successfully down-staged and achiev active waitlist status 
and eventually are transplanted will be determined. 
 
10. Biochemical response defined as > 50% decrease in alpha-fetoprotein level measured 1 
month and 4 months after DEB-TACE. 
 
11. Histopathologic response defined as percentage of tumor necrosis at liver explant 
histopathology. This will only be explored  in the subgroup of patients who undergo a liver 
transplant. Per UCSF clinical standard, tumor necrosis for HCC lesions is reported as 
100%, >90%, 60-90%, 30-59%, and < 30%. 
 
Intention To Treat Exceptions (Patient replacement) 

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1. Patients who proceed to liver transplant or develop hepatic decompensation between the 
time of enrollment and the first DEB-TACE treatment will be replaced. 
 
2. Patients who proceed to liver transplant prior to completion of the 1 month safety window 
after first DEB-TACE will be replaced unless the transplant occurred due to hepatic 
decompensation or other toxicity attributed as at least possibly-related to protocol therapy, 
in which case the hepatic decompensation or other toxicity will be deemed a serious 
adverse event and the patient will be included in safety analysis (see Section 14.1.3). 
13.0 ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects.   
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements.  The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
13.2 
Protocol Review/Changes 
13.2.1 Protocol Review Committee 
This study will be reviewed by the UCSF Comprehensive Cancer Center Protocol Review 
Committee (PRC) for scientific merit and feasibility.  After initial review and approval, the study 
will be reviewed at least once a year for scientific merit.  Any changes to the protocol are to be 
reviewed and approved by the PRC. 
13.2.2 Institutional Review Board / Independent Ethics Committee 
The study will be reviewed by the Committee on Human Research (CHR), UCSF’s IRB.  After 
initial review and approval, the study will be reviewed at least once a year as per FDA 
regulations (21 CFR 56.109).  Any changes to the protocol and consent form are to be reviewed 
and approved by the CHR. 
 
Changes are to be approved prior to being implemented, unless subject safety necessitates an 
immediate change, in which case approval may be given afterwards. 
 
It is the responsibility of the Principal Investigator to keep the CHR informed of the progress of 
the study, including changes to the protocol or consent form, exceptions or deviations from the 
protocol, and any new developments which may affect subject safety or willingness to 
participate. 

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13.3 
Investigational Device Exemption (IDE) 
While LC Bead™ is an FDA-approved device, LC Bead™ loading with doxorubicin is not an 
FDA-approved application of the device. Therefore, an Investigational Device Exemption (IDE) 
application will be filed with the FDA.  
 
The clinical investigation will not begin until the FDA has determined that the study under the 
Investigational Device Exemption (IDE) is allowed to proceed and the Investigator has received 
a letter from FDA stating that the study is fulfills the IDE application requirements. 
13.4 
Data Safety Monitoring 
All subjects will be followed closely in clinic post-procedure by a medical oncologist and/or 
hepatologist, and interventional radiologist for signs of potential complications from the 
procedure. Patients will be discussed bi-weekly at the gastrointestinal oncology site committee 
meeting for the first month following each DEB-TACE.  After the first month following the last 
DEB-TACE treatment, patient’s progress will be monitored at 3 month intervals for a year. 
 
The sponsor-investigator shall immediately conduct an evaluation of any unanticipated adverse 
device effect [21 CFR 812.46(b)]. 
13.5 
CCC Data Safety Monitoring Committee 
13.5.1 Oversight and Monitoring Plan 
The UCSF-CCC Data Safety Monitoring Committee (DSMC) is responsible for monitoring data 
quality and patient safety for all UCSF-CCC institutional clinical studies.  A summary of DSMC 
activities for this study includes:  
• Review of subject data 
• Review of suspected adverse reactions considered “serious” 
• Monitoring every six months (depending on study accrual) 
• Minimum of a yearly regulatory audit 
13.5.2 Monitoring and Reporting Guidelines 
Investigators will conduct continuous review of data and patient safety at weekly study group or 
site committee meetings where the results of each patient’s treatment are discussed and the 
discussion is documented in the minutes. The discussion will include the number of patients, 
significant toxicities as described in the protocol, dose adjustments, and observed responses. 
Quarterly summaries will be submitted to the DSMC for review.  All grade 3-5 AEs and SAEs 
will be entered in the OnCore® database. 
 
All institutional Phase 2 or 3 studies are designated with a moderate risk assessment. The data is 
monitored twice per year with twenty percent of the subjects monitored (or at least three subjects 
if the calculated value is less than three). 
13.5.3 Review and Oversight Requirements 
Adverse Event Reporting 

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Adverse Events (AEs) will be recorded on the OnCore® database; all grade 3-5 expected and 
unexpected AEs will be recorded and updated at each visit. 
 
Unanticipated/Serious Adverse Event Reporting 
Unanticipated/Serious Adverse Event reporting will be in accordance with the UCSF- 
Committee on Human Research Regulations and Code of Federal Regulation Title 21 Volume 8 
Part 812.150.  See also section 14.4.  
 
Per IDE regulations (21 CFR 812.150(a) (1) and 21 CFR 812.150(b) (1)), unanticipated adverse 
device effects will be reported to the FDA within 10 working days of first learning of the event. 
 
UCSF CHR website for guidance in reporting serious adverse events 
http://www.research.ucsf.edu/chr/Guide/Adverse_Events_Guidelines.pdf 
 
If the SAE is death, and is determined to be possibly, probably or definitely related 
to the investigational drug or any research related procedure, the event must be 
reported to the DSMC Chair or his designee within 24 business hours.  The 
reporting procedure is by personal communication via phone or in person with 
written documentation of the one-on-one communication via e-mail with a copy of 
the e-mail to DSMC Administrator and DSMC Analyst. 
 
Review of Adverse Event Rates 
 
All grade(s) 3-5 adverse events, whether or not unexpected, and whether or not considered to be 
associated with the use of DEB-TACE, will be entered into OnCore®, UCSF’s Clinical Trial 
Management System. 
 
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
Site Committee meetings. The Site Committee will review and discuss the selected toxicity, the 
toxicity grade, and the attribution of relationship of the adverse event to theprocedure. All 
grade(s) 3-5 adverse events will be followed-up until SAE has been resolved. 
 
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 
discussed at DSMC meetings, which take place every six weeks. 
 
If a death occurs during the treatment phase of the study or within 30 days after the last 
procedure and it is determined to be related either to DEB-TACE or to a study procedure, the 
Investigator or his/her designee must notify the DSMC Chair within 1 business day of 
knowledge of this event. The contact may be by phone or e-mail. All patient deaths (anticipated 
or unanticipated) will also be reported to the FDA as they occur. 
 
 
Increase in Adverse Event Rates 

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If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert) is noted in the study, a report should be submitted to the 
DSMC at the time the increased rate is identified. The report will indicate if the incidence of 
adverse events observed in the study is above the range stated in the Investigator Brochure or 
package insert. 
 
If at any time the Investigator stops enrollment or stops the study due to safety issues, the DSMC 
Chair and DSMC Manager must be notified within 1 business day via e-mail. The DSMC must 
receive a formal letter within 10 business days and the CHR must be notified. 
 
Study Progress – Quarterly Review 
Principal Investigators are required to submit quarterly study progress reports regarding the trial 
to the DSMC.  These reports must include an update on accrual, information about any new 
amendments or updated consents and a summary of grade 3 and 4 toxicities (expected and 
unexpected) and all internal SAE reports.  At the time of the quarterly report, all external DSMB 
reports and/or external formal audit reports that were received during the reporting quarter are to 
be sent to the committee.  
 
These quarterly reports are reviewed at Data Safety Monitoring Committee meetings.  These 
reports are required:  February 1, May 1, August 1, and October 1.  Failure to submit such 
reports may result in trial suspension.   
 
Data Safety Monitoring Committee Contacts: 
DSMC Chair:  Alan Venook, MD 
DSMC Monitors  
Phone:  
Email: 
Address:  
415-353-2745 
venook@cc.ucsf.edu 
Box 1705 
UCSF 
San Francisco, CA 94115 
Box 1297 
UCSF Helen Diller Family 
Comprehensive Cancer Center 
San Francisco, CA 94115 
 
14.0 ADVERSE EVENT REPORTING 
14.1 
Adverse Event Definitions 
14.1.1 Adverse Events 
Any unfavorable or unintended sign, symptom, or illness that develops or worsens during the 
course of the study (treatment and follow-up) regardless of causality.  This includes abnormal 
clinical or laboratory findings. 
14.1.2 Unanticipated Adverse Events 
Any serious adverse effect on health or safety or any life-threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects [21 CFR 812.3(s)]. 

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Please note: The CHR (UCSF IRB) uses the term ‘Unexpected’ Adverse Events, which 
includes unanticipated events that are not necessarily serious or life-threatening. 
14.1.3 Serious Adverse Events 
A serious adverse event (SAE) is one that results in any of the following outcomes regardless of 
dose: 
• Death 
• Life-threatening (places the subject, in the view of the investigator, at immediate risk of 
death from the reaction as it occurred), including hepatic decompensation requiring 
hospitalization or expedited liver transplantation 
• Inpatient hospitalization or prolongs existing hospitalization, 
• Persistent or significant disability/incapacity (a substantial disruption of a person’s ability 
to conduct normal life functions), 
• Birth defect/congenital anomaly, 
• Any important medical event that may not result in prior listed outcomes but, based upon 
appropriate medical judgment, may jeopardize the subject, and may require medical or 
surgical intervention to prevent one of the prior listed outcomes. 
 
An adverse event is not considered serious if it does not satisfy at least one of these criteria. 
14.1.4 Laboratory Adverse Events 
Laboratory test value abnormalities are recorded as adverse events (AE) if they are designated as 
clinically relevant (defined as any abnormality which requires treatment, causes symptoms,  
places the patient at risk for morbidity, and/or causes premature withdrawal from study) and 
represent a change of ≥ 1 grade from baseline.  Laboratory abnormalities will not be considered 
clinically-relevant adverse events if they do not satisfy at least one of these criteria. 
14.2 
Adverse Event Grading 
All AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 
 
Severity of AEs will be graded using the following general definitions of the CTCAE v4.03 : 
• Grade 1 – Mild (no limitations) 
• Grade 2 – Moderate (some limitations) 
• Grade 3 – Severe (requires medical attention; usual activities stop) 
• Grade 4 – Life-threatening/disabling (requires immediate medical help) 
• Grade 5 - Death 
 
Causality of AEs will be graded by the treating investigator with review by the Study Chair as 
follows: 
• Unrelated 
• Unlikely related 
• Possibly related 
• Probably related 

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• Definitely related 
14.3 
Adverse Event Reporting Period 
Reportable AEs are those that occur after treatment begins and up to 1 month after the last DEB-
TACE treatment. 
 
Unresolved AEs (Reportable AEs that extend past the 1 month post-treatment period) should 
continue to be reported on if the condition worsens or results in death. 
 
AEs that occur after the reporting period (first treatment to 1 month post-treatment) are not 
normally reported unless they are serious AND the investigator or treating physician has reason 
to believe the event(s) might be related to study participation. 
 
AE reporting will discontinue at time of transplant. 
 
AE reporting will discontinue if patients are taken off study to receive more than four DEB-
TACE treatments. 
14.4 
Reporting Procedures 
Serious AEs and Unexpected AEs are to be reported to the CHR within 10 working days after 
first becoming aware of the event. 
 
Adverse events that are unanticipated (see definition above) will be reported in writing to the 
CHR and FDA as soon as possible but no later than 10 working days after first becoming aware 
of the event [21 CFR 812.150(a) (1) and 21 CFR 812.50(b) (1)].  A copy of the CHR report 
should be forwarded to the manufacturer of the device at the address below: 
 
Biocompatibles UK Limited 
Chapman House 
Farnham Business Park 
Weydon Lane 
Farnham, Surrey 
GU9 8QL UK 
Tel No: +44 (0)1252 732 732 
Fax No: +44 (0)1252 732 777 
 
A copy of the CHR forms must be sent to the CCC DSMC at Box 1297.  If the AE is a death 
attributed as at least possibly-related to study drug or treatment during the treatment phase of the 
study or within 30 days after the last DEB-TACE procedure, it must be reported to the CCC 
DSMC Chair (or qualified alternate) within 1 business day of knowledge of the event  (see 
section 13.4).  The contact may be by phone or e-mail.  The date the safety report was sent to all 
required reporting agencies will documented on the OnCore® database, and hard copies of the 
report will be maintain in the regulatory files. 

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15.0 Protection of Human Subjects 
15.1 
Protection from Unnecessary Harm  
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the CHR mechanism and the process of informed consent. The 
CHR reviews all proposed studies involving human experimentation and ensures that the 
subject’s rights and welfare are protected and that the potential benefits and/or the importance of 
the knowledge to be gained outweigh the risks to the individual. The CHR also reviews the 
informed consent document associated with each study in order to ensure that the consent 
document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits.  
15.2 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document. 
16.0 FINANCIAL CONSIDERATIONS 
The costs of treatment will be charged to the subject and/or their insurance company. 

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46. Ritter 2011. "Spontaneous liver rupture after treatment with drug-eluting beads." 
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for hepatocellular carsinoma (hcc) in cirrhotics." Hepato-Pancreato-Biliary Association 
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48. Slanic. (2008). "Precision TACE: Improved possibilities in fighting liver cancer." WCIO & 
Best of ASCO  
49. Sousa 2011. "Transcatheterarterial chemoembolization with doxorubicin eluting beads in the 
treatment of hepatocellular carcinoma." Acta Medica Portuguesa 24: 029-036. 
50. Tokh. (2010). "Transarterial chemoembolization (TACE) with drug-eluting beads (DEB) in 
hepatocellular carcinoma (HCC): A large single-institution experience. ." ASCO. 

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51. Varela 2007. "Chemoembolization of hepatocellular carcinoma with drug eluting beads: 
efficacy and doxorubicin pharmacokinetics." J Hepatol 46(3): 474-481. 
52. Zach 2010. "Multiple ischaemic strokes after transcatheter arterial chemoembolization for 
Hepatocellular carcinoma with a radiographic and pathological correlate." Journal of Stroke 
and Cerobrovascular Disease. 
53. Hong K, et al. New intra-arterial drug delivery system for the treatment of liver cancer: 
Preclinical assessment in a rabbit model of liver cancer. Clinical Cancer Research 2006; 
12(8):2563. 
54. Lewis A, et al. Pharmacokinetic and safety study of doxorubicin-eluting beads in a 
porcine model of hepatic arterial embolization. J Vasc Interv Radiol 2006; 17(8):1335. 
55. Eyol et al. Chemoembolisation of rat colorectal liver metastases with drug-eluting beads 
loaded with irinotecan or doxorubicin. Clin Exp Metastasis 2006; 25(3):273-82. 
56. Doxorubicin eluting beads –1: Effects of drug loading on bead characteristics and drug 
distribution. J Mater Sci: Mater Med DOI 10.1007/s10856-007-3068-8. 
57. Doxorubicin eluting beads –2: Methods for evaluating drug elution and in vitro: in vivo 
correlation. J Mater Sci: Mater Med DOI 10.1007/s10856-006-0040-y. 
58. Varela M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: 
Efficacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46:474-481. 
59. Poon R, et al. A phase I/II trial of chemoembolization for hepatocellular carcinoma using 
a novel intra-arterial drug-eluting bead. J Clin Gastroenterol and Hepatol 2007; 5:1100-
1108. 
60. Erttmann R, et al. Pharmacokinetics of doxorubicin in man: dose and schedule 
dependence. J Cancer Res Clin Oncol 1988; 114:509-513. 
61. Lee YT, et al. Distribution of Adriamycin in cancer patients: tissue uptakes, plasma 
concentration after IV and hepatic IA administration. Cancer 1980; 45:2231-2239. 
62. Johnson, et al. Pharmacokinetics and toxicity of intraarterial adriamycin for 
hepatocellular carcinoma: effect of coadministration of lipiodol. J Hepatol 1991; 13:120-
127. 
 
 

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Appendix 1 
ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
Grade Descriptions 
0 
Normal activity 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Symptoms, but ambulatory 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, office work) 
2 
In bed < 50% of the time 
Ambulatory and capable of all self-care, but unable to carry out any work activities 
Up and about more than 50% of waking hours 
3 
In bed > 50% of the time 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
100% bedridden 
Completely disabled 
Cannot carry on any self-care 
Totally confined to bed or chair 
5 
Dead 
 
 
 
 
 

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Appendix 2 Child-Pugh Score 
http://homepage.mac.com/sholland/contrivances/childpugh.html 
Below is an example of a calculated score: 
 

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Appendix 3 MELD Score 
http://www.mayoclinic.org/meld/mayomodel6.html 
The MELD Model, UNOS Modification 
In the following model, survival probability of a patient with end-stage liver disease is estimated based on the 
following variables. Please enter data in the corresponding boxes. 
What is the INR? 
  
What is the bilirubin? 
 (mg/dl) 
What is the creatinine? 
 (mg/dl) 
Has the patient had dialysis at least twice in the past week? 
 No 
 Yes  
 
MELD score:   
 
 

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Appendix 4 Modified RECIST 
 

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Appendix 5. DC Bead® Drug Delivery Embolization System Instructions for Use 
 

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Appendix 6. Loading of LC Bead™ using doxorubicin powder 50mg vials  
 
1
2
3
4
5
6
7
8
9
10
ml
6
7
8
9
10
ml
4
5
1
2
3
Pierce bung with a
second needle to
eliminate vacuum.
If a filter needle is
not available, place
flattened tip of
needle against side
of vial to prevent
beads being drawn
into the needle.
1
2
3
4
5
6
7
8
9
10
ml
3
4
5
6
7
8
9
10
ml
1
2
1
2
3
4
5
6
7
8
9
10
ml
1
3
4
5
6
7
8
9
10
ml
2
3
10
20
ml
30
10
20
ml
30
Non-ionic
Contrast
1
2
3
4
5
ml
1
2
3
4
5
m
2
ml
* Tolerance of ±3%
Loading time for up to 37.5mg of doxorubicin per ml of 
DC Bead® (75mg per vial)
Doxorubicin
Uptake
500-700µm
300-500µm
100-300µm
90%*
60 minutes
45 minutes
30 minutes
98%*
120 minutes
90 minutes
60 minutes
Using a syringe and needle add the
required dose of doxorubicin solution
directly to the vial(s) of DC Bead®.
DC Bead® is manufactured by Biocompatibles UK Ltd,
Chapman House, Farnham Business Park, Weydon Lane,
Farnham, Surrey, GU9 8QL. Biocompatibles UK Ltd is 
a BTG International group company. DC Bead is a 
registered trademark of Biocompatibles UK Ltd. BTG 
and the BTG roundel logo are registered trademarks 
of BTG International Ltd. © Copyright 2012 
Biocompatibles UK Ltd. EC10-158 Rev 2. 
Biocompatibles UK Limited
Tel:      +44 (0)1252 732 732
Fax:     +44 (0)1252 732 777                           
email: marketing@biocompatibles.com          
www.biocompatibles.com
DC Bead®: Important information
DC Bead® Indications:
• DC Bead is CE marked and is indicated for the
treatment of malignant hypervascular tumours 
and loading with doxorubicin drug
• DC Bead is also indicated for loading with
irinotecan for the treatment of metastatic 
colorectal cancer (mCRC). 
Both indications may not be available in your territory
DC Bead® Cautions:
• Embolisation with DC Bead should only be
performed by a physician with appropriate
interventional occlusion training in the region
intended to be embolised
• Exceeding a loading dose of 37.5mg doxorubicin
per 1ml DC Bead may lead to some systemic
distribution of doxorubicin and related side effects
• Exceeding a loading dose of 50mg irinotecan per
1ml DC Bead may lead to some systemic
distribution of irinotecan and related side effects
• On addition of contrast/water mixture to loaded
beads some irinotecan will be eluted. On delivery 
a bolus of between 10-20mg irinotecan may be
delivered
• Do not use irinotecan loaded beads with contrast
agents containing salts (eg. Calcium chloride)
DC Bead® Potential Complications:
1. Undesirable reflux or passage of DC Bead 
into normal arteries adjacent to the targeted 
lesion or through the lesion into other arteries 
or arterial beds
2. Non-target embolisation
3. Pulmonary embolisation
4. Ischemia at an undesirable location
5. Capillary bed saturation and tissue damage
6. Ischemic stroke or ischemic infarction
7. Vessel or lesion rupture and haemorrhage
8. Neurological deficits including cranial nerve palsies
9. Vasospasm
10. Death
11. Recanalisation
12. Foreign body reactions necessitating medical
intervention
13. Infection necessitating medical intervention
14. Clot formation at the tip of the catheter and
subsequent dislodgement causing arterial
thromboembolic sequelae
For instructions for use, please refer to
www.biocompatibles.com/dcbead-ifu
DC Bead® is not currently cleared by the 
FDA for sale or distribution in the USA.
Biocompatibles
Excellence in Interventional Oncology
After loading, the solution in the vial
will retain some red colouration as
shown. This is to be expected and is
not an indication that the DC Bead®
has failed to load.
Take flip cap off DC Bead® vial(s) but do not
remove metal around the bung. Remove as
much saline as possible from DC Bead®
vial(s) using a syringe and filter needle. 
Agitate the DC Bead® with doxorubicin
solution gently to encourage mixing and
allow to stand for required loading time.
Gently agitate the mixture occasionally
during loading time.
POWDER
Step 1
POWDER
Step 2
POWDER
Step 4
When loading time is complete, transfer
the loaded beads into a 20-30ml syringe
using an 18-gauge needle or equivalent.
Expel excess liquid (a 5-micron needle
can help with this process).
POWDER
Step 5
POWDER
Step 6
POWDER
Step 3
Reconstitute each 50mg doxorubicin
vial with 2ml of sterile water for injection
(NOT sodium chloride). Mix well to obtain
a clear red solution.
Loading and preparation of DC Bead®
must be carried out using strict aseptic
technique under controlled conditions.
To prepare the loaded DC Bead® for
injection, add 5-10ml of non-ionic contrast
medium per ml of DC Bead® and mix gently
to give a good suspension. Inject solution 
at a rate of 1ml per minute.
Biocompatibles UK Ltd is a 
BTG International group company
Physical and chemical stability
DC Bead® 100-700µm
Doxorubicin-loaded                                 14 days
DC Bead® (75mg/2ml)                               (at 2-8°C)
Doxorubicin-loaded                                  7 days
DC Bead® with non-ionic contrast         (at 2-8°C)
DC Bead® Ordering Information
Product
Code
Volume
of Beads
Nominal 
Bead Size
DC2V103
2ml
100-300µm
DC2V305
2ml
300-500µm
DC2V507
2ml
500-700µm
To give                                 Number of vials            Number of 
required dose                         doxorubicin                   vials of 
of doxorubicin                      powder (50mg)              DC Bead®
   75mg                                          2                                  1
100mg                                          2                                  2
150mg                                          3                                  2
Loading of DC Bead®
using
Doxorubicin Powder 50mg
in vial
  

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