Pharmacokinetics of Doxorubicin in Conventional Transarterial Chemoembolization (cTACE) of Primary and Secondary Liver Cancer
Phase: PHASE1
Conditions: Liver Cancer
Sponsor: Yale University

 
 
Pharmacokinetics of doxorubicin in conventional transarterial 
chemoembolization (cTACE) of primary and secondary liver cancer 
 
ClinicalTrials.gov#: NCT02753881 
 
Version Date: April 20, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Pharmacokinetics of doxorubicin in conventional transarterial chemoembolization 
(cTACE) of primary and secondary liver cancer 
 
HIC Protocol #: 1506016008 
 
Principal Investigator: Todd Schlachter, MD 
Yale University School of Medicine 
Department of Radiology and Biomedical Imaging 
330 Cedar Street, PO Box 208042 
New Haven, CT 06520-8042 
Phone: (203) 785-5885 
Fax: (203) 737-1077 
E-mail: todd.schlachter@yale.edu 
 
Co-Investigators and Study Team 
Co-Investigators: 
Hyun Kim, MD 
Jeff Pollak, MD 
Rajasekhara Ayyagari, MD 
Juan Carlos Perez Lozada, MD 
Julius Chapiro, MD 
 
Research Nurse: 
Teresa White 
 
Study Coordinator: 
Eliot Funai 

 
 
 
 
 
 
Study Sponsor: 
Investigator-Initiated: Todd Schlachter, MD 
 
Financial Support:  
Guerbet 
 
Protocol Revision Record 
Original Version: July 10, 2015 
Protocol Amendment #1: June 22, 2016 
Protocol Amendment #2: October 10, 2016 
Protocol Amendment #2.1: January 19, 2017 
Protocol Amendment #2.2: April 20, 2017 
 
 
 
 
 
 

HIC #: 1506016008 
Todd Schlachter, MD 
Table of Contents 
Section 
Page # 
Investigator Agreement Page 
5 
Log of protocol revisions 
6 
Schema/Synopsis 
7 
List of Abbreviations 
10 
1. Introduction 
11 
 
1.1 Background/Rationale 
11 
 
1.2 Hepatocellular Carcinoma 
11 
 
1.3 Hepatic Metastases from Solid Tumors 
12 
 
1.4 Transarterial Chemoembolization for Hepatocellular Carcinoma and  
 
     Metastatic Disease 
13 
 
1.5 Lobar and Superselective TACE 
14 
 
1.6 Transarterial Chemoembolization Safety Profile 
15 
2. Study Objectives and Endpoints 
16 
 
2.1 Primary Objectives/Endpoints 
16 
 
2.2 Secondary Objectives/Endpoints 
17 
3. Subject Selection 
17 
 
3.1 Subject Selection 
17 
 
3.2 Inclusion Criteria 
18 
 
3.3 Exclusion Criteria 
19 
 
3.4 Inclusion of Women and Minorities 
19 
4. Subject Registration Procedures 
19 
 
4.1 General Guidelines 
19 
 
4.2 Registration Process 
19 
 
4.3 Screening Assessments 
20 
5. Study Design/Investigational Plan 
20 
 
5.1 Overall Design 
20 
 
 
5.1.1 Routine Care Procedures 
21 
 
 
5.1.2 Research Procedures 
22 
 
5.2 Visit Schedule and Study Evaluation 
23 
 
5.3 Duration for Therapy 
24 
 
5.4 Duration of Follow-up 
24 
 
5.5 Criteria for Removal from Study 
24 
6. Adverse Event Collection and Reporting Requirements 
24 
 
6.1 Definitions 
24 
 
6.2 Adverse Event Coding 
25 
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6.3 Adverse Event Capture and Reporting 
25 
7. Statistical Methods 
26 
 
7.1 Primary Outcome Variable 
26 
 
7.2 Secondary Outcome Variables 
26 
 
7.3 Statistical Plan 
27 
 
7.4 Early Stopping Rules 
28 
8. Regulatory Considerations 
28 
 
8.1 Data and Safety Monitoring Plan 
28 
 
8.2 Case Report Forms 
29 
 
8.3 Record Retention 
29 
9. Ethics 
29 
 
9.1 Institutional Review Board (IRB)  
29 
 
9.2 Ethical Conduct of the Study 
30 
 
9.3 Subject Information and Consent 
30 
10. References 
31 
11. Appendices 
35 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Todd Schlachter, MD 
 
Investigator Agreement Page 
Study Title: Pharmacokinetics of doxorubicin in conventional transarterial chemoembolization 
(cTACE) of primary and secondary liver cancer 
 
I confirm agreement to conduct the study in compliance with the protocol and all applicable 
regulations. 
 
Investigator Name: __________________________________________________ 
 
Affiliation: _________________________________________________________ 
 
 
Investigator Signature: __________________________________      Date:_____________ 
 
 
 
 
 
 
 
 
 
 
 
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Log of protocol revisions –  
Version 4/20/2017 
• Change of principal investigator from Jeff Geschwind, MD to Todd Schlachter, MD 
• Addition of Juan Carlos Perez Lozada, MD as co-investigator 
Version 1/19/2017 
• Modification of inclusion criteria #7 to only exclude previous chemoembolization to 
target area within 1 year.  
• Addition of Rajasekhara Ayyagari, MD as co-investigator 
Version 10/10/2016 
• Addition of Jeff Pollak, MD as co-investigator 
• Minor edits and revisions, the most significant being correction of inclusion criteria 
ECOG 0-2 to ECOG 0-1. 
Version 6/22/2016 
• Clarification of inclusion criteria #7 on page 8, 18 
• Minor edits and revisions. 
• Addition of co-investigators Hyun Kim, MD, and Todd Schlachter, MD 
• Addition of research nurse Teresa White 
• Addition of shipping information for PK samples 
 
 
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Schema/Synopsis 
Name of Sponsor: 
Principal Investigator: Todd Schlachter, MD (Investigator initiated) 
Title of Study: 
Pharmacokinetics of doxorubicin in conventional transarterial chemoembolization (cTACE) of 
primary and secondary liver cancer  
Co-Investigators: 
Hyun (Kevin) Kim MD, Jeff Pollak MD, Rajasekhara Ayyagari, MD, Juan Carlos Perez Lozada, MD, 
Julius Chapiro, MD 
Study Center: 
Yale University School of Medicine 
Anticipated Study Period (years): 
July 2015 – August 2017 (2 years) 
Phase of Development: 
Phase I 
Abstract: 
Problem: 
Conventional transarterial chemoembolization (cTACE) was the first type of TACE developed.  
cTACE consists of the injection of a mixture of chemotherapeutic drugs with Lipiodol, a contrast 
agent, followed by the injection of small beads to occlude the tumor feeding arteries.  Despite 
the local injection of the chemotherapeutic drugs, pharmacokinetic (PK) studies of cTACE dating 
back to the 1990s demonstrated a high serum concentration peak of the chemotherapeutic 
drugs right after administration. 
Research hypothesis: 
This is not a hypothesis driven study.  The purpose of this study is to perform a dedicated PK 
analysis of doxorubicin and its metabolite doxorubicinol after cTACE. 
Importance of the research: 
Newer forms of TACE that include drug eluting microsphere technology have been developed, 
with more favorable PK profiles than those found in the studies of cTACE which were performed 
several decades ago.  The cTACE procedure has since matured, and in fact is now often 
administered selectively so that the chemotherapy can be delivered in close proximity to the 
tumor, rather than administered in a lobar or whole liver fashion.  It is important to determine 
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Todd Schlachter, MD 
the PK profile of the modern cTACE procedure in order to make comparisons with the newer 
forms of TACE.  Finally, it is also important to know whether superselective cTACE results in less 
serum exposure of doxorubicin and doxorubicinol than when it is administered in a lobar non-
selective manner.  The findings may truly lead to a change in practice and a new set of technical 
guidelines. 
Study Design: 
Single site, prospective study, designed to measure PK of doxorubicin and its metabolite 
doxorubicinol at various timed intervals after cTACE in patients with primary or secondary liver 
cancer. 
# of Patients (planned):   
30 patients to be enrolled, approximately 15 patients with primary liver cancer and 15 patients 
with secondary liver cancer.  Up to 40 patients may be consented if necessary in order to 
account for potential patients who screen-out or who are unable to complete sample collection 
for the PK (80% of planned draws).  15 patients will be assigned to the lobar treatment arm and 
15 patients will be assigned to the superselective treatment arm. 
Diagnosis and Main Criteria for Inclusion: 
Patients with primary or secondary liver cancer that are recommended for cTACE and meet the 
inclusion/exclusion criteria. 
Inclusion criteria: 
1. Age ≥ 18 years. 
2. Histologically, cytologically, or radiologically confirmed liver dominant or liver only 
malignancy. 
3. Preserved liver function (Child-Pugh A-B class) without significant liver decompensation. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at study entry. 
5. Measurable or evaluable disease that will be directly treated with intrahepatic therapy 
(as defined by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). 
6. Suitable for TACE based on blood parameters such as platelet count, bilirubin, and 
international normalized ratio. 
7. May be enrolled with a history of prior liver directed chemoembolization if 
chemoembolization to the target lesion occurred > 1 year prior to enrollment date.  TACE 
to different targets within 1 year prior to enrollment date, radioembolization to target 
location, or other form of intra-arterial therapy will not exclude subjects. 
Exclusion criteria: 
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1. Serum total bilirubin > 3.0 mg/dL 
2. Creatinine > 2.0 mg/dL 
3. Platelets < 50000/µL 
4. Complete portal vein thrombosis with reversal of flow 
5. Ascites (trace ascites on imaging is acceptable) 
Duration of treatment:  
Patients are on study for 4 weeks, starting from the initial blood draw at baseline prior to the 
cTACE procedure until the last blood draw taken 3-4 weeks post-cTACE. 
Statistical methods: 
Primary outcome variable: 
Pharmacokinetic profile of doxorubicin and doxorubicinol after cTACE 
 
Pharmacokinetic parameters to be measured for each patient: 
• Peak of the plasma concentration, time of maximum concentration, and area 
under the concentration-time curve (AUC). 
• Pharmacokinetic profiles for each patient will be correlated with toxicity and 
tumor burden (size of target lesion), BSA, gender. 
• PK profiles of lobar cTACE as compared to that of super-selective cTACE. 
Secondary outcome variables: 
1. Feasibility 
• Technical success of the cTACE procedure (technical failure is defined as the 
inability to administer the cTACE material, in which case the patient would be 
excluded from the study). 
• Dose of doxorubicin delivered. 
2. Safety 
• All toxicities assessed as being at least possibly related, up to the 3-4 week follow-
up visit (post cTACE) will be analyzed by descriptive statistics to show type, grade 
(NCI Common Toxicity Criteria v4.0), frequency, and time from cTACE. 
 
 
 
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List of Abbreviations 
 
Abbreviation 
Definition 
AE 
Adverse event 
AUC 
Area under concentration-time curve 
CRF 
Case report form 
cTACE 
Conventional transarterial chemoembolization 
CTCAE 
NIH Common Terminology Criteria for Adverse Events 
DEB-TACE 
Drug eluting bead transarterial chemoembolization 
DSMC 
Data and Safety Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group performance status 
GCP 
Good Clinical Practice 
HCC 
Hepatocellular carcinoma 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
NET 
Neuroendocrine tumor 
PET 
Pancreatic endocrine tumor 
PK 
Pharmacokinetics 
PRC 
Protocol Review Committee 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
UPIRSOs 
Unanticipated Problems Involving Risks to Subjects and Others 
 
 
 
 
 
 
 
 
 
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1. Introduction 
1.1 Background/Rationale 
Transarterial chemoembolization (TACE) is the combination of locally injected chemotherapy 
and embolization of the tumor feeding arteries.  Due to good tumor response rates and a low 
incidence of side effects, this technique has evolved into the standard palliative treatment for a 
number of primary and secondary liver cancers, including hepatocellular, intrahepatic 
cholangiocellular, colorectal, and neuroendocrine cancer.  Conventional TACE (cTACE), the first 
type of TACE developed, consists of the injection of a mixture of chemotherapeutic drugs with 
Lipiodol, an oil-based contrast agent, followed by the injection of small beads to occlude the 
tumor feeding arteries.  Despite the local injection of the chemotherapeutic drugs, this 
technique was shown to result in a high serum concentration peak of the chemotherapeutic 
drugs right after injection.  Drug-eluting beads were developed to release the 
chemotherapeutic agent over a longer period of time, resulting in a lower initial serum 
concentration and a higher concentration of the chemotherapeutic drug in the tumor treated 
area over time. 
Since the development of drug-eluting beads, many research teams have focused on the 
advantages of Drug Eluting Bead TACE (DEB-TACE) over cTACE, including better tumor response 
and lower incidence of side-effects (1,2).  Several PK studies comparing various bead types have 
been performed in different animal models (3-5).  According to these studies, the serum 
concentration of chemotherapeutic drugs is lower using DEB-TACE compared to cTACE.  
However, the cTACE studies used for comparison date back to the 1990, at which time a variety 
of cTACE protocols were being used as the cTACE technique was still in its infancy.  Over the 
years, several studies were performed to develop the optimal drug combination and delivery 
schema with regard to efficacy and toxicity (6, 7).  To our knowledge, there is only a single, 
rather recent PK study comparing DEB-TACE to cTACE (8), however this study had only 5 
patients in the c-TACE arm. 
Thus, the purpose of this study is to perform a dedicated PK analysis of doxorubicin and its 
metabolite doxorubicinol after cTACE, and compare the PK profile of the two most widely used 
methods for cTACE, lobar and superselective. 
1.2 Hepatocellular Carcinoma 
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and represents 
more than 5% of all cancers.  Approximately 500,000 cases of HCC are diagnosed each year and 
it is the third cause of cancer-related deaths (9, 10).  There are wide geographical variations in 
the incidence of the disease with the highest rates in the developing countries of Asia and 
Africa.  However, the incidence of HCC is increasing in North America and Europe (11). 
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Untreated HCC carries a poor prognosis and is directly related to degree of underlying cirrhosis 
and tumor stage.  Early detection offers the only possibility for cure.  Patient survival is 
generally not more than 6 months in patients with large tumor mass and advanced cirrhosis.  
Patients with small HCCs (<5cm diameter) and stable liver function have a better prognosis with 
2-year survival rates of 56% (12). 
HCC is now responsible for 14,000 deaths annually in the United States.  It is generally accepted 
that surgical resection, liver transplantation, and percutaneous ablation are the only curative 
treatments for patients with early stage HCC.  The shortage of donor livers further diminishes 
liver transplantation as a viable option for many patients.  The majority of HCC patients 
(approximately 85-90%) are not candidates for curative treatments either due to poor liver 
function or the presence of advanced disease.  These patients are treated with palliative 
treatments. 
Chemotherapeutic agents (e.g. doxorubicin) can be infused directly into the systemic circulation 
but patients who receive this treatment suffer serious side effects that may be life threatening 
(e.g. cardiac toxicity), pain, nausea, vomiting, myelosuppression, and alopecia.  For those 
patients able to receive systemic chemotherapy, response rates ranged from 15% to 20% and 
have had virtually no impact on survival. 
These factors, combined with local pattern of disease dissemination, have made local 
interventional therapy the cornerstone of hepatocellular carcinoma treatment for unresectable 
disease and patients who are not eligible for treatment. 
 
1.3 Hepatic Metastases from Solid Tumors 
There are many solid-organ malignant tumors (colorectal carcinoma, neuroendocrine tumors, 
pancreatic endocrine tumors, and other non-colorectal non-neuroendocrine tumors) for which 
cure is not possible with current systemic agents.  Many of these tumors are found to have 
already metastasized to the liver at the time of diagnosis or eventually metastasize to the liver 
despite best therapeutic efforts with available systemic agents.  The liver is the most common 
site of metastases from colorectal carcinoma and is a frequent metastatic site for pancreatic 
endocrine tumors (PET), neuroendocrine tumors (NET), and other tumor types.  Overall, the 
largest risk factor for the development of hepatic metastases is the stage of the primary tumor 
(colorectal carcinoma) or the size of the primary tumor (NET, PET).  In hepatic metastatic 
disease, the most important prognostic factor is the percent of liver replaced by tumor.  If 
allowed to grow and disseminate within the liver, metastatic deposits become the dominant, 
and often, the most life-threatening feature of the metastatic disease, either through 
progressive hepatic failure or production of excess endocrine products that produce potentially 
lethal systemic consequences (NET, PET). 
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Due to the relative sensitivity of the liver to radiation, external beam radiation has had limited 
utility in treating hepatic metastatic disease.  Modest improvements have been achieved in the 
treatment of metastatic colorectal cancer using new combination regimens of systemic agents; 
however, most patients ultimately fail first-line therapy either based on lack of efficacy or 
inability to tolerate further courses of treatment (13).  A number of new, non-radiation based 
liver-directed therapies have been developed for reducing or controlling tumor mass in the liver 
that have demonstrated varying efficacy and patient tolerance.  These treatments also may 
produce serious morbidity that adversely impacts patient quality of life, and can result in life-
threatening complications and adverse events. 
In summary, the status of clinical managements of patients with metastatic disease involving 
the liver has experienced modest improvements over the past 40 years.  Standardization of 
treatment approach has been hampered by the need to adapt therapy to tumor type and 
presentation, initial response to first line therapy and patient tolerance for therapeutic 
interventions.  Diverse drugs, biologics, medical devices and surgical procedures are available 
for treatment of hepatic metastases.  There is a clinical need to develop new, liver-directed 
therapies with less morbidity and improved patient tolerance compared with existing therapies.  
In addition, new therapies are needed that can be applied at any time in the ongoing course of 
treatment for a patient with metastatic liver disease. 
 
1.4 Transarterial Chemoembolization for Hepatocellular Carcinoma and 
Metastatic Disease 
Liver directed forms of therapy have become the mainstay of therapy for patients with 
unresectable HCC.  These therapies include chemical (alcohol, acetic acid) and thermal 
(radiofrequency ablation, microwave, laser, etc) ablative techniques, as well as intra-arterial 
chemotherapy treatments.  Intra-arterial therapies have been developed to take advantage of 
the fact that the hepatic artery supplies most of the blood flow and nutrients to hepatic tumors. 
Of those, TACE is the most widely performed procedure for patients with unresectable HCC.  
Transarterial chemoembolization involves the periodic injection of a chemotherapeutic agent, 
mixed with an embolic material, into selected branches of the hepatic arteries feeding a liver 
tumor, thus combining chemotherapy administration with intra-tumor ischemia.  The rationale 
for TACE is that the infusion of drugs such as doxorubicin, mitomycin-C, and cisplatin suspended 
in an oily medium followed by embolization of the blood vessel with embolic agents will reduce 
arterial blood supply to the tumor allowing greater delivery of the chemotherapy to the tumor 
and thus causing necrosis of the tumor.  Lipiodol is the most common vehicle used for the intra-
arterial administration of the chemotherapeutic agents.  The advantage of TACE is that higher 
concentrations of the drug can be delivered to the tumor with decreased systemic exposure 
compared with systemic chemotherapy.  TACE has been shown to deliver up to 400 times the 
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Todd Schlachter, MD 
intra-hepatic concentration of chemotherapy in comparison to intravenous administration 
depending on the chemotherapeutic agent (14).  As such, tissue levels of chemotherapy within 
the tumor were found to be 40 times of that found in surrounding normal hepatic tissue.  
Embolization of a branch of the hepatic artery after the administration of chemotherapy results 
in the detection of the chemotherapeutic agent within the tumor of upwards of several months 
post administration (15-17). 
TACE achieves partial response in 15-55% of patients (18-24) and significantly delays tumor 
progression and vascular invasion (20, 24).  Two studies have also reported survival benefits for 
chemoembolization in selected patients (24, 25).  The best candidates for chemoembolization 
are those with preserved liver function and asymptomatic multinodular tumors without 
vascular invasion or extrahepatic spread. 
The impact of TACE on survival has been assessed through numerous prospective and 
retrospective studies.  Two recently published randomized prospective clinical trials have 
shown a statistically significant survival advantage for TACE compared to symptomatic 
treatment.  The first trial, which utilized cisplatin, Lipiodol, and gelatin sponge particles in 80 
Asian patients, showed one-, two- and three-year survival rates of 57%, 31%, and 26% in 
treated patients compared to 32%, 11%, and 3% (respectively) in control patients treated with 
best available supportive care, giving a relative risk of death of 0.49 (CI, 0.29-0.81) (26).  A 
second trial performed in Europe also showed a survival benefit in highly selected patients 
using Lipiodol, doxorubicin, and gel foam (23).  A recent meta-analysis published by Llovet and 
Lo confirmed the findings of the two randomized trials and showed that chemoembolization 
provides significant survival benefit in a selected group of patients, namely those with good 
performance status (22).  Based on those and other studies, chemoembolization is currently the 
standard of care for patients with intermediate stage HCC and has been included since 2006 as 
part of the official guidelines for the treatment of patients with HCC (by the American 
Association for the Study of Liver Diseases (AASLD), as well as the National Cancer Care 
Network (NCCN) and European Association of the Study of the Liver (EASL).  TACE has also been 
used with success in secondary unresectable hepatic malignancies. 
 
1.5 Lobar and Superselective TACE 
The lobar conventional TACE approach consists of the administration of chemotherapy and 
Lipiodol to via the left or right hepatic lobar branch followed by embolization.  As a 
consequence of this approach, a large region of the liver is treated which would make it 
suitable for cases where there are multiple lesions within a lobe.  However, this technique was 
also correlated to a high serum concentration of the chemotherapeutic drug after 
administration, which compared unfavorably to an alternate form of treatment, the drug-
eluting bead TACE (DEBTACE). 
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While the lobar technique is still very much in use today, TACE protocols have been refined and 
new specialized protocols developed.  The superselective approach would advance the 
microcatheter further into the hepatic arterial branch afferent to the segment in which the 
tumor is located, or if possible the tip of the catheter will be further advanced into the 
subsegmental branches feeding the tumor, where chemotherapy will be administered followed 
by embolization.  In this manner, the chemotherapy is delivered in a more selective fashion, 
sparing more of the healthy liver parenchyma. 
Logistically, the superselective approach introduces new complexities including a lengthier 
operation and being more technically demanding, but some studies have observed that the 
superselective approach may result a higher rate of complete tumor necrosis with small HCCs in 
comparison to the lobar approach (27-29).  In Golfieri’s study, tumor necrosis was greater in the 
superselective arm vs the lobar arm (75.1% vs 52.8%), and complete tumor necrosis was 
observed in approximately two times more patients on the selective arm when compared to 
the lobar nonselective arm, which also resulted in a reduced need for further treatments (27).  
The damage to liver parenchyma and function was also reduced with the superselective 
approach, with less adverse events when compared to the nonselective TACE (28).  A 
superselective or subsegmental approach could also be performed in patients who may be 
contraindicated for conventional nonselective TACE due to severe cirrhosis and risk of serious 
ischemic complications (30, 31).  Given the reduced adverse event profile of the subsegmental 
approach and the selective nature of treatment, it is conjectured that the serum doxorubicin 
concentration would also be decreased. 
 
1.6 Transarterial Chemoembolization Safety Profile 
Generally, TACE is a well-tolerated procedure, although side effects are common.  Embolization 
of the liver has been performed for decades for a variety of indications and is well-tolerated.  
Embolization of solid organs causes a self-limited post-embolization syndrome in the majority 
of patients, consisting of varying degrees of pain, nausea, vomiting, and fever.  This is 
independent of chemotherapeutic drug use, reason for embolization (e.g. bleeding, tumor), and 
the organ treated (e.g. liver, kidney, spleen, uterus).  With current medical care (e.g. hydration, 
anti-emetic therapy, and pain control), post-embolization syndrome is well-tolerated and 50% 
of patients can be discharged from the hospital the day after chemoembolization.  The average 
length of stay is 1.5 days.  Liver function is transiently affected with an increase in liver 
aminotransferase levels.  These values usually peak 3-5 days after therapy and return to 
baseline levels by 10-14 days after embolization.  There is no sustained degradation of liver 
function in properly selected patients who do not meet the well-established exclusion criteria 
for hepatic artery occlusion, even in the presence of cirrhosis (32).  Because most of the 
injected drug is retained in the liver, systemic toxicity is minimized, with little bone marrow 
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suppression.  The cumulative toxicity is far more limited than is experienced with systemic 
chemotherapy, which requires protracted drug exposure for an indefinite period of time.  
Treatment related complications occur in approximately 10% of performed procedures, with 
mortality rate around 2% (33). 
Serious adverse events occur after approximately 5% of chemoembolization procedures.  The 
most common serious adverse events are liver abscess or liver infarction, which occur in 
approximately 2% of cases each.  The 30-day mortality rate is 1% (34-36) (37). 
Constitutional symptoms: The post embolization syndrome consisting of transient abdominal 
pain, ileus, fever and malaise affects 60% to 80% of patients receiving TACE.  Prophylactic 
antibiotics are not routinely administered as the fever is a predictor of treatment response.  
This fever is a result of tumor necrosis initiated by the therapy. 
Gastrointestinal side effects and complications: Transaminases commonly rise 10 fold.  Patients 
may develop ischemic cholecystitis, hepatic abscess, or biliary strictures.  Additionally, a 
minority of patients will develop nausea/vomiting and ascites. 
Endocrine complications: Some patients may develop symptomatic hypothyroidism as a result 
of retained iodine load. 
Hematologic complications: Some patients may develop a leukemoid reaction.  Bone marrow 
toxicity is uncommon occurring in less than 4% of patients and includes neutropenia and 
thrombocytopenia.  A small cohort of patients has developed gastrointestinal hemorrhage as a 
result of TACE therapy. 
2. Study Objectives and Endpoints 
2.1 Primary Objectives/Endpoints 
Doxorubicin pharmacokinetics will be performed on all 30 patients.  Peripheral blood will be 
sampled for doxorubicin concentrations just before the cTACE procedure at baseline, and then 
after cTACE at the following time points: 5 minutes, 10 minutes, 20 minutes, 40 minutes, 1 
hour, 2 hours, 4 hours, 24 hours, and 3 or 4 weeks post cTACE.  This will be used to construct a 
pharmacokinetic profile of doxorubicin/doxorubicinol to include: 
• Parameters of PK analysis including peak of the plasma concentration (Cmax), time of 
maximum concentration, and area under the concentration time-curve (AUC). 
• PK profiles for each patient will be correlated with toxicity and tumor burden (size of 
target lesion), BSA and gender. 
• Comparison of PK profile between lobar administration and superselective 
administration. 
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2.2 Secondary Objectives/Endpoints 
Feasibility: 
• Technical success of the cTACE procedure (technical failure is defined as the inability to 
administer the cTACE material, in which case the patient would be excluded from the 
study) 
• Dose of doxorubicin delivered 
Safety: 
• All toxicities assessed as being at least possibly related, up to the 3-4 week follow-up 
visit (post cTACE) will be collected.  Toxicities will be analyzed by descriptive statistics to 
show type, grade (NCI Common Toxicity Criteria v4.0), frequency and time from cTACE. 
 
3. Subject Selection 
3.1 Subject Selection 
Patients must have histologically, cytologically, or radiologically confirmed liver dominant or 
liver only malignancy.  Patients must have an ECOG performance status of 0-1 at study entry 
and maintain a Child-Pugh class of A-B without significant liver decompensation (see Tables 
below).  There must be measurable or evaluable disease that will be directly treated with 
intrahepatic therapy (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
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 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
5 
Death 
ECOG Performance Status: describes a patient’s functional level in terms of self-care and 
physical activity. 
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Parameter 
Points Assigned 
1 
2 
3 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin, mg/dL 
≤ 2 
2-3 
> 3 
Albumin, G/dL 
> 3.5 
2.8-3.5 
< 2.8 
Prothrombin Time 
 
 
 
Seconds over control 
1-3 
4-6 
> 6 
INR 
< 1.7 
1.8-2.3 
> 2.3 
Encephalopathy 
None 
Grade 1-2 
Grade 3-4 
 
Child-Pugh Classification of Liver Disease Severity: Modified Child-Pugh classification of liver 
disease severity according to the degree of ascites, the plasma concentrations of bilirubin and 
albumin, the prothrombin time, and the degree of encephalopathy.  A total score of 5-6 is 
considered grade A (well-compensated disease); 7-9 is grade B (significant functional 
compromise); and 10-15 is grade C (decompensated disease).  These grades correlate with one-
year and two-year percent survival; grade A – 100 and 85 percent; grade B – 80 and 60 percent; 
and grade C – 45 and 35 percent, respectively. 
 
3.2 Inclusion Criteria 
Inclusion criteria as follows: 
1. Patient’s age is ≥ 18 years. 
2. Histologically, cytologically, or radiologically confirmed liver dominant or liver only 
malignancy. 
3. Preserved liver function (Child-Pugh A-B class) without significant liver 
decompensation. 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at study 
entry. 
5. Measurable or evaluable disease that will be directly treated with intrahepatic 
therapy (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). 
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6. Suitable for TACE, based on blood parameters such as platelet count, bilirubin, and 
international normalized ratio. 
7. May be enrolled with a history of prior liver directed chemoembolization if 
chemoembolization to the target lesion occurred > 1 year prior to enrollment date.  
TACE to different targets within 1 year prior to enrollment date, radioembolization 
to target location, or other form of intra-arterial therapy will not exclude subjects. 
 
3.3 Exclusion Criteria 
Exclusion criteria as follows: 
1. Serum total bilirubin > 3.0 mg/dL. 
2. Creatinine > 2.0 mg/dL 
3. Platelets < 50000/µL 
4. Complete portal vein thrombosis with reversal of flow. 
5. Ascites (trace ascites on imaging is acceptable). 
 
3.4 Inclusion of Women and Minorities 
All patients, regardless of sex or ethnicity, presenting for cTACE for primary or secondary liver 
cancer will be reviewed for study eligibility.  For participants who are not fluent in spoken or 
written English, interpreter services will be available both during the informed consent process 
and during the subject’s participation as needed.  A translated short form consent will be 
provided. 
4. Subject Registration Procedures 
4.1 General Guidelines 
All patients would be seen for an initial visit at the Interventional Radiology clinics, where a 
clinician would present all treatment options.  If the patient expresses an interest in the study, 
a member of the study team designated to consent patients would discuss the protocol in 
greater detail explaining the risks and benefits of the study, and obtain informed consent from 
the patient or a legally acceptable representative.  Imaging, laboratory results, and medical 
history will be used as part of the screening process to determine the patient’s eligibility for the 
study. 
4.2 Registration Process 
Patients consented for the study will be registered with OnCore, Yale’s Clinical Trials 
Management System, and be assigned a study identifier and counted for the final data analysis.  
Patients’ progress while on the study will be managed via OnCore. 
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4.3 Screening Assessments 
Assessment completed in the initial clinic visits (pre-consent), as part of standard of care 
assessments, may be used as part of the study screening assessment. 
• Detailed medical history including previous cancer history and cancer treatment.  Any 
additional relevant medication taken one year prior to study start will also be recorded. 
• History and physical exam (including vital signs, ECOG-PS assessment, height, weight) 
within 30 days of cTACE. 
• Chemistry panel: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
bilirubin (total and direct), alkaline phosphatase (AP), total protein, albumin, calcium, 
phosphate, glucose, creatinine, blood urea nitrogen (BUN). 
• Electrolyte panel: sodium, potassium, chloride. 
• Complete blood count: hemoglobin, hematocrit, platelet count, white blood cell count 
(WBC).  WBC should include differential neutrophil, lymphocyte, monocyte, basophil, 
and eosinophil counts. 
• Prothrombin time and INR. 
• Appropriate tumor marker: alpha feto-protein (AFP), carcinoembryonic antigen (CEA), 
CA 19-9, etc. 
• Serum or urine pregnancy test for women of childbearing potential (must be negative) 
• Contrast enhanced MRI of the liver within 30 days of treatment.  A CT may be used if a 
MRI would be improbable to obtain. 
 
5. Study Design/Investigational Plan 
5.1 Overall Design 
The study is a single site, prospective study, designed to measure the PK of doxorubicin and its 
metabolite doxorubicinol at various timed intervals after cTACE in patients with primary or 
metastatic liver cancer.   
Up to 30 patients will be enrolled that meet study entry criteria; approximately 15 with primary 
liver cancer and 15 with secondary liver cancer.  Up to 40 patients may be consented if 
necessary in order to enroll these 30 patients, to account for potential patients who screen-out 
or who are unable to complete sample collection for the PK (80% of planned draws).  15 
patients will be enrolled into the lobar cTACE arm and 15 patients will be enrolled into the 
superselective cTACE arm.  The assignment of the treatment arm will be determined by the PI 
or a designated radiologist after review of the patient’s imaging and history. 
The study is planned to complete enrollment in two years, with another month to conclude 
patient follow-up. 
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5.1.1 Routine Care Procedures 
Patients will undergo cTACE according to the standard of care hospital protocol. Depending on 
the assigned treatment arm, a lobar or superselective cTACE procedure will be performed. 
To perform the superselective TACE technique, the tumor-feeding arteries will be catheterized 
with a coaxial microcatheter passed through a 5-Fr catheter previously placed either the right 
or left hepatic artery.  The tip of the microcatheter will be placed into the hepatic arterial 
branch afferent to the segment in which the tumor is located, or if possible the tip of the 
catheter will be further advanced into the subsegmental branches feeding the tumor.  After the 
microcatheter placement, the chemotherapy mixture will be injected under fluoroscopy, 
followed by injection of 1% lidocaine and 100-300 micron embospheres. 
Nonselective lobar TACE will consist of injection of the same chemotherapy materials used in 
the superselective procedures into the right or left lobar branches. 
The amount of chemoembolization material administered is titrated to the area being treated, 
i.e., a smaller area (lesion) may be adequately treated with a portion of the prepared 
chemoembolization material.  The chemoembolization material consists of 10cc of 
chemotherapy, with 50 mg doxorubicin and 10 mg of mitomycin-C mixed 1:1 with Lipiodol 
(approximately 10cc) giving a total of approximately 20cc.  After the chemotherapy is 
administered, approximately 10cc of 1% lidocaine and 1-2 vials of embospheres measuring 100-
300 microns are injected.  The amount of 1% lidocaine and embospheres is titrated to each 
clinical situation. 
Intra-arterial chemotherapy materials: 
• 10 cc of chemotherapy, with 50 mg doxorubicin and 10 mg of mitomycin-C mixed 1:1 
with Lipiodol (approximately 10cc) giving a total of approximately 20 cc. 
• 10 cc of 1% lidocaine 
• 1-2 vials of embospheres measuring 100-300 microns to achieve angiographic end-point 
of 2-5 heart beats to clear the contrast column. 
Following the chemoembolization procedure, the patient is admitted for observation, pain 
control, and hydration, and is discharged home once they are stable.  The day after the TACE 
procedure, a non-contrast CT scan is performed to document the deposition of the Lipiodol. 
Follow-up imaging, labs, and clinical assessment are done 3-4 weeks following the cTACE 
procedure. 
 
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5.1.2 Research Procedures 
Based on previous methodology utilized in our research trial J1306 at Johns Hopkins and other 
TACE trials, venous blood will be sampled for doxorubicin concentrations just before the cTACE 
(pre-) and then repeatedly after cTACE at the following time points: 5 minutes, 10 minutes, 20 
minutes, 40 minutes, 1 hour, 2 hours, 4 hours, 24 hours, and 3-4 weeks post cTACE.  Data will 
be collected and recorded on the Doxorubicin PK Worksheet. 
Instructions for processing PK samples: 
Blood samples will be collected in a heparinized tube (6 mL) from subjects at the time 
points on the study collection calendars (baseline, 5, 10, 20, 40 min, 1, 2, 4, 24 hours, 3-
4 weeks).  Blood samples will be centrifuged at 1000x g (or 3000 rpm) for 10 minutes at 
4oC and stored frozen at -20oC or below until analyzed.  The samples will be analyzed for 
total plasma doxorubicin and doxorubicinol at the Analytical Pharmacology Laboratory 
at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. 
Shipment of PK samples: 
Samples will be kept at the study site and periodically during the study shipped to the APC 
Laboratory.  Unless otherwise stated, samples will be shipped to the Johns Hopkins SKCCC 
Analytical Pharmacology Core (APC) Laboratory under the direction of Michelle A. Rudek, 
Pharm.D., Ph.D.  Specimens should be stored through the duration of the PK study and shipped 
as a batch.  A participant’s samples should be shipped to the APC lab within 3 months of the last 
sample’s collection date.  (i.e., if C1D1 sample is collected on 1/1/2016, all of the participant’s 
samples should be at the APC lab by 4/1/2016).  If another set of participant samples can be 
batched by waiting up to 2 weeks (i.e., 3.5. months), this deviation is allowed. 
Samples will be shipped with a copy of the Doxorubicin PK Worksheet to the APC laboratory.  
Overnight shipments should occur on Monday through Wednesday (Tuesday is the preferred 
day) except when the following day is a holiday.  A fax or call should be placed to the Analytical 
Pharmacology Core Laboratory prior to shipment providing the shipment tracking information.  
Samples should be shipped on dry ice to: 
Analytical Pharmacology Core Laboratory 
Attn: Geschwind/Schlachter cTACE doxorubicin Study Samples 
1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000 
Phone: 410-502-7192 or 410-955-1129 
Fax: 410-502-0895 
 
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5.2 Visit Schedule and Study Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 30 patients (up to 40 consented), approximately 15 with HCC and 15 
with secondary liver cancer (range: 8-20): Obtain informed consent, 
screen potentials subjects by inclusion and exclusion criteria, register 
eligible participants, obtain MRI imaging and labwork if not already 
completed. 
Assignment into lobar or 
superselective arm based on 
imaging and history 
Lobar arm: 
15 subjects (8-20) 
Superselective arm: 
15 subjects (8-20) 
PK baseline blood draw performed prior to cTACE. 
cTACE procedure, lobar vs superselective approach as assigned. 
PK blood draws at: 5, 10, 20, 40 min, 1, 2, 4 hours after cTACE. 
PK blood draw 24 hours after cTACE. 
Standard of care non-contrast abdomen CT to ensure Lipiodol administration. 
Standard of care clinical followup, H&P, labwork, MRI or CT imaging. 
PK blood draw at 3-4 weeks. 
Screening 
Day 0 
Day 1 
Day 21-28 
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Please see appendices for additional study calendar. 
5.3 Duration of Therapy 
There will be one cTACE procedure performed at baseline, done as standard of care.  PK blood 
sampling will continue until the 3-4 week time point. 
5.4 Duration of Follow-up 
Patients will return 3-4 weeks after the cTACE for clinic visit, H&P, laboratory tests, and new 
imaging as part of standard of care.  The final PK blood sample will be drawn at this time. 
5.5 Criteria for Removal from Study 
A study participant may be removed from the study for any of the following reasons: 
• At the request of the patient or a representative, i.e., withdrawal of consent. 
• Patient falls out of eligibility criteria 
• Technical failure of the cTACE procedure 
• Use of illicit drugs or other substances that may, in the opinion of the investigator, 
contribute to toxicity 
• The patient is lost to follow-up 
• Death 
 
6. Adverse Event Collection and Reporting Requirements 
6.1 Definitions 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient and that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the treatment. 
A Serious AE (SAE) is an untoward medical occurrence that at any dose produces any of the 
following outcomes: 
• Results in death; 
• Is life threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe): 
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• Requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below for exceptions); 
• Results in persistent or significant disability/incapacity; 
• Is a congenital anomaly/birth defect; 
• Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention [e.g., medical, surgical] to prevent one of the other serious outcomes listed 
in the definition above).  Examples of such events include, but are not limited to: 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization. 
NOTE: 
The following hospitalizations are not considered SAEs: 
• Admissions as per protocol for a planned medical/surgical procedure; 
• Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy); 
• Medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study.  Appropriate documentation is required in these 
cases; 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, care-giver respite, family circumstances, administrative). 
 
6.2 Adverse Event Coding 
CTCAE term (AE description) and grade: the descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all 
AE reporting. 
6.3 Adverse Event Capture and Reporting 
Risks associated with the research procedures are expected to be minimal, and are involved 
with the drawing of blood and the placement of the IV catheter (second sheath).  They include 
pain, bruising, swelling and bleeding when the catheter is placed.  There is also a risk of 
infection at the IV site, and very rarely, nerve damage.  
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Adverse Events are collected through 3-4 weeks post cTACE and documented for each patient 
on the AE case report form (CRF).  The AEs are transcribed onto a study-specific electronic AE 
log which is reviewed regularly by the PI and is available for the IRB and monitoring committees 
for review. 
Study deviations (protocol deviations: PDs) are collected and reported in the same way as the 
AEs are managed.  PDs are collected through 3-4 weeks post cTACE, and documented on CRFs 
and into PD electronic logs, which are reviewed regularly by the PI and available for IRB and 
monitoring committees for review. 
Unanticipated Problems Involving Risks to Subjects and Others (UPIRSOs) that may require a 
temporary or permanent interruption of study activities will be reported immediately (if 
possible), followed by a written report within 5 calendar days of the Principal Investigator 
becoming aware of the event to the IRB (using the appropriate forms from the website) and 
any appropriate funding and regulatory agencies.  The investigator will apprise fellow 
investigators and study personnel of all UPIRSOs and adverse events that occur during the 
conduct of this research project via email as they are reviewed by the PI.  The Cancer Center 
Protocol Review Committee (PRC), Yale Cancer Center Data and Safety Monitoring Committee 
(DSMC), study sponsor, funding and regulatory agencies will be informed of serious adverse 
events within 5 days of the event becoming known to the Principal Investigator. 
7. Statistical Methods 
7.1 Primary Outcome Variable 
Pharmacokinetic profile of doxorubicin and doxorubicinol after cTACE for each patient: 
• Parameters of PK analysis including peak of the plasma concentration (Cmax), time of 
maximum concentration, and area under the concentration time-curve (AUC). 
• PK profiles for each patient will be correlated with toxicity and tumor burden (size of 
target lesion), BSA and gender. 
• Comparison of PK profile between lobar administration and superselective 
administration. 
7.2 Secondary Outcome Variables 
Feasibility: 
• Technical success of the cTACE procedure (technical failure is defined as the inability to 
administer the cTACE material, in which case the patient would be excluded from the 
study) 
• Dose of doxorubicin delivered 
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Safety: 
• All toxicities assessed as being at least possibly related, up to the 3-4 week follow-up 
visit (post cTACE) will be collected.  Toxicities will be analyzed by descriptive statistics to 
show type, grade (NCI Common Toxicity Criteria v4.0), frequency and time from cTACE. 
7.3 Statistical Plan 
Up to 40 patients may be consented in order to enroll 30 patients, and to account for patients 
who are unable to complete sample collection for the PK (80% of planned draws).  15 patients 
will be enrolled into the lobar cTACE arm and 15 patients will be enrolled into the 
superselective cTACE arm. 
We have assumed a clinically significant change in doxorubicin exposure would be 50%.  In 
order to have 80% power to detect a 50% change with a 5% α, the sample size varies depending 
on the variability noted with TACE therapy.  In the Varella trial utilizing cTACE with a Lipiodol 
doxorubicin formulation, the variability was reported as 30% Coefficient of Variation (CV).  In 
our recent trial (J1306) utilizing TACE with a Drug Eluting Bead (DEB) doxorubicin formulation, 
the variability was reported as 90% CV.  We anticipate the Lipiodol formulation to behave more 
like the Varella trial with 15 patients allowing for slightly higher variability. 
*%CV 
30% 
43% 
90% 
Expected Sample Size 
8 
15 
58 
*Methodology/calculator accessed from the websites below on 11/6/2014: 
https://www.statstodo.com/SSizBioequiv_Tab.php 
https://www.statstodo.com/SSizBioequiv_Pgm.php# 
 
Continuous variables will be reported as means and standard deviations, medians and ranges, 
or both.  Categorical variables will be reported as numbers and percentages.  Pharmacokinetic 
parameters will be calculated by standard noncompartmental methods using Phoenix 
WinNonlin 6.1 (Pharsight, Mountain View, CA) for each patient.  Pharmacokinetic parameters 
will be summarized using descriptive statistics. 
Comparisons of the pharmacokinetic profiles between the lobar cTACE group and the 
superselective cTACE group will be performed using the Mann-Whitney U test.  Correlations 
between pharmacokinetic profiles and clinical toxicities will be performed using the Kruskal-
Wallis one-way ANOVA test.  Correlations between the pharmacokinetic profiles and tumor 
burden will be performed with the Spearman’s correlation coefficient.  A P value < 0.05 will be 
considered statistically significant in all cases. 
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Interim analysis:  
After the 16th patient has completed the study, including approximately 8 in each cTACE arm, 
the PK parameters will be measured for each patient in order to formally review the 
accumulated data and to inform the investigators whether any protocol modifications need to 
be made. 
7.4 Early Stopping Rules 
Not applicable for this study. 
8. Regulatory Considerations 
8.1 Data and Safety Monitoring Plan 
This study is expected to be of minimal risk, and as such, will follow the guidelines for a minimal 
risk DSMP.  The principal investigator is responsible for monitoring the data, assuring protocol 
compliance, and conducting the safety reviews.  During the review process the principal 
investigator will evaluate whether the study should continue unchanged, require 
modification/amendment, or close to enrollment.  An internal monitoring plan will be 
established with the YCC to facilitate this process, and the study will be reviewed annually at 
minimum. 
The principal investigator, the Institutional Review Board (IRB), Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC) have the authority to stop or suspend the study or 
require modifications. 
This protocol presents minimal risks to the subjects and Unanticipated Problems Involving Risks 
to Subjects and Others (UPIRSOs), including adverse events, are not anticipated.  In the unlikely 
event that such events occur, Reportable Events (which are events that are serious or life-
threatening and unanticipated (or anticipated but occurring with a greater frequency than 
expected) and possibly, probably, or definitely related) or Unanticipated Problems Involving 
Risks to Subjects or Others that may require a temporary or permanent interruption of study 
activities will be reported immediately (if possible), followed by a written report within 5 
calendar days of the Principal Investigator becoming aware of the event to the IRB (using the 
appropriate forms from the website) and any appropriate funding and regulatory agencies.  The 
investigator will apprise fellow investigators and study personnel of all UPIRSOs and adverse 
events that occur during the conduct of this research project via email as they are reviewed by 
the PI.  The Cancer Center Protocol Review Committee (PRC), Yale Cancer Center Data and 
Safety Monitoring Committee (DSMC), study sponsor, funding and regulatory agencies will be 
informed of serious adverse events within 5 days of the event becoming known to the principal 
investigator. 
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8.2 Case Report Forms 
As used in this protocol, the term case report form (CRF) refers to a paper form.  A CRF is 
required and should be completed for each included subject. 
The investigator has ultimate responsibility for the accuracy, authenticity, and timely collection 
and reporting of all clinical, safety, laboratory data entered on the CRFs and any other data 
collection forms. 
All CRFs must be signed by the investigator to verify that the data contained on the CRFs is 
accurate.  Any corrections to entries made in the CRFs and source documents must be dated, 
initialed, and explained (if necessary) and should not obscure the original entry. 
Usually, source documents are the hospital’s or the physician’s subject medical chart.  In these 
instances the data collected on the CRFs must match the data in the corresponding charts.  A 
CRF, or part of the CRF, may also serve as a source document. 
Electronic master logs of all adverse events and protocol deviations will also be recorded and 
kept in an encrypted database with access only available to study team members.  An individual 
physical paper CRF will also be kept with the patient’s research binder. 
 
8.3 Record Retention 
To enable inspections and/or audits from regulatory authorities, the investigator agrees to keep 
records, including the identity of all participating subjects (i.e. information to link records, e.g., 
CRFs and hospital records), all original signed informed consent forms, copies of all CRFs, 
serious adverse event forms, source documents, and detailed records of treatment disposition, 
and adequate documentation of relevant correspondence (e.g., letters, meeting minutes, 
telephone calls reports).  The records should be retained by the investigator according to the 
IRB’s policies or the FDA’s regulations, whichever is longer but for a minimum of 5 years. 
If the investigator is unable for any reason to continue to retain study records for the required 
period (e.g., retirement, relocation), the study records must be transferred to a designee 
acceptable to the investigator such as another investigator or another institution. 
9. Ethics 
9.1 Institutional Review Board (IRB) 
It is the responsibility of the investigator/sponsor to have prospective approval of the study 
protocol, protocol amendments, informed consent forms, and other relevant documents, e.g., 
recruitment advertisements, if applicable, from the IRB.  All IRB correspondence should be 
retained in the Investigator File. 
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9.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (1996).  In addition, the study will be conducted in accordance with the 
protocol, the International Conference on Harmonization guideline on Good Clinical Practice, 
and applicable local regulatory requirements and laws. 
9.3 Subject Information and Consent 
All parties will ensure protection of subject personal data and will not include subject names on 
any reports, publications, or in any other disclosures, except where required by laws. 
The informed consent form must be in compliance with ICH GCP, local regulatory requirements, 
and legal requirements. 
The informed consent form must be used in this study, and any changes made during the 
course of the study must be prospectively approved by the IRB before implementation. 
The investigator must ensure that each subject, or his/her legally acceptable representative, is 
fully informed about the nature and objectives of the study and possible risks associated with 
participation.  The investigator, or a person designated by the investigator, will obtain written 
informed consent from each subject or the subject’s legally acceptable representative before 
any study-specific activity is performed.  The investigator will retain the original of each 
subject’s signed consent form. 
 
 
 
 
 
 
 
 
 
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10. References 
 
1. Lammer J, Malagari K, Vogl T, et al.  Prospective randomized study of doxorubicin-
eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the 
PRECISION V study.  Cardiovasc Intervent Radiol.  2010 Feb; 33(1): 41-52. 
2. Vogl TJ, Lammer J, Lencioni R, et al.  Liver, gastrointestinal, and cardiac toxicity in 
intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-eluting 
beads: results from the PRECISION V randomized trial.  AJR Am J Roentgenol.  2011 Oct; 
197(4): W562-70. 
3. Lee KH, Liapi E, Ventura VP, et al.  Evaluation of different calibrated spherical polyvinyl 
alcohol microspheres in transcatheter arterial chemoembolization: VX2 tumor model in 
rabbit liver.  J Vasc Interv Radiol.  2008 Jul; 19(7): 1065-9. 
4. Lee KH, Liapi EA, Cornell C, et al.  Doxorubicin-loaded QuadraSphere microspheres: 
plasma pharmacokinetics and intratumoral drug concentration in an animal model of 
liver cancer.  Cardiovasc Intervent Radiol.  2010 Jun; 33(3): 576-82.  
5. Namur J, Wassef M, Millot JM, Lewis AL, Manfait M, Laurent A.  Drug-eluting beads for 
liver embolization: concentration of doxorubicin in tissue and in beads in a pig model.  J 
Vasc Interv Radiol.  2010 Feb; 21(2): 259-67. 
6. Geschwind JF, Ramsey DE, Cleffken B, et al.  Transcatheter arterial chemoembolization 
of liver tumors: effects of embolization protocol on injectable volume of chemotherapy 
and subsequent arterial patency.  Cardiovasc Intervent Radiol.  2003 Mar-Apr; 26(2): 
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7. Georgiades CS, Hong K, D’Angelo M, Geschwind JF.  Safety and efficacy of transarterial 
chemoembolization in patients with unresectable hepatocellular carcinoma and portal 
vein thrombosis.  J Vasc Interv Radiol.  2005 Dec; 16(12): 1653-9. 
8. Varela M, Real MI, Burrel M, et al.  Chemoembolization of hepatocellular carcinoma 
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9. El-Serag HB.  Hepatocellular carcinoma.  N Engl J Med.  2011 Sep 22; 365(12): 1118-27. 
10. Bruix J, Sherman M, Llovet JM, et al.  Clinical management of hepatocellular carcinoma.  
Conclusions of the Barcelona-2000 EASL conference.  European Association for the 
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11. El-Serag HB, Mason AC.  Rising incidence of hepatocellular carcinoma in the United 
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12. Barbara L, Benzi G, Gaiani S, et al.  Natural history of small untreated hepatocellular 
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and patient survival.  Hepatology.  1992 Jul; 16(1): 132-7. 
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13. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: 
evidence in terms of response rate.  Advanced Colorectal Cancer Meta-Analysis Project.  
J Clin Oncol.  1992 Jun; 10(6): 896-903. 
14. Watanabe S, Nishioka M, Ohta Y, Ogawa N, Ito S, Yamamoto Y.  Prospective and 
randomized controlled study of chemoembolization therapy in patients with advanced 
hepatocellular carcinoma.  Cooperative Study Group for Liver Cancer Treatment in 
Shikoku area.  Cancer Chemother Pharmacol.  1994; 33 Suppl: S93-6. 
15. Sasaki Y, Imaoka S, Kasugai H, et al.  A new approach to chemoembolization therapy for 
hepatoma using ethiodized oil, cisplatin, and gelatin sponge.  Cancer.  1987 Sep 15; 
60(6): 1194-203. 
16. Kanematsu T, Furuta T, Takenaka K, et al.  A 5-year experience of lipiodolization: 
selective regional chemotherapy for 200 patients with hepatocellular carcinoma.  
Hepatology.  1989 Jul; 10(1): 98-102. 
17. Ensminger WD, Gyves JW.  Clinical pharmacology of hepatic arterial chemotherapy.  
Semin Oncol.  1983 Jun; 10(2): 176-82. 
18. Lin DY, Liaw YF, Lee TY, Lai CM.  Hepatic arterial embolization in patients with 
unresectable hepatocellular carcinoma—a randomized controlled trial.  
Gastroenterology.  1988 Feb; 94(2): 453-6. 
19. Pelletier G, Roche A, Ink O, et al.  A randomized trial of hepatic arterial 
chemoembolization in patients with unresectable hepatocellular carcinoma.  J Hepatol.  
1990 Sep; 11(2): 181-4. 
20. A comparison of lipiodol chemoembolization and conservative treatment for 
unresectable hepatocellular carcinoma.  Groupe d’Etude et de Traitement du Carcinome 
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37. Brown DB, Fundakowski CE, Lisker-Melman M, et al.  Comparison of MELD and Child-
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11. Appendices 
Study Visit Calendar 
 
Day -30 to 0 
Day 0 (baseline) 
Day 1 
Day 21-28 
Informed consent 
X 
 
 
 
I/E criteria 
X 
 
 
 
Medical history, H&P 
X 
 
 
X 
Serum/urine pregnancy test 
(if applicable) 
X 
 
 
 
Blood chemistry, 
hematology/coagulation 
X 
 
 
X 
Tumor marker: AFP, CEA, CA 
19-9, etc. 
X 
 
 
X 
MRI scan, contrast enhanced 
of the liver 
X 
 
 
X 
cTACE procedure 
 
X 
 
 
Doxorubicin PK* 
 
X 
X 
X 
Non-contrast CT abdomen 
(standard of care) 
 
 
X 
 
*PK blood samples will be drawn at: baseline (pre-cTACE), 5, 10, 20, 40 min, 1, 2, 4, 24 hours, and at 3-4 
week time points after cTACE. 
 
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