Clinical trial NCT02994251
Conditions: Unresectable Intrahepatic Cholangiocarcinoma
Sponsor: Yale University
Start date: 2017-06-21; Completion date: 2018-11-06
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study will be a single-center, single-arm, Phase II study of gemcitabine and cisplatin in combination with conventional trans-arterial chemoembolization therapy in adult patients with advanced ICC. 25 patients will be enrolled over the course of 2 years, with an additional 1.5 years for patient follow-up.

Detailed description:
Eligible patients enrolled on study will receive a chemotherapy regimen of gemcitabine and cisplatin administered intravenously on Days 1 and 8 of a 21-day cycle. After every 2 cycles of systemic chemotherapy, patients will receive contrast-enhanced MRI to assess liver disease; conventional trans-arterial chemoembolization (TACE) will be performed as indicated based on this assessment. Patients will receive a maximum of 8 cycles of the gemcitabine/cisplatin combination. Up to 3 TACE treatments may be delivered in this same time frame, with the first TACE taking place after 2 cycles of systemic chemotherapy. Following the treatment period, patients will continue clinical follow-up at 3 month intervals until study exit at 18 months post the start of treatment.

It is hypothesized that the addition of conventional transarterial chemoembolization to standard chemotherapy will result in an improvement in PFS in patients with advanced, unresectable ICC, including patients with extra-hepatic disease.

Arms: arm 1: Patients must have advanced, unresectable intrahepatic cholangiocarcinoma (ICC) defined as biopsy-confirmed adenocarcinoma in the liver, with an immunohistochemical profile consistent with a pancreatico-biliary primary, not involving the common bile duct or bifurcation, and not amenable to surgical resection.
Interventions: intervention 1: gemcitabine intervention 2: Cisplatin intervention 3: Conventional TACE (transarterial chemoembolization) with Doxorubicin/Mitomycin-C
Intervention descriptions: intervention 1: 1000 mg/m\^2 of gemcitabine on Day 1 and 8, Dosages may be modified or delayed due to toxicities intervention 2: 25 mg/m\^2 on Day 1 and 8, Dosages may be modified or delayed due to toxicities intervention 3: If conventional transarterial chemoembolization (TACE) is warranted based on MRI assessment and the patient meets all the eligibility criteria for TACE therapy, then cTACE will be scheduled to take place during Week 3 of that cycle. Patients will always receive the first cTACE for study; follow-up cTACE will occur on demand.

Protocol documents:
Prot_SAP_000.pdf: 
 
A Phase II Trial of Systemic Chemotherapy (Gemcitabine and Cisplatin) in 
Combination with Conventional Transarterial Chemoembolization (cTACE) in 
Patients with Advanced Intra-Hepatic Cholangiocarcinoma (ICC) 
 
ClinicalTrials.gov#: NCT02994251 
 
Version Date: 7/19/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


A Phase II Trial of Systemic Chemotherapy (Gemcitabine and Cisplatin) in Combination with 
Conventional Transarterial Chemoembolization (cTACE) in Patients with Advanced Intra-
Hepatic Cholangiocarcinoma (ICC) 
 
HIC Protocol #: 1603017367 
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 
Julius Chapiro, MD 
Stacey Stein, MD 
Jill Lacy, MD 
 
Research Nurse: 
Teresa White, RN, BSN, OCN 
Study Coordinator: 
Eliot Funai 
 
Biostatistician: 
Daniel Zelterman, PhD 
Yale Center for Analytical Sciences 
 
 
 
 
 


 
 
 
Study Sponsor: 
Investigator-Initiated: Todd Schlachter, MD 
 
Financial Support: 
Guerbet LLC 
821 Alexander Rd, Suite 204 
Princeton, NJ 08540 
 
 
Protocol Revision Record 
Original Version: March 7, 2016 
Protocol Amendment #1: April 27, 2017 
Protocol Amendment #2: July 19, 2018 
 
 
 
 
 
 
 
 


HIC#: 1603017367 
PI: Todd Schlachter, MD 
Table of Contents 
 
Section 
Page # 
 
Investigator Agreement Page ...................................................................................................................... 8 
Schema/Synopsis ......................................................................................................................................... 9 
List of Abbreviations .................................................................................................................................. 13 
1. 
Introduction: Background Information and Scientific Rationale ...................................................... 15 
1.1. 
Study Disease: Intrahepatic Cholangiocarcinoma ..................................................................... 15 
1.2. 
Chemotherapy: Gemcitabine and Cisplatin for Cholangiocarcinoma ...................................... 16 
1.3. 
Transarterial Chemoembolization for Intrahepatic Cholangiocarcinoma ................................ 18 
1.4. 
Combination of TACE and Systemic Chemotherapy for Intrahepatic Cholangiocarcinoma .... 20 
2. 
Study Objectives ................................................................................................................................. 21 
2.1. Primary Objectives/Endpoints ........................................................................................................ 21 
2.2. Secondary Objectives/Endpoints.................................................................................................... 22 
3. 
Study Enrollment and Withdrawal .................................................................................................... 22 
3.1. Subject Selection ............................................................................................................................. 22 
3.2. Subject Inclusion Criteria ................................................................................................................ 23 
3.3. Subject Exclusion Criteria ................................................................................................................ 23 
3.4. Subject Registration Process ........................................................................................................... 24 
3.5. Subject Withdrawal ......................................................................................................................... 24 
3.6. Premature Termination or Suspension of Study ............................................................................ 25 
4. 
Study Design/Investigational Plan ..................................................................................................... 25 
4.1. Overview.......................................................................................................................................... 25 
4.2. Study Schedule ................................................................................................................................ 26 
4.3. Systemic Treatment Cycles: Combination of Cisplatin and Gemcitabine ..................................... 28 
4.3.1. Treatment Schedule and Dosage ............................................................................................. 28 
4.3.2. Criteria for a Patient Starting the Next Systemic Treatment Cycle ........................................ 28 
4.3.3. Dose Modifications and Treatment Changes .......................................................................... 29 
4.4. IR Clinical Visit ................................................................................................................................. 31 
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4.5. Conventional TACE with Doxorubicin/Mitomycin-C ...................................................................... 31 
4.5.1. Treatment Phase – Conventional TACE with Doxorubicin/Mitomycin-C ............................... 31 
4.5.2. Conventional TACE Overview .................................................................................................. 32 
4.6. Treatment Delays ............................................................................................................................ 32 
4.7. Concomitant Medications, Therapies, and Supportive Care ......................................................... 33 
5. 
Clinical and Study Procedures ............................................................................................................ 33 
5.1. Screening/Baseline Evaluations ...................................................................................................... 33 
5.2. Treatment Phase – Systemic Chemotherapy Cycles ...................................................................... 34 
5.3. Treatment Phase – IR Clinical Visits and TACE Interventions ........................................................ 34 
5.4. Study Follow-up Phase .................................................................................................................... 34 
5.5. Final Study Visit ............................................................................................................................... 35 
6. 
Study Evaluations ............................................................................................................................... 35 
6.1. Tumor Response (mRECIST, qEASL, vRECIST Criteria) .................................................................... 35 
6.2. Toxicities, Survival, Time to Progression, and Time to Untreatable Progression ......................... 36 
7. 
Safety Profiles of Study Interventions ............................................................................................... 37 
7.1. Gemcitabine .................................................................................................................................... 37 
7.1.1. Gemcitabine Description ......................................................................................................... 37 
7.1.2. Gemcitabine Mechanism of Action ......................................................................................... 37 
7.1.3. Pharmacology of Gemcitabine ................................................................................................ 38 
7.1.4. Toxicology of Gemcitabine ...................................................................................................... 39 
7.2. Description of Cisplatin ................................................................................................................... 39 
7.2.1. Cisplatin Description ................................................................................................................ 39 
7.2.2. Cisplatin Mechanism of Action ................................................................................................ 40 
7.2.3. Pharmacology of Cisplatin ....................................................................................................... 40 
7.2.4. Toxicology of Cisplatin ............................................................................................................. 41 
7.3. Doxorubicin Profile ......................................................................................................................... 42 
7.4. Mitomycin-C Profile ........................................................................................................................ 43 
7.5. Medical Risks or Expected Adverse Events Associated with TACE ................................................ 44 
8. 
Adverse Events ................................................................................................................................... 45 
8.1. Adverse Event Definitions ............................................................................................................... 45 
8.1.1. Unanticipated Problems .......................................................................................................... 45 
8.1.2. Adverse Events ......................................................................................................................... 46 
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8.1.3. Serious Adverse Events ............................................................................................................ 46 
8.2. Adverse Event Capture .................................................................................................................... 47 
8.3. Characteristics of an Adverse Event ............................................................................................... 47 
8.3.1. Relationship to Study Intervention ......................................................................................... 47 
8.3.2. Expectedness of SAEs ............................................................................................................... 47 
8.3.3. Severity of Event ...................................................................................................................... 48 
8.4. Reporting Procedures ..................................................................................................................... 48 
8.4.1. Events Requiring Prompt Reporting to IRB ............................................................................. 48 
8.4.2. Events Not Requiring Prompt Reporting to IRB ...................................................................... 49 
8.4.3. Reporting of SAEs and AEs to Guerbet as Lipiodol Provider .................................................. 49 
9. 
Study Oversight and Monitoring ....................................................................................................... 49 
10. 
Statistical Considerations ............................................................................................................... 51 
10.1. General Overview.......................................................................................................................... 51 
10.2. Trial Design .................................................................................................................................... 52 
10.3. Analysis of Primary Endpoints ...................................................................................................... 52 
10.4. Analysis of Secondary Endpoints .................................................................................................. 52 
10.5. Safety and Toxicity Analysis .......................................................................................................... 52 
11. 
Ethics/Protections of Human Subjects .......................................................................................... 52 
11.1. Ethical Standard ............................................................................................................................ 53 
11.2. Institutional Review Board ........................................................................................................... 53 
11.3. Subject Information and Consent ................................................................................................. 53 
11.4. Inclusion of Women and Minorities ............................................................................................. 53 
12. 
Data Handling and Record Keeping ............................................................................................... 54 
12.1. Data Capture Methods: Case Report Forms ................................................................................. 54 
12.2. Study Records Retention .............................................................................................................. 54 
13. 
Protocol Deviations and Noncompliance ...................................................................................... 54 
13.1. Definitions of Noncompliance and Protocol Deviations .............................................................. 54 
13.2. Reporting of Noncompliance and Protocol Deviations ............................................................... 57 
14. 
Literature References ..................................................................................................................... 58 
15. 
Appendices ..................................................................................................................................... 63 
Appendix A – ECOG Performance Status ............................................................................................... 63 
Appendix B – Child-Pugh Classification ................................................................................................. 64 
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Appendix C – New York Heart Association Classification ..................................................................... 65 
Appendix D – Tables for Dose Modifications ........................................................................................ 66 
Appendix E – Study Calendar ................................................................................................................. 68 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Investigator Agreement Page 
 
 
Study Title: A Phase II Trial of Systemic Chemotherapy (Gemcitabine and Cisplatin) in 
Combination with Conventional Transarterial Chemoembolization (cTACE) in Patients with 
Advanced Intra-Hepatic Cholangiocarcinoma (ICC) 
 
 
 
 
 
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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Schema/Synopsis 
 
Name of Sponsor: 
 
Todd Schlachter, MD (Investigator Initiated) 
Title of Study: 
 
A Phase II Trial of Systemic Chemotherapy (Gemcitabine and Cisplatin) in Combination with 
Conventional Transarterial Chemoembolization (cTACE) in Patients with Advanced Intra-Hepatic 
Cholangiocarcinoma (ICC) 
 
Investigators: 
 
Todd Schlachter, MD 
Hyun (Kevin) Kim, MD 
Jeff Pollak, MD 
Julius Chapiro, MD 
Stacey Stein, MD 
Jill Lacy, MD 
 
Study Center: 
 
Yale University School of Medicine 
 
Anticipated Study Period (years): 
 
June 2016 – Dec 2019 (3.5 years) 
Phase of Development: 
 
Phase II 
 
Abstract: 
 
Cholangiocarcinoma is a primary cancer of the bile ducts arising from malignant transformation of 
cholangiocytes, the epithelial cells that line the biliary apparatus.  The disease is relatively uncommon, 
with an annual incidence of 5,000 new cases in the United States, but incidence rates are rising 
particularly in industrialized countries.  The cause is not completely clear, but studies have shown an 
increasing prevalence of associated risk factors with chronic hepatic damage including alcoholic liver 
cirrhosis, non-alcoholic steatohepatitis, HCV infection, and diabetes. 
 
Intrahepatic cholangiocarcinoma frequently presents as a mass lesion in the absence of jaundice or 
other constitutional symptoms, and treatment can revolve around resection, radiation, systemic 
chemotherapy, or intra-arterial directed therapies among others.  However, the majority of patients are 
not eligible for curative treatments due to extent of disease.  Patients who are not eligible for curative 
treatments for unresectable ICC may still benefit from locoregional therapy.  Transarterial 
chemoembolization is already the most widely performed procedure for patients with unresectable 
hepatocellular carcinoma, and 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. 
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Gemcitabine and platinum-based systemic chemotherapy regimens have been explored with 
encouraging results, but benefits for a combined approach in treating ICC have been found not only in 
combination with conventional TACE (Lipiodol-based transarterial chemoembolization), but also DEB-
TACE (drug-eluting bead TACE) and radioembolization.  These studies provide the foundation for the 
proposed protocol, demonstrating that TACE is a feasible, safe, and efficacious option for the treatment 
of advanced ICC. 
 
Hypothesis: 
 
We hypothesize that the addition of conventional TACE (cTACE) to standard chemotherapy will result in 
an improvement in PFS in patients with advanced, unresectable ICC, including patients with extra-
hepatic disease. 
 
Advances in knowledge: 
 
Results of the study will be used to develop guidelines for the integration of TACE with standard 
chemotherapy in clinical practice for the treatment of patients with intrahepatic cholangiocarcinoma.   
 
Primary objective: 
 
• 
Evaluate the 12-month progression-free survival (PFS) rate in adult patients with intrahepatic 
cholangiocarcinoma after treatment with gemcitabine and cisplatin in combination with 
conventional TACE.  Radiographic assessment of disease burden will be evaluated by mRECIST 
and qEASL using MRI taken after every 2 cycles of systemic chemotherapy. 
 
Secondary objectives: 
 
• 
Evaluation of overall survival (OS) of adult patients with advanced ICC treated with 
gemcitabine/cisplatin in combination with conventional TACE. 
• 
Evaluation of the overall time to progression (TTP) and time to untreatable progression (TTUP) 
in liver lesions in adult patients with ICC treated with gemcitabine/cisplatin in combination with 
cTACE. 
• 
Evaluation of toxicities of the gemcitabine and cisplatin regimen in combination with cTACE 
therapy in adult patients with advanced ICC.  Toxicities to be assessed using CTCAE v5.0. 
• 
Evaluate whether early changes in dynamic contrast-enhanced MRI (DCE-MRI) will correlate 
with long term PFS or OS, specifically as they relate to lesions targeted with cTACE therapy.  
Tumor response to be assessed by mRECIST and 3D volumetric assessments including qEASL and 
vRECIST. 
 
Study Design: 
 
The study will be a single-center, single-arm, Phase II study of gemcitabine and cisplatin in combination 
with conventional trans-arterial chemoembolization therapy in adult patients with advanced ICC.  25 
patients will be enrolled over the course of 2 years, with an additional 1.5 years for patient follow-up. 
 
 
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Treatment Synopsis: 
 
Eligible patients enrolled on study will receive a chemotherapy regimen of gemcitabine and cisplatin 
administered intravenously on Days 1 and 8 of a 21-day cycle.  After every 2 cycles of systemic 
chemotherapy, patients will receive contrast-enhanced MRI to assess liver disease; conventional TACE 
will be performed as indicated based on this assessment.  Patients will receive a maximum of 8 cycles of 
the gemcitabine/cisplatin combination.  Up to 3 TACE treatments may be delivered in this same time 
frame, with the first TACE taking place after 2 cycles of systemic chemotherapy.  Following the 
treatment period, patients will continue clinical follow-up at 3 month intervals until study exit at 18 
months post the start of treatment. 
 
 
Diagnosis: 
 
Patients must have advanced, unresectable intrahepatic cholangiocarcinoma (ICC) defined as biopsy-
confirmed adenocarcinoma in the liver, with an immunohistochemical profile consistent with a 
pancreatico-biliary primary, not involving the common bile duct or bifurcation, and not amenable to 
surgical resection.  Patients must be eligible for the systemic gemcitabine and cisplatin regimen as well 
as fit the requirements for conventional transarterial chemoembolization.  Patients are allowed up to 2 
cycles of gemcitabine/cisplatin therapy performed as standard of care prior to enrollment on protocol.  
Disease must be liver-dominant with no other active malignancy within 2 years.  Patients must have an 
ECOG performance status of 0-1 at study entry and a Child-Pugh class of A to B7 without significant liver 
decompensation. 
 
Inclusion Criteria: 
 
1. Patient is at least 18 years of age. 
2. Patient has advanced, unresectable intrahepatic cholangiocarcinoma (ICC).  Advanced, 
unresectable ICC is defined as biopsy-confirmed adenocarcinoma in the liver, with an 
immunohistochemical profile consistent with a pancreatico-biliary primary, not involving the 
common bile duct or bifurcation, and not amenable to surgical resection. 
3. Eligible for conventional TACE as defined by local treatment guidelines. 
4. Child-Pugh class of A to B7. 
5. Adequate end-organ and bone marrow function as manifested as: 
• 
Hemoglobin ≥ 9 g/dL 
• 
Absolute neutrophil count ≥ 1500/mm3 
• 
Creatinine ≤ 2.0 g/dL 
• 
AST and ALT ≤ 5 x ULN 
• 
Albumin ≥ 2.4 mg/dL 
• 
Total bilirubin ≤ 2.5 mg/dL 
• 
Platelets ≥ 100,000/mm3 
• 
For TACE procedures, subjects are allowed to have platelets ≥ 75,000/mm3. 
6. Disease is liver-dominant with >70% of measurable disease burden within the hepatic 
parenchyma. 
7. ECOG performance status of 0-1. 
8. No other active malignancy within 2 years. 
9. Women of child-bearing potential and men must agree to use adequate contraception prior to 
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PI: Todd Schlachter, MD 
study entry and for the duration of the study. 
10. Ability to understand and willingness to sign a written informed consent document. 
 
Exclusion Criteria: 
 
1. Greater than 2 cycles of prior gemcitabine and/or cisplatin therapy for advanced ICC. 
2. History of allergic reactions attributed to compounds of similar chemical or biological 
composition to gemcitabine, cisplatin, doxorubicin, or mitomycin-C. 
3. Active treatment with CYP3A4 strong inhibitors or inducers. 
4. Recent surgical procedure within 21 days of study enrollment precluding TACE or systemic 
therapy. 
5. Severe and/or uncontrolled co-morbid medical conditions including, but not limited to, active 
infection, viral hepatitis, congestive heart failure, cardiac arrhythmia, unstable angina pectoris, 
and psychiatric illness or social circumstance that would limit compliance with study 
requirements. 
6. Pregnancy during study duration. 
7. Active immunosuppressive medications. 
8. Presence of grade 2 or higher hepatic encephalopathy. 
9. Complete occlusion of the entire portal venous system.  Partial or branch portal vein occlusion 
allowed if without reversal of flow. 
10. Radiotherapy within 21 days from treatment with study interventions or medications. 
11. Current, recent (within 4 weeks of first infusion of this study), or planned participation in 
additional experimental drug. 
12. Unstable angina. 
13. New York Heart Association (NYHA) Grade II or greater congestive heart failure (Appendix C). 
14. History of myocardial infarction or CVA within 6 months prior to study enrollment. 
15. Clinically significant peripheral vascular disease. 
16. Inability to comply with study and/or follow-up procedures. 
17. Life expectancy of less than 12 weeks. 
 
Statistical Considerations: 
 
The primary endpoint of this phase II study is the 12-month progression-free survival (PFS) in adult 
patients with ICC after treatment with gemcitabine and cisplatin in combination with conventional 
transarterial therapy.  The currently used drug regimen in this patient population is expected to have a 
12-month PFS rate of 20%.  Alternatively, the experimental treatment will be considered worthy of 
further study if the PFS at 12 months is 40% or better. 
 
Secondary endpoints include OS, TTP, TTUP, and toxicities.  Correlations between early changes in DCE-
MRI with long-term PFS or OS will be examined, specifically as related to lesions treated with cTACE 
therapy.  This will include mRECIST, qEASL, and 3D volumetric assessments of tumor response on 
imaging. 
 
 
 
 
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List of Abbreviations 
 
Abbreviation 
Definition 
5-FU 
5-Fluorouracil 
ADL 
Activities of Daily Living 
AE/SAE 
Adverse Event/Serious Adverse Event 
AJCC 
American Joint Committee on Cancer 
ALKP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
APHI 
Acute progressive hepatic insufficiency 
AST 
Aspartate transaminase 
BTC 
Biliary tract cancer 
BUN 
Blood urea nitrogen 
CA 19-9 
Cancer antigen 19-9 
CBC 
Complete blood count 
CEA 
Carcinoembryonic antigen 
CMP 
Complete metabolic panel 
CR 
Complete response 
CRF 
Case report form 
CT scan 
Computerized tomography scan 
cTACE 
Conventional transarterial chemoembolization 
CVA 
Cerebrovascular accident 
DCE-MRI 
Dynamic contrast-enhanced magnetic resonance imaging 
DEBTACE 
Drug-eluting bead transarterial chemoembolization 
DSMB 
Data Safety Monitoring Board 
DSMC 
Data Safety Monitoring Committee 
EASL 
European Association for the Study of the Liver 
ECC 
Extrahepatic cholangiocarcinoma 
ECOG-PS 
Eastern Cooperative Oncology Group – Performance Status 
FDA 
Food and Drug Administration 
H&P 
History and physical 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCV 
Hepatitis C Virus 
HIC 
Human Investigation Committee (Yale IRB) 
HRPP 
Human Research Protection Program 
IAT 
Intra-arterial therapy 
ICC 
Intrahepatic cholangiocarcinoma 
ICH GCP 
International Conference on Harmonization: Good Clinical Practice 
IR 
Interventional radiology 
IRB 
Institutional review board 
mRECIST 
Modified RECIST 
NCI CTCAE 
National Cancer Institute: Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
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OS 
Overall survival 
 
PD 
Protocol deviation 
PD (tumor 
response) 
Progressive disease 
PFS 
Progression-free survival 
PHI 
Protected health information 
PI 
Principal investigator 
PR 
Partial response 
PRC 
Protocol Review Committee 
PT/INR 
Prothrombin time/International normalized ratio 
PVA particles 
Polyvinyl alcohol particles 
qEASL 
Quantitative EASL 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
TACE 
Transarterial chemoembolization 
TAE 
Transarterial embolization 
TTP 
Time to progression 
TTUP 
Time to untreatable progression 
UICC 
Union for International Cancer Control 
ULN 
Upper limit of normal 
UPIRSOs 
Unanticipated Problems Involving Risks to Subjects and Others 
WBC 
White blood count 
Y-90 
Yttrium-90 
YCC 
Yale Cancer Center 
 
 
 
 
 
 
 
 
 
 
 
 
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1. Introduction: Background Information and Scientific Rationale 
1.1. Study Disease: Intrahepatic Cholangiocarcinoma 
Cholangiocarcinoma is a primary cancer of the bile ducts arising from malignant transformation of 
cholangiocytes, the epithelial cells that line the biliary apparatus.  Cholangiocarcinoma are encountered 
in three anatomic regions along the biliary tract: as intrahepatic (ICC), hilar/perilhilar (Klatskin) which 
occur at the bifurcation of the left and right hepatic ducts, and as distal extrahepatic.  The disease is 
relatively uncommon, with an annual incidence of 5,000 new cases in the United States.  Worldwide, it 
accounts for 3% of all gastrointestinal cancers (1). Specifically regarding ICC, incidence data from the 
American Cancer Society are somewhat difficult to interpret as both ICC and primary hepatocellular 
carcinoma (HCC) are classified within one group, with about 33,190 cases diagnosed and 23,000 cancer-
related deaths in 2014 (2).  Registry data suggests that about 10-15% of these cases are truly ICC.  
Incidence rates of ICC are rising, particularly in industrialized countries, and though the cause is not 
completely clear (3) studies have shown an increasing prevalence of associated risk factors with chronic 
hepatic damage including alcoholic liver cirrhosis, non-alcoholic steatohepatitis, HCV infection, and 
diabetes (4). 
Cholangiocarcinoma of the proximal or distal bile duct often presents with features of biliary 
obstruction.  In contrast, ICC occurs within the hepatic parenchyma where it frequently presents as a 
mass lesion in the absence of jaundice or other constitutional symptoms.  As such, it was traditionally 
staged according to HCC criteria; but with recent developments necessitating the distinction between 
HCC and ICC, the 7th edition of the AJCC/UICC staging manual reflects new guidelines for staging 
intrahepatic bile duct cancers.  One of the new updates is eliminating tumor size as a prognostic factor.  
T-classification is instead based on number of lesions, vascular invasion, intrahepatic metastasis, and 
invasion into adjacent structures which were better discriminatory predictors of survival (5).  On 
imaging, ICC typically appears hypointense on T1-weighted MRI and hyperintense on T2-weighted 
images.  Dynamic CT scanning can help differentiate between intrahepatic cholangiocarcinoma and 
hepatocellular carcinoma: up to 81% of ICC are characterized by progressive contrast uptake from 
arterial to venous, and HCC is characterized by rapid enhancement during the arterial phase and 
washout in venous or delayed phases (6).  Radiological assessments of ICC are often insufficient for 
diagnosis other than in non-cirrhotic patients who will undergo surgical resection; pathological diagnosis 
is required in most cases. 
Curative options such as hepatic resection exist for cholangiocarcinoma patients, but unfortunately 
most present with unresectable disease with a survival rate of less than 12 months following diagnosis 
(7).  ICC in particular is generally associated with lower resectability and curability when compared to 
other hepatobiliary malignancies (8).  Liver transplantation for cholangiocarcinoma has historically been 
controversial by being associated with disease recurrence and poor survival rates, but may be improved 
with careful patient selection (9).   
For patients not eligible for resection or transplant, therapeutic options include external beam radiation 
therapy, locoregional procedures (transarterial chemoembolization or TACE, radioembolization, 
ablation), molecular targeting, and chemotherapy among others.  Due to the small number of patients 
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and the heterogeneous patient population in biliary tract cancers as compared with other more 
common malignancies, randomized phase III studies examining systemic chemotherapy and other 
treatments have been a challenge to conduct.  However, based on current experience from phase II 
studies, systemic chemotherapy has improved from traditional fluoropyrimidine-based regimens that 
have response rates of only 10% to 30% to gemcitabine-based combination regimens with response 
rates in the range of 22% to 50% (10).  Molecularly targeted agents that inhibit angiogenesis and 
epidermal growth factor receptor pathways have recently started to enter clinical trials for unresectable 
ICC, but none have shown to improve patient survival as of yet.  Most clinical practitioners based their 
treatment paradigms on the ABC-02 trial completed in 2009 which confirmed the combination of 
gemcitabine and cisplatin as the standard first line therapy for cases of advanced biliary tract cancers 
(11).  This combination therapy yielded a median progression-free survival of 8.0 months but did not 
stratify the patients based on intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma due 
to small numbers in each group.   
Despite the observation that growth in the primary tumor is the first site of disease progression in 70% 
of ICC cases, there is no approved liver-directed therapy for this disease.  Therefore, we hypothesize 
that the addition of conventional transarterial chemoembolization to standard chemotherapy will result 
in an improvement in PFS in patients with advanced, unresectable ICC, including patients with extra-
hepatic disease. 
 
1.2. Chemotherapy: Gemcitabine and Cisplatin for Cholangiocarcinoma 
Patients with advanced ICC are under-represented in clinical trials, and have traditionally been 
assimilated in studies of biliary tract cancers with extra-hepatic cholangiocarcinoma (ECC) and 
gallbladder cancer due to small patient population.  As a result, conducting trials to develop an effective 
chemotherapy regimen presented many challenging obstacles that needed to be overcome.  The first 
trial to demonstrate increased overall survival and quality of life using systemic chemotherapy over best 
supportive care in patients with advanced pancreatic and biliary cancer utilized a combination of 5-
fluorouracil plus leucovorin and etoposide therapy (12).  Another trial looked at a combination of 5-FU, 
mitomycin-C, and doxorubicin in 17 patients and found 31% of the patients had measurable tumor 
response (13).  In another trial comprised of two consecutive studies, both gemcitabine therapy and a 
combination of 5-FU, leucovorin, and mitomycin-C were found to be feasible, although the studies 
lacked patients with impaired liver function (14). 
Since then, several studies have looked at treatment regimens for biliary tract and gallbladder cancer.  In 
a multicenter phase II study in the treatment of BTC examining single-agent gemcitabine or in 
combination with levofolinic acid and IV 5-FU, Gebbia noted that single-agent gemcitabine is active 
against advanced, unresectable BTC with a partial response recorded in 4 cases (22%) with a median 
duration of 4.5 months.  Stable disease was seen in 5 cases (28%) and toxicities were mild with no 
severe grade 4 toxicities (15).  Gemcitabine was also used in a phase II study as part of a regimen in 
combination with cisplatin for patients with gallbladder cancer: median overall survival was 20 weeks 
with 1-year survival rate of 18.6% (16).  4 (13.3%) of the patients were complete responders with 
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disappearance of all disease, 7 (23.3%) partial responders, and 7 (23.3%) patients had stable disease.  
The authors concluded that the gemcitabine and cisplatin combination was well tolerated and active in 
this disease profile.  A study looking at chemotherapy in comparison with best supportive cancer in gall 
bladder cancer concluded not only the efficacy of chemotherapy in improving overall survival and 
progression-free survival over best supportive care, but the superiority of the gemcitabine and 
oxaliplatin combination over fluorouracil and folinic acid (17).  By RECIST criteria, the disease response 
rate was 30.7% (7.7% complete response and 23.1% partial response) in the gemcitabine/oxaliplatin 
arm.   
Gemcitabine’s efficacy in the treatment of advanced BTC along with its favorable toxicity profile has 
been exemplified in numerous other clinical trials.  A review of gemcitabine regimens as a single agent 
and in combination with other chemotherapeutic drugs noted remarkable tolerance for gemcitabine, 
with less than 5% of patients experiencing grade 4 hematological toxicities (18).  In Japan where one of 
the prominent treatments is with S-1 (tegafur/gimeracil/oteracil), a multi-center retrospective analysis 
of chemotherapy for unresectable biliary tract cancer concluded that gemcitabine was the most 
effective treatment studied with a reduction in mortality of 50% (19).  Chemotherapy regimens 
examined in this study were 5-FU based regimens; S-1 alone; gemcitabine alone; 5-FU, doxorubicin, and 
mitomycin-C; and cisplatin-based regimens.  Cisplatin was also found to reduce mortality by 40% albeit 
with more toxicities, and future studies examining a combination of gemcitabine and cisplatin were 
recommended.  With its unique mechanism of action and low toxicity profile, gemcitabine is seen to be 
safe to combine with other drugs (20). 
While gemcitabine is grounded as a treatment option for advanced BTC, the role and identity of a 
combinatory chemotherapeutic drug is more debatable.  The EORTC trial (21) was the first randomized 
study to evaluate a combination chemotherapy regimen with platinum-based compounds for the 
treatment of BTC.  The trial compared high-dose 5-FU vs 5-FU, folinic acid, and cisplatin and found an 
improved response rate in the combination therapy.  On the 5-FU arm, no patients expressed a 
complete response and 7% a partial response; the combination arm had an improved objective response 
rate (4% for complete response and 15% for partial response), as well as an increase in overall median 
survival (8.0 months compared to 5.0 months on the high-dose 5-FU arm).  A Phase III study comparing 
5-FU, etoposide, leucovorin vs epirubicin, cisplatin, 5-FU as first-line therapy for patients with advanced 
BTC failed to enroll enough subjects to detect a significant difference between the two regimens.  
However, the patients on the epirubicin/cisplatin/5-FU regimen produced similar response rate, 
symptom resolution, and failure-free survival as the other arm but with significantly less acute toxicity 
(22).  The combination of gemcitabine and docetaxel was examined in another study that reported an 
overall median survival rate of 11 months for patients with gallbladder, biliary, or cholangiocarcinomas 
(23). 
Of the various combinations of gemcitabine, platinum-based compounds showed the most promise with 
improved response rate over gemcitabine monotherapy and increased progression free survival over 5-
FU and other therapies (24-26).  Oxaliplatin and cisplatin are the most commonly seen additions: 
gemcitabine/oxaliplatin chemotherapy is frequently used due to easier administration of oxaliplatin, but 
gemcitabine/cisplatin may have a short survival advantage (27).  Part of this may be due to a synergistic 
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interaction between cisplatin and gemcitabine related to reduced DNA repair, as the combination did 
not cause any additive DNA damage than gemcitabine alone (28).  This leads to a synergistic or additive 
effect found both in vitro and in vivo; but is time-dependent and thus dependent on the scheduling of 
both drugs (29). 
Numerous Phase II trials have been conducted investigating the efficacy, safety, dosage and 
administration of the gemcitabine and cisplatin combination treating patients with biliary tract cancer: 
generally, results have been improved tumor response and overall survival compared to other 
treatment options with low to moderate toxicities (30-37).  The studies that have established the 
gemcitabine and cisplatin treatment for cholangiocarcinomas were the Phase II ABC-01 and subsequent 
Phase III ABC-02 trials performed in the UK (10, 38).  These two studies examined the gemcitabine and 
cisplatin combination against gemcitabine monotherapy and found that the combination lead to 
significantly improved progression-free survival of 8.0 months compared to 5.0 months on 
monotherapy, and overall median survival of 11.7 months to 8.1 months.  Tumor control (complete 
response plus partial response plus stable disease) was achieved in 131 (81.4%) of patients in the 
combination therapy and 102 (71.8%) on monotherapy.  The effectiveness of gemcitabine and cisplatin 
over gemcitabine alone were also supported by the BT22 Phase II study in Japan (39).  Disease control 
rate was 68.3% for the combination and 50.0% for monotherapy.  Median survival and progression-free 
survival were both superior on the combination arm, at 11.2 months and 5.8 months respectively 
compared to 7.7 months and 3.7 months on the monotherapy arm.  With both ABC-01/ABC-02 and BT22 
trials showing superior outcomes with combination therapies despite different risk factors for BTC in 
Western and East Asian populations, gemcitabine/cisplatin became an accepted standard of treatment 
for cholangiocarcinoma (40). 
 
1.3. Transarterial Chemoembolization for Intrahepatic Cholangiocarcinoma 
Patients who are not eligible for curative treatments for unresectable intrahepatic cholangiocarcinoma 
may still benefit from locoregional therapy.  Transarterial chemoembolization is already the most widely 
performed procedure for patients with unresectable hepatocellular carcinoma, and 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 conventional 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 and thus causing necrosis of the tumor.  In HCC, TACE has been shown to deliver up to 
400 times the intra-hepatic concentration of chemotherapy in comparison to intravenous administration 
depending on the chemotherapeutic agent (41).  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 (42-44). 
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Early studies suggested prolonged survival in patients treated with arterial chemotherapy infusion 
therapy.  One study examined arterial chemoinfusion in the context of 3 different chemotherapy 
regimens: 8 patients with 5-FU, Adriamycin or epirubicin, mitomycin C, and/or cisplatin; 1 patient with 
5-FU; 2 patients with 5-FU and cisplatin (45).  A greater than 50% decrease in tumor size was seen in 5 
(45.5%) out of 11 patients, with 2 (18.2%) patients exhibiting a minor response of 25-50% tumor 
decrease in size, 2 patients with stable disease, and 2 patients that had progressed.  Mean survival 
period was 26.0 months.   
With the effectiveness of TACE in improving survival for patients with unresectable HCC (46, 47) along 
with previous studies showing potential for intra-arterial treatment of cholangiocarcinoma, Burger, et al, 
examined 17 patients with unresectable cholangiocarcinoma that were treated with TACE (48).  15 of 
the 17 patients were treated with conventional TACE consisting of a mixture of cisplatin, doxorubicin, 
and mitomycin-C emulsified in Lipiodol before embolization with polyvinyl alcohol or Embosphere 
particles.  One of the remaining 2 patients received two cisplatin hepatic arterial infusions before 
starting on the standard cTACE therapy, and the last received a mixture of cisplatin and Lipiodol for the 
first procedure before the standard therapy.  Estimated median survival was 23 months from date of 
diagnosis, and 7 of 9 patients still alive had evidence of significant tumor necrosis without progression 
on MR imaging.  Tumor response by RECIST criteria was not very demonstrated, although this may be 
due to RECIST criteria being based on tumor size, whereas TACE does not usually result in tumor size 
reduction (49).  Nevertheless, 79% of the patients showed significant tumor necrosis, and the procedure 
was well-tolerated by the patients with 9 (53%) experiencing no side effects, and 5 (29%) experienced 
common transient post-embolization symptoms that quickly resolved.  Another study demonstrating 
promise of TACE in ICC patients was conducted by Kiefer et al, which presented elevated survival 
outcomes (50).  62 patients were treated on study with a chemoembolization mixture of Lipiodol, 
mitomycin-C, doxorubicin, and cisplatinum followed by PVA particles: 37 with pathologically proven 
cholangiocarcinoma and 25 with poorly differentiated adenocarcinoma of unknown primary but likely to 
be cholangiocarcinoma.  By RECIST criteria, 5 (11%) exhibited partial response, 29 (64%) stable disease, 
and 11 (24%) with progression of disease.  Median survival was found to be 20 months from time of 
diagnosis; 1-year survival was 75%, 2-year survival 39%, and 3-year survival 17%. 
A multivariate analysis evaluating the clinical efficacy of chemoembolization or arterial chemoinfusion 
for unresectable ICC looked at 49 patients and found  tumor vascularity to be the only significant factor 
associated with success after TACE for ICC out of tumor size and treatment group (51).  For survival, 
tumor size, vascularity, and Child-Pugh class were found to be independent factors.  The authors also 
noted that a large percentage of their patients demonstrated hypervascularity on angiography in the 
area of the disease similar to other studies (49, 52), concluding that TACE could be effective palliative 
treatment for these cases.  When compared to supportive therapy for unresectable ICC, TACE was found 
to result in significantly greater survival benefits with a median survival of 12.2 months compared to 3.3 
months when treated with symptomatic relief (53).  Within the subgroup of patients who received TACE 
therapy, survival rates were significantly higher in those that showed objective tumor response to TACE 
(median survival of 22 months) compared to those who showed no response to TACE (median of 10.9 
months).   
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Gemcitabine-based regimens for conventional TACE were explored in a single-institute study performed 
by Gusani, et al (54).  42 patients with unresectable cholangiocarcinoma were treated: 18 received 
gemcitabine only; 2 with gemcitabine followed by cisplatin; 4 with gemcitabine followed by oxaliplatin; 
14 with gemcitabine and cisplatin in combination; and 4 with gemcitabine and cisplatin, followed by 
oxaliplatin.  Based on RECIST criteria, 20 patients were found to have stable disease, 15 patients had 
progressive disease, and 7 patients were not evaluable.  Median overall survival from the date of first 
TACE was 9.1 months; however, there was significant variation by response to TACE and by regimen.  
For patients who had stable disease, the median survival was 13.1 months post-TACE in contrast to 
patients who had progressive disease with a median survival of 6.9 months.  By TACE regimen, there was 
a statistically significant increase in survival for patients receiving gemcitabine-cisplatin combination 
(13.8 months) to those receiving gemcitabine alone (6.3 months).   
Another trial with varying TACE-regimens in the context of intrahepatic cholangiocarcinoma examined 
retrospectively a total of 115 patients with unresectable ICC (55): 24 patients were treated with 
mitomycin-C only; 8 with gemcitabine-only; 54 with gemcitabine-mitomycin-C; and 29 with gemcitabine, 
mitomycin-C, and cisplatin.  Median and mean survival times from start of TACE treatment were 13 and 
20.8 months respectively: 1-year survival rate was 52%, 2-year 29%, and 3-year 10%.  By RECIST criteria, 
8.7% (10/115) patients achieved partial response, 57.4% stable disease, and 33.9% progressive disease.   
Our group has published a retrospective analysis of almost 200 patients with intrahepatic 
cholangiocarcinoma who underwent some form of intra-arterial therapy at one of five participating 
academic institutions (56).  This analysis covered a 20 year period up to 2012, and comprised patients 
with a median age of 61 years, about half of whom had a solitary lesion in the liver with a median tumor 
size of 8.1 cm.  Most of these patients were treated with conventional TACE (64.7%), with smaller 
numbers receiving Y-90 radioembolization (23.2%), drug-eluting bead (DEB-TACE 5.6%), or bland 
embolization (TAE 6.6%).  Two-thirds of these patients underwent at least two separate IAT sessions, 
with younger patients, and those with multifocal or bulkier tumors more likely to receive multiple 
sessions.  Treatments were generally associated with a low morbidity, and only 30% of patients 
developed a post-procedure complication.  8% of patients developed a more significant complication, 
requiring extensive medical or surgical intervention.  Encouraging tumor responses were observed in 
this patient population, with 25% exhibiting a partial or complete response, and 60% exhibiting stable 
disease per mRECIST criteria.  Responses did correlate well with overall survival in this retrospective 
study, and the median OS for the cohort was 13.2 months, with a 1-year survival of 54%.  Those patients 
achieving a complete or partial response to initial therapy had a median OS of 32.4 months. 
 
1.4. Combination of TACE and Systemic Chemotherapy for Intrahepatic 
Cholangiocarcinoma 
There have been few studies that sought to combine both systemic chemotherapy and trans-arterial 
therapies in the treatment of ICC.  For hepatocellular carcinoma, Jang, et al conducted a retrospective, 2 
arm study of 52 patients with unresectable HCC: one arm was treated with transarterial infusion of 
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cisplatin and epirubicin, systemic infusion of 5-FU, and additional percutaneous ethanol injection; the 
other received transarterial infusion with doxorubicin followed by embolization with Gelfoam (57).  
Objective tumor response was increased in the combination arm (53.3%) compared to the monotherapy 
arm (22.7%), although no complete responses were observed on either arm.  Overall survival was also 
elevated on the combination arm, with survival rates for 6, 12, 18, and 24 months at 90%, 57%, 27%, 
and 17% respectively; for the doxorubicin group, they were 73%, 37%, 7%, and 0%.  As such, the 
combination therapy appeared to be feasible and possibly confer a survival benefit, although it should 
be noted that the patients in this study were in a more advanced stage with regards to tumor burden, 
and a high proportion of the patients had portal vein thrombosis. 
In 2005, Kirchhoff, et al, conducted a prospective single arm study of 8 patients with nonresectable 
cholangiocarcinoma with gemcitabine and conventional TACE (58).  Both systemic and locoregional 
therapies were well-tolerated, with nausea and vomiting were the most common toxicities experienced 
by patients; no severe toxicities were reported.  In terms of imaging response, 5 patients had stable 
disease and 3 patients had progressive disease.  The median time to tumor progression was 7 months 
(range 3-18), and overall survival was 12 months.  The authors conclude that in patients with ICC, 
regional chemoembolization in addition to a systemic gemcitabine regimen is well-tolerated, and may 
enhance the palliative effect of systemic therapy alone. 
A retrospective study conducted by Li, et al, examined 66 patients with unilateral, advanced Wilms 
tumors divided into 3 treatment arms: pre-operative systemic therapy, pre-operative conventional 
TACE, and the combination of pre-operative cTACE and systemic chemotherapy (59).  Patients treated 
with the combination therapy demonstrated a significant improvement in response over the systemic 
therapy alone, with 72.0% being good responders (at least 40% reduction in tumor volume) compared 
to only 35% in the systemic arm.  The 2-year relapse-free survival rates were found to be 65.0% in the 
systemic arm, 80.9% in the TACE arm, and 100.0% in the combination group. 
Generally, response rates and survival for ICC appear to be higher for intra-arterial and TACE therapies 
than those with systemic chemotherapy regimens (60).  Benefits for a combined approach in treating 
liver lesions have been found not only in cTACE combinations, but also studies that utilized DEBTACE or 
radioembolization (61-67).  Our experiences with ICC and past studies provide the foundation for the 
proposed protocol, demonstrating that IAT is a feasible, safe, and efficacious option for the treatment of 
advanced ICC, and opening the possibility of improved survival over that seen with systemic therapy 
alone.   
 
2. Study Objectives 
2.1. Primary Objectives/Endpoints 
The primary objective of this study is to evaluate the 12-month progression-free survival (PFS) rate in 
adult patients with intrahepatic cholangiocarcinoma (ICC) after treatment with gemcitabine and 
cisplatin in combination with conventional TACE.  This is the percentage of patients alive and free of 
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progression at 12-months from enrollment on study.  Radiographic assessment of disease burden will be 
evaluated by mRECIST and qEASL using an MRI scan obtained at the IR clinic visit. 
 
2.2. Secondary Objectives/Endpoints 
Secondary objectives include: 
• 
Evaluation of overall survival (OS) of adult patients with advanced ICC treated with gemcitabine 
and cisplatin in combination with conventional TACE.  Overall survival is the time from 
enrollment on study until death of the patient from any cause. 
• 
Evaluate the overall time to progression (TTP) and time to untreatable progression (TTUP) in 
liver lesions in adult patients with ICC treated with gemcitabine and cisplatin in combination 
with conventional TACE.  Overall TTP is the time from enrollment on study until radiographic 
evidence of overall disease progression.  TTUP in liver lesions is measured from the time of 
initiation on cTACE therapy until radiographic evidence of disease progression in targeted 
lesions.  Radiographic assessment will be evaluated by mRECIST using MRI every 2 cycles after 
intra-arterial therapy.  
• 
To evaluate the toxicities of the gemcitabine and cisplatin regimen in combination with cTACE 
therapy in adult patients with advanced ICC.  Safety will be assessed using the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.  Incidence of 
adverse events, serious adverse events, changes in baseline vital signs, ECOG performance 
status, and laboratory data (hematologic, liver and kidney function) will be assessed. 
• 
Evaluate whether early changes in dynamic contrast-enhanced MRI (DCE-MRI) will correlate 
with long term PFS or OS, specifically as they relate to lesions targeted with cTACE therapy.  Pre- 
and post-treatment images will be analyzed for 3D volumetric functional analysis in arterial and 
venous phases with tumor assessments by mRECIST, qEASL, and 3D volumetric response criteria. 
 
3. Study Enrollment and Withdrawal 
3.1. Subject Selection 
Patients must have advanced, unresectable intrahepatic cholangiocarcinoma (ICC) defined as biopsy-
confirmed adenocarcinoma in the liver, with an immunohistochemical profile consistent with a 
pancreatico-biliary primary, not involving the common bile duct or bifurcation, and not amenable to 
surgical resection.  Patients must be eligible for the systemic gemcitabine and cisplatin regimen as well 
as fit the requirements for conventional transarterial chemoembolization.  Patients are allowed up to 2 
cycles of gemcitabine/cisplatin therapy performed as standard of care prior to enrollment on protocol.  
Disease must be liver-dominant with no other active malignancy within 2 years.  Patients must have an 
ECOG performance status of 0-1 (Appendix A) at study entry and a Child-Pugh class of A to B7 without 
significant liver decompensation (Appendix B).  
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Patients who drop out or have incomplete follow-up will be treated as a treatment failure. There will not 
be replacement patients. 
 
3.2. Subject Inclusion Criteria 
In order to be eligible to participate in this study, the prospective participant must meet all of the 
following inclusion criteria: 
1. Patient is at least 18 years of age. 
2. Patient has advanced, unresectable intrahepatic cholangiocarcinoma (ICC).  Advanced, 
unresectable ICC is defined as biopsy-confirmed adenocarcinoma in the liver, with an 
immunohistochemical profile consistent with a pancreatico-biliary primary, not involving the 
common bile duct or bifurcation, and not amenable to surgical resection. 
3. Eligible for conventional TACE as defined by local treatment guidelines. 
4. Child-Pugh class of A to B7. 
5. Adequate end-organ and bone marrow function as manifested as: 
• 
Hemoglobin ≥ 9 g/dL 
• 
Absolute neutrophil count ≥ 1500/mm3 
• 
Creatinine ≤ 2.0 g/dL 
• 
AST and ALT ≤ 5 x ULN 
• 
Albumin ≥ 2.4 mg/dL 
• 
Total bilirubin ≤ 2.5 mg/dL 
• 
Platelets ≥ 100,000/mm3 
• 
For TACE procedures, subjects are allowed to have platelets ≥ 75,000/mm3. 
6. Disease is liver-dominant with >70% of measurable disease burden within the hepatic 
parenchyma. 
7. ECOG performance status of 0-1. 
8. No other active malignancy within 2 years. 
9. Women of child-bearing potential and men must agree to use adequate contraception prior to 
study entry and for the duration of the study. 
10. Ability to understand and willingness to sign a written informed consent document. 
 
3.3. Subject Exclusion Criteria 
Subjects must not have any of the following exclusion criteria in order to participate in this study: 
1. Greater than 2 cycles of prior gemcitabine and/or cisplatin therapy for advanced ICC. 
2. History of allergic reactions attributed to compounds of similar chemical or biological 
composition to gemcitabine, cisplatin, doxorubicin, or mitomycin-C. 
3. Active treatment with CYP3A4 strong inhibitors or inducers. 
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4. Recent surgical procedure within 21 days of study enrollment precluding TACE or systemic 
therapy. 
5. Severe and/or uncontrolled co-morbid medical conditions including, but not limited to, active 
infection, viral hepatitis, congestive heart failure, cardiac arrhythmia, unstable angina pectoris, 
and psychiatric illness or social circumstance that would limit compliance with study 
requirements. 
6. Pregnancy during study duration. 
7. Active immunosuppressive medications. 
8. Presence of grade 2 or higher hepatic encephalopathy. 
9. Complete occlusion of the entire portal venous system.  Partial or branch portal vein occlusion 
allowed if without reversal of flow. 
10. Radiotherapy within 21 days from treatment with study interventions or medications. 
11. Current, recent (within 4 weeks of first infusion of this study), or planned participation in 
additional experimental drug. 
12. Unstable angina. 
13. New York Heart Association (NYHA) Grade II or greater congestive heart failure (Appendix C). 
14. History of myocardial infarction or CVA within 6 months prior to study enrollment. 
15. Clinically significant peripheral vascular disease. 
16. Inability to comply with study and/or follow-up procedures. 
17. Life expectancy of less than 12 weeks. 
 
3.4. Subject Registration Process 
All patients would be seen for an initial clinic visit, where a clinician would present all appropriate 
treatment options.  If the patient expresses an interest in this 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 form 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. 
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. 
 
3.5. Subject Withdrawal 
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 
• 
Unmanageable toxicities related to the study drugs 
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• 
Significant extrahepatic disease progression 
• 
Substantial non-compliance with the requirements of the study 
• 
Reached Time to Untreatable Progression (TTUP) where TTUP is defined as disease progression 
beyond the scope of further intra-arterial therapy, which includes: overt extra-hepatic 
progression to the extent that extrahepatic disease is greater than 30% of the global tumor 
burden, development of clinically significant ascites, markedly abnormal liver function tests, 
complete absence of portal venous blood flow, and deteriorated performance status (greater 
than ECOG 2) 
• 
Concomitant illness that prevents further participation 
• 
Use of illicit drugs or other substances that may, in the opinion of the investigator, contribute to 
toxicity 
 
3.6. Premature Termination or Suspension of Study 
The investigator has the right to close the study, at any time, although this should occur only after 
consultation between involved parties.  The Institutional Review Board (IRB) and associated Ethics 
Committees must be informed.  Events that may trigger a premature termination of a study include, but 
are not limited to: new toxicity finding, results of any interim analysis, completed accrual and follow-up 
of patients, non-compliance with the protocol, change in development plans for the study drug, slow 
recruitment, or poor quality data. 
 
4. Study Design/Investigational Plan 
4.1. Overview 
 
The study will be a single-center, single-arm, Phase II study of gemcitabine and cisplatin in combination 
with conventional trans-arterial chemoembolization therapy in adult patients with advanced ICC.  25 
patients will be enrolled over the course of 2 years, with an additional 1.5 years for patient follow-up. 
Eligible patients enrolled on study will receive a chemotherapy regimen of gemcitabine and cisplatin 
administered intravenously on Days 1 and 8 of a 21-day cycle.  After every 2 cycles of systemic 
chemotherapy, patients will receive contrast-enhanced MRI to assess liver disease; conventional TACE 
will be performed as indicated based on this assessment.  Patients will receive up to a maximum of 8 
cycles of the gemcitabine/cisplatin combination on study protocol.  Patients are allowed up to 2 cycles 
of gemcitabine/cisplatin therapy performed as standard of care prior to enrollment on protocol.  Up to 3 
TACE treatments may be delivered in the initial six months.  Following the treatment cycle, patients will 
continue clinical follow-up at 3 month intervals until study exit at 18 months post the start of treatment. 
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We hypothesize that the addition of conventional TACE therapy to standard chemotherapy will result in 
an improvement in PFS for patients with advanced unresectable ICC, even those patients with 
extrahepatic disease. 
 
4.2. Study Schedule 
Schema: Treatment Overview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Advanced ICC 
1.
Unresectable 
2.
>70% liver 
dominant 
3.
ECOG PS 0-1 
4.
cTACE 
candidate 
Gem/Cis 
x 2 cycles 
Gem/Cis 
x 2 cycles 
Gem/Cis 
x 2 cycles 
Gem/Cis 
x 2 cycles 
Clinic follow-up, 
3-month 
intervals until 
exit at 18 
months post 
start of therapy 
≥6 weeks 
Conventional TACE; delivered after each interval MRI 
assessment as indicated (on demand) as long as treatment 
criteria are met.  At least one week of treatment break 
added after every cTACE to allow for recovery. 
IR clinical visit and liver MRI 
Maximum of 8 cycles of gemcitabine/cisplatin (24 weeks of systemic therapy) on study protocol 
Maximum of 3 cTACE treatments delivered (at each 6-weekly assessment).  The first cTACE treatment is 
required; additional cTACE treatments will be delivered as indicated. 
Dose delay, reduction decision for systemic therapy and cTACE made independently based on schedule of 
clinical and laboratory assessments 
Maximum of 4 week delay in any scheduled therapy (systemic or cTACE) 
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Schema: Gemcitabine/cisplatin x 2 cycles, clinic, and cTACE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 1: IV gemcitabine and cisplatin  
Day 8: IV gemcitabine and cisplatin 
Day 15-21: Treatment break 
Day 1: IV gemcitabine and cisplatin  
Day 8: IV gem/cis 
Day 8 – 14: IR clinical, liver MRI 
Day 15-21: conventional TACE (on demand)* 
At least one week post-cTACE treatment break (if 
cTACE was performed) 
Gem/Cis x 
2 cycles 
cTACE 
Gem/Cis x 
2 cycles 
cTACE 
*cTACE treatment (or systemic therapy) may be delayed without a protocol deviation for a maximum 
of 4 weeks to allow for recovery from toxicities and adverse events. 
Initial doses: 1000 mg/m2 of gemcitabine, 25 mg/m2 cisplatin on Day 1 and 8 of each cycle. 
Instructions for dose reductions noted in Section 4.3.3 
Labs drawn as standard on day of IV chemotherapy prior to administration to confirm patient is 
eligible for treatment. 
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4.3. Systemic Treatment Cycles: Combination of Cisplatin and Gemcitabine 
4.3.1. Treatment Schedule and Dosage 
Intravenous chemotherapy will be delivered on Days 1 and 8 of a 21-day cycle.  The initial doses 
administered for gemcitabine/cisplatin-naïve patients will be 1000 mg/m2 of gemcitabine and 25 mg/m2 
cisplatin intravenously.  Enrolled participants that had prior or current gemcitabine/cisplatin therapy 
may continue at an adjusted dose.  Dosages may be modified or delayed due to toxicities; see Sections 
4.3.2 and 4.3.3 for instructions.  There is a systemic treatment break on Week 3 of every systemic 
chemotherapy cycle.   
There will be a maximum delay of 4 weeks in any scheduled therapy:  patients who exceed that will be 
exited from the study.  Patients will receive a maximum of 8 cycles of systemic chemotherapy for a total 
of 24 weeks of systemic therapy. 
After every two cycles of systemic treatment, patients will be assessed with MR imaging to see if TACE 
treatment is necessary.  If TACE is necessary, the patient will proceed into the TACE treatment phase 
including a treatment break of at least 1 week after TACE to allow the patient to recover.  If TACE is not 
deemed necessary, the next cycles of gemcitabine/cisplatin will proceed without interruption.  All 
patients will receive the first cTACE on study. 
Chemotherapy infusion will take place on an outpatient basis in accordance with standard institutional 
practices.  An example is as follows: patients will be pre-hydrated prior to treatment with 1 liter of 0.9% 
saline, 20 mEq potassium chloride, and 2g magnesium sulfate administered over 2 hours.  Patients will 
then be premedicated prior to starting therapy in accordance with standard clinical practice and the 
gemcitabine and cisplatin package insert.  Gemcitabine in 250-500 mL of 0.9% saline is administered 
over 30 min followed by cisplatin in 250-500 mL of 0.9% saline over 30 min-1 hour with hydration as 
required. 
 
4.3.2. Criteria for a Patient Starting the Next Systemic Treatment Cycle 
A new cycle of gemcitabine/cisplatin may be initiated for patients meeting the following criteria: 
• 
ANC ≥ 1000/mm3 (Grade 2 or lower) 
• 
Platelet count ≥ 75 x 109/L (Grade 1 or lower) 
• 
Liver associated enzymes/function (e.g. AST, ALT, ALKP, bili: Grade 2 or lower) 
• 
Any other drug-related AEs that may have occurred resolved to baseline or Grade 1 severity. 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and a new 
cycle of treatment will not be initiated until the toxicity has resolved as described above.  The maximum 
treatment delay is 4 weeks prior to necessitating withdrawal from the systemic portion of the study.  
The patient may continue on protocol without systemic therapy under the discretion of the investigator.  
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Patients for whom the investigator decides it is in their best interest to stop both TACE and systemic 
therapies are exited from the study and their treatment procedures discontinued. 
 
4.3.3. Dose Modifications and Treatment Changes 
Adjustments to the dosage of either systemic agent will be carried out independent of the plan for intra-
arterial therapy.  Doses may be modified separately based on individual toxicities.  If both systemic 
agents are permanently stopped due to toxicity during the planned 8 cycles of therapy, treatment can 
continue on protocol using TACE alone at the discretion of the treating physician.  Dose modifications 
will follow pre-defined dose levels: 
 
Gemcitabine 
• 
Dose level 1: 1000 mg/m2 
• 
Dose level 2: 750 mg/m2 
• 
Dose level 3: 500 mg/m2 
• 
Dose level 4: Discontinue 
Cisplatin 
• 
Dose level 1: 25 mg/m2 
• 
Dose level 2: 20 mg/m2 
• 
Dose level 3: 15 mg/m2 
• 
Dose level 4: Discontinue 
Doses of both gemcitabine and cisplatin can be modified as per patient tolerance, according to the 
guidelines below: 
• 
Dose re-escalation is not permitted.  If a dose reduction has been instituted during the prior 
cycle, then that most recently delivered dose will become the starting dose for the subsequent 
cycle. 
• 
Doses omitted during cycles will not be made up 
• 
The maximum dose delay in systemic therapy is 4 weeks. 
• 
If more than 2 dose reductions are required in either agent, then the drug should be 
permanently discontinued. 
• 
If the dose of either or both drugs was omitted from Day 8 of the previous cycle, then the 
starting dose for this cycle will be a reduction of one dose level for gemcitabine and/or cisplatin 
(whichever is applicable) compared with most recently delivered dose.   
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Suggested dosing modifications for gemcitabine and cisplatin based upon observed nonhematological 
and hematological toxicities are outline in the tables below.  Toxicities are graded according to CTCAE 
v5.0. 
Table 1: Suggested Dose Modifications for Non-hematological Toxicities 
1. Toxicity 
Grade 
Management/Next Dose 
Gemcitabine 
Management/Next Dose Cisplatin 
Peripheral 
neuropathy 
Grade 1-2, 
tolerable 
No change in dose 
No change in dose 
Grade 2, 
intolerable 
No change in dose 
Hold until ≤ tolerable G2.  Resume 
at dose reduction. 
Grade 3-4 
No change in dose 
Hold until ≤ G2.  Resume at dose 
reduction. 
Elevated creatinine 
≤ 0.4 above 
baseline 
No change in dose 
No change in dose 
0.5-1.0 above 
baseline 
No change in dose 
Hold until ≤ 0.4 above baseline.  
Resume at same dose, increase pre 
and post cisplatin hydration. 
≥ 1.1 above 
baseline 
No change in dose 
Hold until ≤ 0.4 above baseline.  
Resume at dose reduction. 
Other non-
hematologic 
toxicities* 
≤ Grade 1 
No change in dose 
No change in dose 
Tolerable 
Grade 2 
No change in dose 
No change in dose 
Grade 3 or 4 
Hold until ≤ tolerable G2.  
Resume at dose 
reduction. 
Hold until ≤ tolerable G2.  Resume 
at dose reduction. 
 
* Asymptomatic non-hematological laboratory abnormalities will not be cause for dose reduction, but 
will be corrected as per standard clinical practice. 
 
 
Table 2: Suggested Dose Modifications for Hematologic Toxicities 
Toxicity 
Grade/Laboratory 
Value 
Management/Next Dose 
Gemcitabine 
Management/Next Dose 
Cisplatin 
Neutropenia* 
Day 8 of a cycle: 
< 900/mcL 
Hold until ≥ 900, resume at 
reduced dose, if indicated 
Hold until ≥ 900, resume at 
reduced dose, if indicated 
Thrombocytopenia** Day 8 of a cycle: 
< 70 x 109/L 
Hold until ≥ 70, resume at 
reduced dose, if indicated 
Hold until ≥ 70, no change in 
dose, if indicated 
 
* Use of growth factors is permitted 
** A platelet goal of 50K should be considered for those on anticoagulation 
 
 
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 For patients who are noted to have new onset Grade 3 or higher increases in AST, ALT, and/or bilirubin, 
an evaluation for obstruction and cholangitis will be performed; the presence of either obstruction or 
cholangitis will necessitate withholding of treatment until resolution to baseline.  To administer Day 8 
chemotherapy, these liver associated biochemical abnormalities must resolve to ≤ Grade 2 or baseline. 
Supportive care use of transfusion for symptomatic anemia or hemoglobin < 8 g/dL and colony-
stimulating factors (CSFs) for neutropenia is encouraged per established guidelines. 
 
4.4. IR Clinical Visit 
Clinical follow-up with Interventional Radiology will take place on Week 2 of every second cycle of 
systemic chemotherapy.  New MRI of the liver will be obtained and assessed at this time point to 
determine whether further conventional TACE treatment is warranted.  Labs and toxicities will also be 
assessed and recorded. 
 
4.5. Conventional TACE with Doxorubicin/Mitomycin-C 
4.5.1. Treatment Phase – Conventional TACE with Doxorubicin/Mitomycin-C 
 
If conventional TACE is warranted based on MRI assessment and the patient meets all the eligibility 
criteria for TACE therapy, then cTACE will be scheduled to take place during Week 3 of that cycle.  
Patients will always receive the first cTACE for study; follow-up cTACE will occur on demand.  Laboratory 
and imaging results should have been completed on the previous clinical visit, but if any procedures 
need to be repeated they can be repeated up until the day of the TACE.  Patients are allowed a 
maximum of 3 treatments during the treatment phase.  Conventional TACE treatments will be 
performed according to standard of care hospital protocol as detailed in the next section. 
Patients who do not meet the criteria for TACE therapy at the time of treatment may be eligible to 
receive transfusions pre-treatment to meet the requirements for TACE.  If this is the case, new labs will 
be drawn to ensure patients meet the criteria for TACE before treatment.  If the patient is ineligible for 
TACE due to toxicities, therapy can be delayed a maximum of 4 weeks at which point the patient will exit 
the study. 
If patients discontinue all systemic therapy due to toxicities, they may remain on study and receive 
cTACE under the discretion of the principal investigator.   
Patients may continue to receive cTACE if needed after the completion of the treatment phase and 
during the follow-up phase; if this occurs and the patient receives additional cTACE treatment prior to 
the 1 year time point, then their data will be omitted from the PFS analysis. 
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4.5.2. Conventional TACE Overview 
To perform the conventional TACE, the common femoral artery is accessed using Seldinger technique.  A 
5-French vascular sheath is then placed into the artery over a glide wire.  Under fluoroscopic guidance, a 
visceral-shape catheter is used to perform diagnostic visceral arteriogram (celiac and SMA) to depict 
arterial flow to the tumor, hepatic arterial anatomy, and portal vein blood flow.  The diagnostic catheter 
or a microcatheter is advanced into the target hepatic artery branch, depending on tumor location.  
Angiography is performed to confirm safety of the location to delivery of the chemoembolic emulsion, 
which is injected under fluoroscopy, followed by injection of 1% lidocaine and 100-300 micron 
embospheres. 
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 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 
also titrated to each clinical situation. 
Intra-arterial chemotherapy materials include: 
• 
10 cc of chemotherapy (50mg doxorubicin and 10mg of mitomycin-C) mixed 1:1 with Lipiodol 
(approximately 10cc) giving a total of approximately 20cc 
• 
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 stable.  The day after the TACE procedure, a non-contrast CT 
scan is performed to document the deposition of the Lipiodol in the targeted areas. 
Follow-up MR imaging will be performed approximately 6 weeks following the cTACE procedure and 
assessed at the IR clinical visit. 
 
4.6. Treatment Delays 
Gemcitabine/cisplatin therapy and TACE therapy may be delayed up to a maximum of 4 weeks for 
toxicities to allow sufficient time for patient recovery.  Patients who do not recover from toxicity will be 
discontinued from the study. 
Missed chemotherapy doses will not be made up. 
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Treatment may be delayed for no more than 7 days to account for holidays, weekends, scheduling 
conflicts, inclement weather, or other justifiable events and will not be considered a protocol violation.   
 
4.7. Concomitant Medications, Therapies, and Supportive Care 
No other chemotherapy, immunotherapy, hormone therapy, or any other type of therapy (including 
herbal or natural supplements) for treatment of ICC or experimental drugs will be permitted while the 
patients are on study.  In addition, any disease progression requiring other forms of specific antitumor 
therapy will also necessitate discontinuation from the study.  Appropriate documentation for all forms 
of premedications, supportive care, and concomitant medications must be captured on the case report 
form. 
Necessary supportive measures for optimal medical care will be given throughout the study, including IV 
antibiotics to treat infections, growth factor support, and blood components, etc.  Additional care, 
including palliative radiotherapy (excluding target lesions and lesions representing progressive disease) 
may be administered as indicated by the treating physician and patient’s medical need. 
 
5. Clinical and Study Procedures 
5.1. Screening/Baseline Evaluations 
Assessments completed in the initial clinic visits (pre-consent), as part of standard of care, may be used 
as part of the study screening assessment.  Laboratory tests, MRI, and H&P should be performed within 
30 days of treatment.  If clinically indicated, laboratory tests will be repeated within 1 week of 
treatment. 
• 
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 study enrollment. 
• 
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. 
• 
Tumor marker (CA 19-9, CEA, etc) 
• 
Serum or urine pregnancy test for women of childbearing potential (must be negative). 
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• 
Contrast enhanced MRI of the liver within 30 days of treatment.  A CT may be used if a MRI 
would be improbable to obtain. 
• 
CT of the chest without contrast. 
Eligible patients that have completed their screening procedures will be enrolled on study and start 
treatment on Cycle 1 Day 1. 
 
5.2. Treatment Phase – Systemic Chemotherapy Cycles 
Subjects will complete 8 cycles (each cycle consisting of 21 days) of a systemic chemotherapy regimen of 
gemcitabine and cisplatin on this study for a total of 24 weeks of systemic therapy.  Study drugs will be 
administered on Day 1 and Day 8 of every cycle.  Starting doses are 1000 mg/m2 of gemcitabine 
intravenously Day 1 and Day 8, along with 25 mg/m2 intravenously Day 1 and Day 8.  Doses may be 
reduced or skipped due to toxicities but re-escalation is not permitted.  Doses omitted during a 
treatment cycle will not be made up; the maximum dose delay in systemic therapy is 4 weeks.  If more 
than 2 dose reductions are required, then the drug should be discontinued. 
Patients will need to have new CMP (comprehensive metabolic panel) and CBC (complete blood count 
with differentials) labs drawn prior to administration of chemotherapy on Day 1 and Day 8.  Exceptions 
may be made if recent and relevant labs were drawn (for screening or clinical assessment). 
 
5.3. Treatment Phase – IR Clinical Visits and TACE Interventions 
During each second cycle of systemic treatment, patients will return for clinical follow-up on Days 8-14.  
Clinical follow-up will include: H&P, laboratory tests (CMP, CBC, PT/INR, tumor markers), and contrast-
enhanced MR imaging (CT if MRI is not possible).   
If conventional TACE is warranted based on MRI assessment, it will be scheduled for the next week 
(Days 15-21 of a cycle).  At least a one-week rest period following the TACE will be allotted to allow the 
patient to recover with extensions up to 4 weeks if toxicities are unresolved; afterwards, the patient will 
restart the gemcitabine/cisplatin cycles.   Otherwise, if the patient does not require TACE treatment, the 
regular schedule of gemcitabine/cisplatin will apply. 
 
5.4. Study Follow-up Phase 
After completion of the treatment phase, patients will enter the follow-up phase.  Follow-up clinical 
assessments occur every 3 months at a minimum, although they may occur more frequently if 
warranted or if the patient undergoes further TACE procedures.  Clinical assessments will include H&P, 
laboratory tests (CMP, CBC, PT/INR, tumor markers), and contrast-enhanced MR imaging. 
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Patients will be followed for approximately 1 year after the treatment phase, for a total of 18 months on 
study. 
 
5.5. Final Study Visit 
Patients that have completed their follow-up phase will exit the trial after their final clinical follow-up.  
The final study visit will include the standard assessments performed at each clinical visit.  Patients will 
continue to be followed off-protocol by the clinical team to ensure any toxicities or adverse events are 
followed and resolved. 
 
6. Study Evaluations 
6.1. Tumor Response (mRECIST, qEASL, vRECIST Criteria) 
 
Patients with measurable disease will be evaluated prior to starting treatment, and at regular intervals 
afterwards to occur about week 2 of every 2nd cycle of systemic gemcitabine/cisplatin therapy.  Lesions 
and tumor response as analyzed from contrast-enhanced MR imaging will be determined utilizing 
mRECIST (modified Response Evaluation Criteria in Solid Tumors) and qEASL (quantitative or volumetric 
European Association for the Study of the Liver) criteria.  The details for each guideline are listed below.  
Tumor response is defined as complete response and partial response. 
The RECIST criteria were designed primarily for the evaluation of cytotoxic agents with the only criterion 
for tumor response being shrinkage in size.  However, RECIST assessments alone can be misleading 
when applied to other anti-cancer therapies, such as molecular-targeted therapies and 
chemoembolization which could induce tumor necrosis but with no change in total size.  The modified 
RECIST criteria as utilized in this trial include changes in size of tumor necrosis as a factor of response.  
With the mRECIST criteria, viable tumor is defined as uptake of contrast agent in the arterial phase of 
dynamic CT or MRI. 
To select a target lesion using mRECIST, a lesion should meet all of the following criteria at baseline: 
• 
The target lesion can be classified as a RECIST measurable lesion (i.e., the lesion can be 
accurately measured in at least one dimension as 1 cm or more). 
• 
The lesion is suitable for repeat measurement. 
• 
The lesion shows intratumoral arterial enhancement on contrast-enhanced CT or MRI. 
The mRECIST criteria for tumor response are: 
• 
Complete response – disappearance of any intratumoral arterial enhancement in all target 
lesions. 
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• 
Partial response – at least a 30% decrease in the sum of diameters of viable (enhancement in 
the arterial phase) target lesions, taking as a reference the baseline sum of the diameters of 
target lesions. 
• 
Stable disease – Any cases that do not qualify for complete response, partial response or 
progressive disease. 
• 
Progressive disease – 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. 
In contrast to the RECIST criteria, the EASL criteria evaluate response to treatment based on changes in 
tumor enhancement.  However, there are some limitations in its application to hepatic tumors treated 
with TACE therapy, which result in inhomogeneous tumor necrosis.  Furthermore, RECIST, mRECIST, and 
EASL are applied to one representative axial slice of the tumor, and a different slice selection could lead 
to different response assessments.  For EASL, assessments of percent enhancement of tumoral area are 
made based on visual approximation and grouped into brackets, but the assessment could be inaccurate 
if the enhancement percentage is within the boundary thresholds between two brackets.  The criteria 
also do not take into account the entire tumor volume. 
As a result, quantitative EASL assessments will be performed to account for entire tumor volume, and to 
determine percentage enhancement throughout (68-71).  Semi-automatic three-dimensional volumetric 
segmentation will be performed using software by an experienced interventional radiologist utilizing the 
contrast-enhanced MRI obtained for the study as source data.  Comparisons can then be performed on a 
voxel by voxel basis, giving a 3D volumetric assessment of tumor enhancement based on total tumoral 
volume rather than a 2D assessment of tumoral area. 
The qEASL criteria for tumor response are: 
• 
Complete response – disappearance of any intratumoral arterial enhancement in all target 
lesions. 
• 
Partial response – at least a 65% decrease in the sum of enhancing tissue volume of the lesions. 
• 
Stable disease – Any cases that do not qualify for complete response, partial response, or 
progressive disease. 
• 
Progressive disease – An increase of at least 73% in the sum of enhancing tissue volume of the 
lesions. 
 
6.2. Toxicities, Survival, Time to Progression, and Time to Untreatable Progression 
Toxicities will be assessed and reported based on the NIH Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0.  These would include laboratory data for hematologic, liver, and kidney function, 
post embolization syndrome, incidences of adverse events and serious adverse events, and clinical 
observations. 
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Overall survival will be measured from enrollment on study until death of the patient from any cause. 
Time to progression (TTP) will be measured from enrollment on study until radiographic evidence of 
overall disease progression. 
Time to untreatable progression (TTUP) in liver lesions will be measured from time of initiation of cTACE 
therapy until radiographic evidence of disease progression in targeted lesions.   
 
7. Safety Profiles of Study Interventions 
7.1. Gemcitabine 
7.1.1. Gemcitabine Description 
Gemcitabine hydrochloride (Gemzar®) is a nucleoside analog of deoxycitidine.  Its full chemical name is 
2’-deoxy-2’,2’-difluorocytidine monohydrochloride.  It is a white to off-white or translucent solid with 
empirical formula C9H11F2N3O4 • HCl and molecular mass of 299.66 g/mol.  It is soluble in water, slightly 
soluble in methanol, and practically insoluble in ethanol and polar organic solvents. 
Gemzar is supplied in a sterile form for intravenous use only.  Vials of Gemzar contain either 200 mg or 1 
g of gemcitabine HCl formulated with mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 
mg or 62.5 mg, respectively) as a sterile lyophilized powder.  Hydrochloric acid and/or sodium hydroxide 
may have been added for pH adjustment.  The lyophilized compound should be stored at controlled 
room temperature, 59o to 96oF (15o to 30oC). 
To make a solution containing 38 mg/mL final concentration, add 5 mL normal saline (0.9% sodium 
chloride) to the 200mg vial or 25 mL normal saline to the 1,000 mg vial.  Normal saline is the only diluent 
approved.  Do not use other diluents. 
Handling precautions: gemcitabine is a toxic material which could cause skin and eye irritation.  
Ingestion or inhalation exposure of sufficient quantities could result in decreased white and red blood 
cells, hypospermatogenesis, gastrointestinal disturbances, and other signs of toxicity.  Laboratory animal 
studies indicate that compounds in this therapeutic class may be reproductive toxins and may induce 
fetal malformations.  Contact or inhalation should be avoided. 
Gemcitabine is commercially available and should therefore be purchased by a third party.  This drug 
will not be supplied by the NCI. 
 
7.1.2. Gemcitabine Mechanism of Action 
Gemcitabine kills cells undergoing DNA synthesis and inhibits the progression of cells through the G1/S-
phase boundary.  It is metabolized by nucleoside kinases to a diphosphate (dFdCDP) and triphosphate 
(dFdCTP) nucleosides.  The diphosphate inhibits ribonucleotide reductase, an enzyme responsible for 
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catalyzing the generation of deoxynucleoside triphosphates for DNA synthesis including dCTP.  
Gemcitabine triphosphate competes with dCTP for incorporation into DNA, which results in only one 
additional nucleotide being added to the growing DNA strands eventually leading to initiation of 
apoptosis. 
 
7.1.3. Pharmacology of Gemcitabine 
The pharmacokinetics of gemcitabine were examined in 353 patients with solid tumors.  PK parameters 
were derived from patients treated with varying durations of therapy, given weekly with periodic rest 
weeks, and using both short and long infusions.  The volume of distribution was increased with infusion 
length; from 50 L/m2 in infusions lasting <70 min to 370 L/m2 in longer infusions.  Gemcitabine 
pharmacokinetics are linear and described by a 2-compartment model.  Analyses of combined single and 
multiple dose studies showed that the volume of distribution was significantly influenced by duration of 
infusion and gender.   
Gemcitabine is metabolized intracellularly to form active gemcitabine diphosphate and triphosphates.  
Additional metabolites have not been identified in either plasma or urine.  The gemcitabine di- and tri-
phosphates do not appear to circulate in plasma in measurable amounts.  The compound is metabolized 
principally by the liver to form an inactive uridine derivative (dFdU or 2’-deoxy-2’,2’-difluorouridine).  
The plasma protein binding of gemcitabine is negligible. 
Following a single 1,000 mg/m2/30 min radiolabelled gemcitabine infusion, 92% to 98% of the dose was 
recovered within 1 week after administration.  Urinary excretion of gemcitabine and its metabolite dFdU 
accounted for 99% of the excreted dose, and less than 1% of the dose was excreted in feces.  The renal 
clearance of gemcitabine is less than 10%; therefore, the parent drug appears to be almost completely 
metabolized to the inactive dFdU. 
Half-life ranged from 11 to 26 minutes for patients receiving single dose infusions (1000 mg/m2 to 2500 
mg/m2 and 3600 mg/m2.  The increase in half-life may relate to the appearance of a possible third 
exponential phase (representing a deep compartment) that is not observed following the shorter 
infusions.  Clearance obtained for female patients was 46.2 L/hr/m2 and for males was 66.8L/hr/m2.  
These moderate to high gemcitabine values suggest that the molecule is metabolized by various tissues, 
including the liver.  The renal clearance for gemcitabine is less than 10% of the systemic clearance. 
Maximum dFdU plasma concentrations were achieved from 0 to 30 minutes after the discontinuation of 
gemcitabine infusions, ranging from 0.4 to 4.75 hours.  The apparent formation of dFdU (determined 
from the fraction of the gemcitabine dose excreted as dFdU) ranged from 91.2% to 98.2% of 
gemcitabine clearance in a single-dose study.  Based on the imputed formation rate of dFdU, the mean 
dFdU volume of distribution at steady-state was 150.4 L/m2, indicating that dFdU was extensively 
distributed into tissues.  The metabolite was excreted in urine without undergoing further 
biotransformation.  The mean apparent clearance of dFdU was 2.5L/hr/m2. 
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7.1.4. Toxicology of Gemcitabine 
Dose limiting toxicity is bone marrow suppression with mild to moderate granulocytopenia, anemia, and 
thrombocytopenia.  There has been no evidence of cumulative white blood cell or platelet toxicity.   
Gastrointestinal toxicities include nausea, vomiting, and diarrhea.  Gemcitabine should be used with 
caution in patients with impaired liver function since abnormalities of liver transaminase enzymes have 
been reported.   
Mild proteinuria and hematuria have been reported but were not clinically significant and usually not 
associated with any change in serum creatinine or BUN.  A few cases of renal failure of uncertain 
etiology have been reported.  While on study, one patient who received prior mitomycin developed 
hemolytic uremic syndrome requiring dialysis.  The relationship of this event to gemcitabine is not 
known.  Gemcitabine should be used with caution in patients with impaired renal function. 
Toxicities associated with allergic reaction include rash, pruritus, desquamation, vesiculation, ulceration, 
and dyspnea.  Bronchospasm has been reported in less than 1% of patients.  20% of patients have also 
experienced flu-like symptoms such as fever, headache, back pain, chills, myalgia, asthenia, anorexia, 
cough, rhinitis, malaise, sweating, and insomnia. 
Other toxicities include edema or peripheral edema in 30% of patients, alopecia, somnolence, 
constipation, and oral toxicity (soreness and erythema).  Pulmonary edema has been a rare occurrence 
(less than 1%).  A few cases of hypotension have been reported, as well as myocardial infarction, 
congestive heart failure, and arrhythmia.  However, there is no clear evidence that gemcitabine causes 
cardiac toxicity. 
Gemcitabine may cause fetal harm when administered to a pregnant woman.  This agent has produced 
teratogenic effects when administered at a dose of < 2 mg/m2.  Adverse effects included decreased fetal 
viability, weight, and morphologic defects.  There is no data on gemcitabine administration during 
human pregnancy, and it is not currently known if metabolites are excreted in human milk.  However, 
many drugs are excreted in human milk, and there is a potential for adverse effects in nursing infants.  
Therefore, the use of gemcitabine should be avoided in pregnant or nursing women because of the 
potential hazard to the fetus or infant. 
 
7.2. Description of Cisplatin 
7.2.1. Cisplatin Description 
 
Cisplatin is a platinum-based, alkylating-like agent.  Its full chemical name is (SP-4-2)-
diamminedichloroplatinum(II) with empirical formula of H6Cl2N2Pt and molecular mass of 300.01 g/mol.  
Cisplatin is a yellow to orange crystalline powder that is soluble in water or saline at 1 mg/mL and in 
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dimethylformamide at 24 mg/mL.  Intact vials of cisplatin are stored at room temperature; solutions 
diluted with sodium chloride or dextrose are stable up to 72 hours at room temperature.  Due to the risk 
of precipitation, cisplatin solutions should not be refrigerated. 
The desired dose of cisplatin is diluted with 250-1000 mL of saline and/or dextrose solution.  Varying 
concentrations of 0.225-5% sodium chloride and 5% dextrose may be used.  To maintain stability of 
cisplatin, a final sodium chloride concentration of at least 0.2% is recommended. 
Cisplatin is usually administered as an intravenous infusion over 30 minutes to 24 hours; multiday 
continuous infusions are occasionally used.  The drug may also be administered intra-arterially, 
intraperitoneally, and intravesicularly.  Pre-treatment hydration is recommended prior to cisplatin 
administration, with between 1 and 2 liters of fluid, and adequate post-hydration to maintain urine 
output of 100 cc/hr thereby avoiding renal precipitation. 
Caution should be exercised in handling the powder and preparing the solution of cisplatin.  Procedures 
for proper handling and disposal of anticancer drugs should be utilized.  To minimize the risk of dermal 
exposure, always wear impervious gloves when handling vials and IV sets containing cisplatin for 
injection.  Skin reactions associated with accidental exposure may occur.  If cisplatin powder or solution 
contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush 
the mucosa with water. 
 
7.2.2. Cisplatin Mechanism of Action 
Cisplatin inhibits DNA synthesis by the formation of DNA cross-links; a chloride ligand of cisplatin is 
displaced allowing the platinum atom to bind to a DNA base.  This denatures the double helix and 
disrupts DNA function, ultimately leading to cell apoptosis if not fixed by DNA repair enzymes.  The cis-
isomer of cisplatin is 14 times more cytotoxic than the trans-isomer; although both forms cross-link DNA 
and bind to nucleotide bases, the cis- isomer is less easily recognized by cellular repair mechanisms and 
thus less likely to be fixed.  Cisplatin can also bind two adjacent guanine bases on the same strand of 
DNA producing intrastrand cross-linking and breakage. 
 
7.2.3. Pharmacology of Cisplatin 
Cisplatin distributes rapidly into tissues, and requires no metabolic steps for activation.  Rather, the 
chlorine atoms are more subject to displacement by nucleophiles.  The ratios of cisplatin to total free 
platinum in the plasma vary between patients and range from 0.5 to 1.1 after a dose of 100 mg/m2.  
Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is 
characteristic of normal drug-protein binding, but the platinum atom binds to several plasma proteins 
with greater than 90% protein binding in circulation.  The platinum-albumin molecule complex 
dissociate slowly and are eliminated with a minimum half-life of 5 days.  Metabolism is non-enzymatic, 
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with inactivation by sulfhydryl groups in both cells and in the bloodstream.  Cisplatin covalently binds to 
glutathione and thiosulfate. 
High concentrations of platinum are achieved in kidneys, liver, prostate; somewhat lower in bladder, 
muscle, testicle, pancreas, and spleen; lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum.  
Platinum is present in tissue for as long as 180 days after last administration. 
The half-life of cisplatin ranges from 14 to 49 minutes for initial elimination, with beta- and gamma-
elimination occurring in 0.7-4.6 hours and 24-127 hours respectively.  After a 7 hour infusion of 100 
mg/m2, the total body clearances and volumes of distribution at steady-state for cisplatin are about 15 
to 16 L/h/m2 and 11 to 12 L/m2.  The renal clearance of free platinum also exceeds the glomerular 
filtration rate indicating that cisplatin is actively secretly by the kidneys.  Excretion is almost entirely 
renal, with minimal excretion noted in feces. 
 
7.2.4. Toxicology of Cisplatin 
Dose-related, cumulative renal tubular injury can occur with administration of cisplatin, a risk that is 
usually minimized with adequate hydration and diuresis.  Salt-wasting nephropathy and/or orthostatic 
hypotension with hyporeninemic hypoaldosteronism can occur in up to 10% of patients. 
Dose-related ototoxicity, manifested by high-frequency hearing loss and tinnitus occurs in about 30% of 
patients.  Paresthesias, decreased vibratory, position, and touch sensations are less common particularly 
at cumulative doses < 400 mg/m2. 
Mild leukopenia and thrombocytopenia occur in 25-30% of patients, but are rarely dose-limiting.  
Anemia is more uncommon.  A potentially fatal hemolytic uremic syndrome has been reported. 
Severe, dose-limiting nausea and vomiting may occur in almost 100% of patients unless adequate 
antiemetic prophylaxis is given.  Even with successful prophylaxis of acute nausea, a delayed (72-96 
hour) reaction, requiring additional therapy may occur.  Anorexia and taste changes may also occur. 
Allergic reactions are reported in up to 20% of patients.  Symptoms include: rash, facial edema, 
wheezing, hypotension, and tachycardia.  Severe anaphylaxis is rare. 
Other toxicities including electrolyte wasting (magnesium, potassium, and sodium), papilledema, optic 
neuritis, retrobulbar neuritis have been reported. 
Prior to administration of cisplatin, assessments of labs (complete blood count, platelet count, BUN, 
creatinine), urine output (100-150 mL/hr for at least 4-6 hours), and for signs of ototoxicity or 
neurotoxicity should be made.  Supportive medications to be administered include antiemetics (5HT3 
antagonists and dexamethasone combinations can usually be once daily), hydration (diuretics), and 
observe for signs of allergic reaction. 
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Cisplatin administration is incompatible with amsacrine, cefepime, gallium nitrate, mesna, piperacillin, 
sodium bicarbonate, and thiotepa.  Cisplatin may react with aluminum which is found in some syringe 
needles or IV sets, forming a black precipitate. 
Cisplatin can cause fetal harm when administered to a pregnant woman.  In mice, cisplatin is teratogenic 
and embryotoxic.  Cisplatin has also been reported to be found in human milk.  Patients receiving 
cisplatin should be apprised of the potential hazard to the fetus, and should avoid becoming pregnant or 
breast-feeding while receiving the drug. 
 
7.3. Doxorubicin Profile 
Other Names: Adriamycin, Rubex, Adriamycin RDF, Adriamycin PFS, hydroxydaunorubicin, ADR. 
Mechanism of Action: Doxorubicin is an anthracycline antibiotic that intercalates between adjoining 
nucleotide pairs in the DNA helix, causing inhibition of DNA and DNA-dependent RNA synthesis.  Free 
radical generation is responsible for cardiac toxicity.  Doxorubicin is also an inhibitor of topoisomerase II. 
Storage and Stability: Rubex or Adriamycin RDF intact vials are stable protected from light at room 
temperature.  Adriamycin PFS vials must be refrigerated.  Reconstituted solutions are stable for 24 hours 
at room temperature and 48 hours under refrigeration.  The Adriamycin RDF 150 mg multidose vial is 
stable after reconstitution for 7 days at room temperature or 15 days if refrigerated and protected from 
sunlight. 
Availability: Commercially available as powder for injection in 10, 20, 50, 100, 150 mg vials, and as 2 
mg/mL solution for injection in 10, 20, 50, and 200 mg vials. 
Preparation: 50 mg doxorubicin is reconstituted with mitomycin-C in sterile contrast and water to give a 
final drug concentration of 5 mg/mL doxorubicin in a total volume of 10 mL. 
Administration: The chemotherapy solution of doxorubicin and mitomycin-C is emulsified with 10 mL of 
Lipiodol.  The chemotherapy-Lipiodol mixture is administered into the target vessel with embolic agents 
to follow.  The amount of the mixture administered is titrated to the area being treated.  
Incompatibilities: Physically incompatible with heparin, fluorouracil, aminophylline, cephalothin, 
dexamethasone, diazepam, hydrocortisone, and furosemide. 
Side Effects: 
Hematologic: Leukopenia (Dose-limiting), also thrombocytopenia and anemia.  Nadir 10-14 days, 
recovery in 21 days. 
Dermatologic: Alopecia, usually complete; hyperpigmentation of nailbeds and dermal creases; radiation 
recall. 
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Gastrointestinal: Nausea and vomiting, sometimes severe; anorexia, diarrhea; mucositis. 
Cardiovascular: Arrhythmias, ECG changes; rarely sudden death.  Congestive heart failure due to 
cardiomyopathy related to total cumulative dose; risk is greater with doses greater than 550 mg/m2, 
mediastinal irradiation, pre-existing cardiac disease, advanced age; risk is reduced with weekly or 
continuous infusion regimens. 
Other: Red discoloration of urine; fever; anaphylactoid reaction; may enhance cyclophosphamide cystitis 
or mercaptopurine hepatotoxicity; secondary AML/MDS (risk is uncommon, but may be increased when 
given in combination with an alkylating agent, especially if one or both are given at higher than standard 
doses.) 
Local effects: Vesicant if extravasated; flush along vein, facial flush. 
 
7.4. Mitomycin-C Profile 
Other Names: Mutamycin, mitomycin 
Mechanism of Action: Mitomycin is an antitumor antibiotic that is cell cycle non-specific.  It appears to 
be most active in the late G1 and early S phase of the cell cycle.  The mechanism of action is similar to 
alkylating agents, causing cross-linking of DNA and possible inhibition of RNA and protein synthesis. 
Storage and Stability: Unreconstituted vials are stored at room temperature.  At a concentration of 0.5 
mg/mL the drug is chemically stable for at least 7 days at room temperature and 14 days when 
refrigerated and protected from light. 
Availability: Commercially available in 5, 20, and 40 mg vials. 
Preparation: 10 mg mitomycin-C is reconstituted with doxorubicin in sterile contrast and water to give a 
final drug concentration of 1 mg/mL doxorubicin for a total volume of 10 mL. 
Administration: The chemotherapy solution of doxorubicin and mitomycin-C is emulsified with 10 mL of 
Lipiodol.  The chemotherapy-Lipiodol mixture is administered into the target vessel with embolic agents 
to follow.  The amount of the mixture administered is titrated to the area being treated. 
Incompatibilities: Undergoes rapid decompensation at acidic and basic pH. 
Compatibilities: Dilute solutions (20-40 mg/mL) are chemically stable at room temperature in normal 
saline for 12 hours, in 5% dextrose for 3 hours, and in sodium lactate 1/6 M for 24 hours.  Mitomycin 5-
15 mg is compatible with heparin (1000-10,000 units) in 30 mL normal saline for 48 hours at room 
temperature.  The pH of maximal stability is 6-10. 
Side Effects: 
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Hematologic: Leukopenia, thrombocytopenia: late, cumulative and dose-limiting; anemia; hemolytic 
uremic syndrome (renal failure, profound thrombocytopenia, pulmonary edema, and hypotension) 
rarely. 
Dermatologic: Stomatitis, alopecia, dermatitis, pruritus; tissue necrosis, ulceration, and cellulitis if 
extravasation occurs; skin erythema and ulceration weeks to months after administration and distant 
from the site of injection. 
Gastrointestinal: Nausea, vomiting, anorexia. 
Hepatic: Veno-occlusive disease of the liver, manifested as abdominal pain, hepatomegaly and liver 
failure, in patients receiving mitomycin and autologous bone marrow transplantation. 
Neurologic: Paraesthesias. 
Pulmonary: Interstitial pneumonitis (infrequent but severe); acute bronchospasm. 
Renal: Nephrotoxicity, increasing in frequency when doses exceed 50 mg/m2, manifested as increased 
serum creatinine and BUN. 
Other: Fatigue, pain on injection, phlebitis, fever, lethargy, weakness, blurred vision; secondary 
AML/MDS (risk is uncommon, but may be increased when given in combination with an anthracycline, 
especially if one or both drugs are given at higher than standard doses); secondary tumors (rare). 
 
7.5. Medical Risks or Expected Adverse Events Associated with TACE 
Overall, the rate of complications of chemoembolization is approximately 20-25%.  Serious 
complications are estimated to be approximately 5-7%. 
The following are recognized complications of chemoembolization in the liver: 
• 
30 day mortality (usually from liver failure or infection) occurs in approximately 4% of cases.  
The risk of post procedure mortality increases with the number of treatments and the treatment 
of patients with portal vein thrombosis, non-selective embolization and severe liver impairment. 
• 
Post-embolization syndrome, a constellation of flu-like symptoms, is seen in almost 100% of the 
patients who undergo solid organ arterial embolization.  The symptoms include nausea, 
vomiting, fever, leukocytosis, pain, and adynamic ileus.  The severity of the pain usually peaks 
around 12 to 24 hours post procedure and may last up to 3 to 5 days.  The pain is generally 
managed according to standard hospital practice. 
• 
Acute Progressive Hepatic Insufficiency (APHI) occurs in approximately 2-13% of cases.  APHI is 
defined as a new onset of ascites, encephalopathy, and increased serum bilirubin (> 2 mg/dL) or 
doubling of the bilirubin or greater than 3 second increase in PTT after TACE from pre-TACE 
levels.  Most insufficiency returns to baseline within 1 week.  It is also common for liver enzymes 
to demonstrate a transient rise peaking at 24-36 hours and returning to baseline after 5-7 days. 
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• 
Non-target embolization to the gut 
• 
Liver abscess 
• 
Cholecystitis, gall bladder perforation 
• 
Periprocedural cardiac events 
• 
Renal insufficiency 
• 
Pulmonary embolism 
• 
Gastrointestinal bleeding 
• 
Bile duct injury 
• 
Acute pancreatitis 
• 
Peptic ulcer 
 
8. Adverse Events 
8.1. Adverse Event Definitions 
8.1.1. Unanticipated Problems 
 
As defined by Yale policy, adverse events and unanticipated problems are stated as follows: 
Unanticipated Problem Involving Risks to Subjects or Others: 
An Unanticipated Problem Involving Risks to Subjects or Others (UPIRSOs) comprises any incident, 
experience, or outcome that meets all 3 of the following criteria: 
1. Is unexpected (in terms of nature, specificity, severity, or frequency) given (a) the research 
procedures described in the protocol-related documents, such as the IRB-approved protocol and 
informed consent document and (b) the characteristics of the subject population being studied; 
AND 
2. Is related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, legal, or social harm) than was previously known or recognized. 
Unanticipated Problems Involving Risks or Others (UPIRSOs) may be medical or non-medical in nature, 
and include – but are not limited to – serious, unexpected, and related adverse events and unanticipated 
adverse device/drug effects.  Please note that adverse events (as defined below) are reportable to the 
IRB as UPIRSOs only if they meet all 3 criteria listed above. 
Unanticipated Adverse Device/Drug Effect: 
Any serious adverse effect on health or safety, or any life-threatening problem or death caused by (or 
associated with) a device or drug, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan or application; any other 
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unanticipated, serious problem associated with a device or drug that relates to the rights, safety, or 
welfare of subjects. 
 
8.1.2. Adverse Events 
An Adverse Event (AE) is defined as any 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.  An AE can arise 
with any use of the drug (e.g., off-label use, use in combination with another drug) and with any route of 
administration, formulation, or dose, including an overdose. 
 
8.1.3. Serious Adverse Events 
A Serious Adverse Event (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); 
• 
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); 
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• 
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 encounter 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). 
 
8.2. Adverse Event Capture 
Adverse Events are collected at baseline, and at clinical follow-ups for each cycle.  AEs are documented 
for each patient on the case report form (CRF), and are transcribed to a study-specific electronic 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 throughout the study duration, documented on CRFs, and transcribed to a 
study-specific electronic log reviewed by the PI and available for the IRB and monitoring committees.  
Both AEs and PDs are submitted during continuing reviews. 
 
8.3. Characteristics of an Adverse Event 
8.3.1. Relationship to Study Intervention 
 
To assess relationship of an event to study intervention, the following guidelines are used: 
• 
Definite - The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is likely not to be related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
For purposes of reporting, AEs attributed as “unlikely” or “unrelated” will not be subject to expedited 
reporting. 
 
8.3.2. Expectedness of SAEs 
The Study PI will be responsible for determining whether an SAE is expected or unexpected.  An adverse 
event will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the intervention. 
 
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8.3.3. Severity of Event 
CTCAE term (AE description) and grade: the descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized to grade severity of 
the AE and for all AE reporting.  The criteria are as follows: 
• 
Grade 1 – Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 – Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
• 
Grade 3 – Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• 
Grade 4 – Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 - Death 
 
8.4. Reporting Procedures 
8.4.1. Events Requiring Prompt Reporting to IRB 
 
UPIRSOs that may require a temporary or permanent interrupt 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. 
The following events may represent UPIRSOs that should be promptly reported: 
• 
Adverse device effects that are unanticipated; 
• 
Adverse events or injuries that are serious, unexpected, and related; 
• 
Breaches of confidentiality involving risks; 
• 
Data and Safety Monitoring Board (DSMB) reports, interim analysis, or other oversight 
committee/monitoring reports altering the risk/benefit profile by identification of increased 
risks; 
• 
Revisions to safety information, such as Investigational New Drug (IND) Safety Reports and 
MedWatch Reports, that meet the definition of a UPIRSO; 
• 
New information indicating an unexpected increase in risks or decrease in potential benefits 
(e.g., literature/scientific reports or other published findings); 
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• 
Protocol deviations, violations, or other accidental or unintentional changes to the protocol or 
procedures involving risks or with the potential to recur; 
• 
Unapproved changes made to the research to eliminate an apparent immediate hazard to a 
subject; 
• 
Other problem or finding (e.g. loss of study data or forms) that an investigator or research staff 
member believes could influence the safe conduct of the research. 
 
8.4.2. Events Not Requiring Prompt Reporting to IRB 
Potential risks and adverse events that may be reasonably anticipated (i.e., “expected”) are described in 
the informed consent form and do not require prompt reporting to the IRB.  The following are examples 
of events that do not require prompt reporting: 
• 
Adverse device effects that are non-serious, anticipated, or unrelated; 
• 
Adverse events or injuries that are non-serious, expected, or unrelated; 
• 
Deaths not attributed to the research (e.g., from “natural causes”, accidents, or underlying 
disease when the Principal Investigator has ruled out any connection between the study 
procedures and the subject’s death); 
• 
DSMB reports, interim analyses; or other reports, findings, or new information not altering the 
risk/benefit profile; 
• 
Protocol deviations or violations unlikely to recur or not involving risks to subjects; 
• 
Subject complaints that were resolved or complaints not involving risks; 
• 
Problems or findings not involving risk (unless the PI believes the information could affect 
subjects’ willingness to continue in the research). 
All related internal and external events involving risks but not meeting the prompt reporting 
requirements will be reported to the IRB in summary form at the time of continuing review. 
 
8.4.3. Reporting of SAEs and AEs to Guerbet as Lipiodol Provider 
SAE submissions to Guerbet are made at: Guerbet LLC, phone: 1-877-729-6679 or at 
Pharmacovigilance.headquarters@guerbet-group.com. 
 
9. Study Oversight and Monitoring 
Personnel Responsible for the Safety Review and its Frequency: 
This study is expected to be of moderate risk, and as such, will follow the guidelines for a greater than 
minimal risk DSMP.  The principal investigator is responsible for monitoring the data, assuring protocol 
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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 every 6 months 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. 
Risks Associated With the Current Study: 
The proposed study is not assessed as high risk due to the established safety and validity of each 
treatment regimen, conventional TACE and systemic chemotherapy of gemcitabine and cisplatin for 
intrahepatic cholangiocarcinoma as established in the medical literature.  The risks of the combination 
therapy are not expected to exceed any risk for each individual treatment alone. 
Although the assessment of the proposed study is one of greater than minimal risk, the potential exists 
for anticipated and/or unanticipated adverse events, serious or otherwise, to occur since it is not 
possible to predict with certainty the absolute risk in any given individual or in advance of first-hand 
experience with the proposed study methods.  Therefore, we provide a plan for monitoring the data and 
safety of the proposed study as follows: 
Attribution of Adverse Events: 
To assess relationship of an event to study intervention, the following guidelines are used: 
• 
Definite - The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is likely not to be related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
For purposes of reporting, AEs attributed as “unlikely” or “unrelated” will not be subject to expedited 
reporting. 
Plan for Grading Adverse Events: 
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 to grade severity of 
the AE and for all AE reporting.  The criteria are as follows: 
• 
Grade 1 – Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 – Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
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• 
Grade 3 – Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• 
Grade 4 – Life-threatening consequences; urgent intervention indicated. 
• 
Grade 5 – Death. 
Plan for Determining Seriousness of Adverse Events: 
The criteria for a serious adverse event are as noted in Section 8.1.3 above.  It is important to note that 
an adverse event may be graded as severe by the grading criteria but still not meet the criteria for a 
Serious Adverse Event.  Similarly, an adverse event may be graded as moderate but still meet the criteria 
for an SAE.  It is important for the PI to consider the grade of the event as well as its seriousness to 
determine whether reporting to the IRB is necessary. 
Plan for Reporting UPIRSOs (Including Adverse Events) to the IRB: 
As noted in Sections 8.1.1 and 8.4.1.  
Plan for reporting adverse events to co-investigators on the study, as appropriate the protocol’s 
research monitor(s), e.g., industrial sponsor, Yale Cancer Center Data and Safety Monitoring 
Committee (DSMC), Protocol Review Committee (PRC), DSMBs, study sponsors, funding and 
regulatory agencies, and regulatory and decision-making bodies: 
For the current study, the following individuals, funding, and/or regulatory agencies will be notified: all 
co-investigators listed on the protocol; Yale Cancer Center Data and Safety Monitoring Committee 
(DSMC); funding company Guerbet. 
The principal investigator, Todd Schlachter, MD, will conduct a review of all adverse events upon 
completion of every study subject.  The PI will evaluate the frequency and severity of the adverse events 
and determine if modifications to the protocol or consent form are required. 
 
10. Statistical Considerations 
10.1. General Overview 
 
The primary endpoint of this phase II study is the 12-month progression-free survival (PFS) in adult 
patients with ICC after treatment with gemcitabine and cisplatin in combination with conventional 
transarterial therapy.  The currently used drug regimen in this patient population is expected to have a 
12-month PFS rate of 20%.  Alternatively, the experimental treatment will be considered worthy of 
further study if the PFS at 12 months is 40% or better.  We plan to enroll 25 patients over 2 years, with 
1.5 years of follow-up for a total duration of 3.5 years. 
 
 
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10.2. Trial Design 
The 25 patients will be enrolled in a non-randomized, single arm, single cohort with no planned stopping 
rule for lack of efficacy.  The primary endpoint is 12-month PFS.  The length of follow-up required to 
assess this endpoint made a Simon two-stage design less ideal, and no early termination is planned in 
this study for efficacy or futility reason.  The primary endpoint will be analyzed as a binomial distribution 
with a sample size of 25 and probability of success equal to 0.2 under the null hypothesis.  If nine or 
more patients are progression-free at 12 months then the trial rejects the null hypothesis with 
significance 0.047.  If the underlying rate is 45% then this criteria has power 87%.  If the underlying rate 
is 40% then the power is 73%. 
 
10.3. Analysis of Primary Endpoints 
The primary endpoint is the 12-month progression free survival rate.  Radiographic assessment of 
disease burden will be evaluated by mRECIST and qEASL after every 2 cycles of systemic chemotherapy.  
Descriptive statistics will be used to present the statistical results of this phase II trial. 12-month 
progression free survival rate will be calculated with an exact 95% confidence interval.  
 
10.4. Analysis of Secondary Endpoints 
Secondary endpoints include overall survival, time to progression, time to untreatable disease 
progression, time to toxicity.  All of these endpoints will be examined with a product limit (Kaplan-
Meier) estimate of the time to event data including censoring.  Rates and duration of toxicities will be 
listed by frequency and duration.  We will evaluate whether early changes in DCE-MRI will correlate with 
long term PFS or OS, specifically as they relate to lesions targeted with cTACE therapy.  This will include 
mRECIST, qEASL and 3D volumetric assessments of tumor response on imaging.  We have not powered 
for any of these secondary endpoints and will not correct for multiplicity of statistical tests. 
 
10.5. Safety and Toxicity Analysis 
Safety analysis, which include tabulated summaries of adverse events, changes in lab results and vital 
signs, will be performed on patients who receive at least one treatment cycle. 
Adverse event data will be listed and tabulated by cohort and severity level.  Furthermore, adverse 
events will be classified based on the likelihood they are treatment-related.  Adverse events which lead 
to treatment withdrawal and all serious adverse events will be summarized separately. 
 
11. Ethics/Protections of Human Subjects 
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11.1. Ethical Standard 
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 (ICH GCP), and applicable 
local regulatory requirements and laws. 
 
11.2. Institutional Review Board 
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. 
 
11.3. 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. 
 
11.4. Inclusion of Women and Minorities 
All patients, regardless of sex and ethnicity, presenting for cTACE for intrahepatic cholangiocarcinoma 
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. 
Women that are breastfeeding or pregnant will not be eligible to join the study due to the possible toxic 
effects that the chemotherapy regimen may have on a fetus or an infant. 
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12. Data Handling and Record Keeping 
12.1. Data Capture Methods: 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, and laboratory data entered on the CRFs and any other data collection 
forms. 
All CRFs must be signed by the investigator to verify 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. 
 
12.2. Study Records 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. 
 
13. Protocol Deviations and Noncompliance 
13.1. Definitions of Noncompliance and Protocol Deviations 
 
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As outlined in Yale policy, noncompliance is defined as any action or activity associated with the conduct 
or oversight of research involving human participants that fails to comply with either the research plan 
as approved by a designated IRB, or federal regulations or institutional policies governing human subject 
research.  Noncompliance may range from minor to serious, be unintentional or willful, and may occur 
once or several times.  Noncompliance includes failure to have protocols reviewed by IRB as required, 
protocol deviations in protocols approved by the IRB, including deviations made in the interest of a 
single participant such as changing a participant’s scheduled study visits.  Noncompliance may result 
from the action of the investigator, research personnel, or a participant, and may or may not impact the 
rights and welfare of research participants or others or the integrity of the study.  Complaints or reports 
of noncompliance from someone other than the Principal Investigator or study team personnel are 
handled as allegations of noncompliance until such time that the report is validated or found to be 
invalidated or dismissed.  
Minor Noncompliance: Any behavior, action, or omission in the conduct or oversight of research 
involving human participants that deviates from the approved research plan, federal regulations, or 
institutional policies but, because of its nature, the research project, or subject population, does or does 
not: 
1. Harm or pose an increased risk of substantive harm to a research participant; 
2. Result in a detrimental change to a participant’s clinical or emotional condition or status; 
3. Have a substantive effect on the value of the data collected; and 
4. Result from willful or known misconduct on the part of the investigators or study staff. 
Examples of minor noncompliance may include, but are not limited to, the following: 
• 
Changing study personnel without notifying the IRB; 
• 
Shortening the duration between planned study visits; 
• 
Implementing minor wording changes in study questionnaires without first obtaining IRB 
approval; 
• 
Routine lab missed at scheduled visit and re-drawn later. 
Serious Noncompliance: Any behavior, action, or omission in the conduct or oversight of human 
research that, in the judgment of a convened IRB, has been determined to: 
1. Adversely affect the rights and welfare of participants; 
2. Harm or pose an increased risk of substantive harm to a research participant; 
3. Result in a detrimental change to a participant’s clinical or emotional condition or status; 
4. Compromise the integrity or validity of the research; or 
5. Result from willful or knowing misconduct on the part of the investigators or study staff. 
Examples of serious noncompliance may include, but are not limited to, the following: 
• 
Conducting non-exempt research that requires direct interaction or intervention with human 
participants without first obtaining IRB approval; 
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• 
Enrolling participants who fail to meet the inclusion or exclusion criteria in a protocol that 
involves greater than minimal risk and that in the opinion of the IRB Chair, designee, or 
convened IRB, places the participants at greater risk; 
• 
Failing to submit a continuing review application to the IRB before study expiration for an 
ongoing study; 
• 
Failing to obtain and/or document a participant’s informed consent provided the IRB has not 
granted a waiver of consent; 
• 
Failing to retain copies of signed informed consent forms; 
• 
Performing a study procedure not approved by the IRB; or failing to perform a required study 
visit or procedure that, in either case, may affect subject safety or data integrity; 
• 
Failing to follow the safety monitoring plan; 
• 
Enrolling study subjects after the IRB-approval of a study has expired; or 
• 
Failing to report serious adverse events and/or unanticipated problems to the IRB in accordance 
with IRB policy. 
Continuing Noncompliance: A pattern of noncompliance that in the judgment of a convened IRB: 
1. Indicates a lack of understanding or disregard for the regulations or institutional requirements 
that protect the rights and welfare of the participants; 
2. Compromises the scientific integrity of a study such that important conclusions can no longer be 
reached; 
3. Suggests a likelihood that noncompliance will continue without intervention; or 
4. Involves frequent instances of minor noncompliance, for example, repetitive protocol 
deviations. 
Examples of continuing noncompliance may include, but are not limited to, the following: 
• 
Repeated failure to respond to requests from the IRB to resolve an episode of noncompliance or 
a pattern of minor noncompliance, such as repetitive protocol deviations; or 
• 
Consistently late submissions of continuing review applications or other items that require 
prompt reporting to the IRB 
Protocol Deviation: Any alternation/modification to an IRB-approved protocol made without prior IRB 
approval. 
Note: Whether a protocol deviation qualifies as minor or serious noncompliance depends heavily on 
the specific facts of the situation.  The examples of minor or serious noncompliance provided above 
are not intended to be an exhaustive list.  The key to whether a protocol deviation will qualify as 
“minor” or “serious’ depends upon whether, under the specific circumstances, it may adversely 
affect the rights and welfare of participants, harm or pose an increased risk of substantive harm to a 
research participant, have a substantive effect on the value of the data collected, or result from 
willful or knowing misconduct on the part of the investigators or study staff. 
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Deviations from the study design and/or procedures that are due to a study participant’s non-adherence 
do not need to be reported to the IRB (e.g., study participant did not return for a scheduled study visit or 
participant refused to have blood drawn) unless they impact the participant’s safety or well-being, or if a 
pattern of protocol deviations indicate a need for changes in the protocol and/or informed consent 
documents. 
 
13.2. Reporting of Noncompliance and Protocol Deviations 
Serious and/or continuing noncompliance will be reported to the IRB office within 5 working days of 
becoming aware of the incident/issue.  Reports will be submitted using HIC Form 700 FR1 (Notification 
of Deviation from a Protocol/Noncompliance Report Form) to the Human Research Protection Program 
(HRPP) Compliance Manager. 
Minor noncompliance will be summarized for the IRB at the time of continuing review. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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24. Hezel AF, Zhu AX.  Systemic therapy for biliary tract cancers.  Oncologist.  2008 Apr; 13(4): 415-
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26. André T, Tournigand C, Rosmorduc O, et al.  Gemcitabine combined with oxaliplatin (GEMOX) in 
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28. Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Peters GJ.  Synergistic interaction 
between cisplatin and gemcitabine in vitro.  Clin Cancer Res.  1996 Mar; 2(3): 521-30. 
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Interaction between cisplatin and gemcitabine in vitro and in vivo.  Semin Oncol.  1995 Aug; 22(4 
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30. Malik IA, Aziz Z, Zaidi SH, Sethuraman G.  Gemcitabine and Cisplatin is a highly effective 
combination chemotherapy in patients with advanced cancer of the gallbladder.  Am J Clin 
Oncol.  2003 Apr; 26(2): 174-7. 
31. Thongprasert S, Napapan S, Charoentum C, Moonprakan S.  Phase II study of gemcitabine and 
cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma.  Ann Oncol.  2005 Feb; 
16(2): 279-81. 
32. Lee GW, Kang JH, Kim HG, Lee JS, Lee JS, Jang JS.  Combination chemotherapy with gemcitabine 
and cisplatin as first-line treatment for immunohistochemically proven cholangiocarcinoma.  Am 
J Clin Oncol.  2006 Apr; 29(2): 127-31. 
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33. Meyerhardt JA, Zhu AX, Stuart K, et al.  Phase-II study of gemcitabine and cisplatin in patients 
with metastatic biliary and gallbladder cancer.  Dig Dis Sci.  2008 Feb; 53(2): 564-70. 
34. Park BK, Kim YJ, Park JY, et al.  Phase II study of gemcitabine and cisplatin in advanced biliary 
tract cancer.  J Gastroenterol Hepatol.  2006 Jun; 21(6): 999-1003. 
35. Kim ST, Park JO, Lee J, et al.  A Phase II study of gemcitabine and cisplatin in advanced biliary 
tract cancer.  Cancer.  2006 Mar 15; 106(6): 1339-46. 
36. Lee J, Kim TY, Lee MA, et al.  Phase II trial of gemcitabine combined with cisplatin in patients 
with inoperable biliary tract carcinomas.  Cancer Chemother Pharmacol.  2008 Jan; 61(1): 47-52. 
37. Goldstein D, Gainford MC, Brown C, et al.  Fixed-dose-rate gemcitabine combined with cisplatin 
in patients with inoperable biliary tract carcinomas.  Cancer Chemother Pharmacol.  2011 Mar; 
67(3): 519-25. 
38. Valle JW, Wasan H, Johnson P, et al.  Gemcitabine alone or in combination with cisplatin in 
patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a 
multicenter randomised phase II study – The UK ABC-01 Study.  Br J Cancer.  2009 Aug 18; 
101(4): 621-7. 
39. Okusaka T, Nakachi K, Fukutomi A, et al.  Gemcitabine alone or in combination with cisplatin in 
patients with biliary tract cancer: a comparative multicenter study in Japan.  Br J Cancer.  2010 
Aug 10; 103(4): 469-74. 
40. Furuse J, Okusaka T, Bridgewater J, et al.  Lessons from the comparison of two randomized 
clinical trials using gemcitabine and cisplatin for advanced biliary tract cancer.  Crit Rev Oncol 
Hematol.  2011 Oct; 80(1): 31-9. 
41. 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. 
42. 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. 
43. 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. 
44. Ensminger WD, Gyves JW.  Clinical pharmacology of hepatic arterial chemotherapy.  Semin 
Oncol.  1983 Jun; 10(2): 176-82. 
45. Tanaka N, Yamakado K, Nakatsuka A, Fujii A, Matsumura K, Takeda K.  Arterial chemoinfusion 
therapy through an implanted port system for patients with unresectable intrahepatic 
cholangiocarcinoma – initial experience. 
46. Llovet JM, Real MI, Montana X, et al.  Arterial embolisation or chemoembolisation versus 
symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised 
clinical trial.  Lancet.  2002 May 18; 359(9319): 1734-9. 
47. Lo CM, Ngan H, Tso WK, et al.  Randomized controlled trial of transarterial lipiodol 
chemoembolization for unresectable hepatocellular carcinoma.  Hepatology.  2002 May; 35(5): 
1164-71. 
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48. Burger I, Hong K, Schulick R, et al.  Transcatheter arterial chemoembolization in unresectable 
cholangiocarcinoma: initial experience in a single institution.  J Vasc Interv Radiol.  2005 Mar; 
16(3): 353-61. 
49. Kamel IR, Bluemke DA, Ramsey D, et al.  Role of diffusion-weighted imaging in estimating tumor 
necrosis after chemoembolization of hepatocellular carcinoma.  AJR Am J Roentgenol.  2003 Sep; 
181(3): 708-10. 
50. Kiefer MV, Albert M, McNally M, et al.  Chemoembolization of intrahepatic cholangiocarcinoma 
with cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study.  
Cancer.  2011 Apr 1; 117(7): 1498-505. 
51. Kim JH, Yoon HK, Sung KB, et al.  Transcatheter arterial chemoembolization or chemoinfusion for 
unresectable intrahepatic cholangiocarcinoma: clinical efficacy and factors influencing 
outcomes.  Cancer.  2008 Oct 1; 113(7): 1614-22. 
52. Herber S, Otto G, Schneider J, et al.  Transarterial chemoembolization (TACE) for inoperable 
intrahepatic cholangiocarcinoma.  Cardiovasc Intervent Radiol.  2007 Nov-Dec; 30(6): 1156-65. 
53. Park SY, Kim JH, Yoon HJ, Lee IS, Yoon HK, Kim KP.  Transarterial chemoembolization versus 
supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma.  
Clin Radiol.  2011 Apr; 66(4): 322-8. 
54. Gusani NJ, Balaa FK, Steel JL, et al.  Treatment of unresectable cholangiocarcinoma with 
gemcitabine-based transcatheter arterial chemoembolization (TACE): a single-institution 
experience.  J Gastrointest Surg.  2008 Jan; 12(1): 129-37. 
55. Vogl TJ, Naguib NN, Nour-Eldin NE, et al.  Transarterial chemoembolization in the treatment of 
patients with unresectable cholangiocarcinoma: Results and prognostic factors governing 
treatment success.  Int J Cancer.  2012 Aug 1; 131(3): 733-740.   
56. Hyder O, Marsh JW, Salem R, et al.  Intra-arterial therapy for advanced intrahepatic 
cholangiocarcinoma: a multi-institutional analysis.  Ann Surg Oncol.  2013 Nov; 20(12): 3779-86. 
57. Jang JW, Park YM, Bae SH, et al.  Therapeutic efficacy of multimodal combination therapy using 
transcatheter arterial infusion of epirubicin and cisplatin, systemic infusion of 5-fluorouracil, and 
additional percutaneous ethanol injection for unresectable hepatocellular carcinoma.  Cancer 
Chemother Pharmacol.  2004 Nov; 54(5): 415-20. 
58. Kirchhoff T, Zender L, Merkesdal S, et al.  Initial experience from a combination of systemic and 
regional chemotherapy in the treatment of patients with nonresectable cholangiocellular 
carcinoma in the liver.  World J Gastroenterol.  2005 Feb 28; 11(8): 1091-5. 
59. Li MJ, Zhou YB, Huang Y, et al.  A retrospective study of the preoperative treatment of advanced 
Wilms tumor in children with chemotherapy versus transcatheter arterial chemoembolization 
alone or combined with short-term systemic chemotherapy.  J Vasc Interv Radiol.  2011 Mar; 
22(3): 279-86. 
60. Zechlinski JJ, Rilling WS.  Transarterial therapies for the treatment of intrahepatic 
cholangiocarcinoma.  Semin Intervent Radiol.  2013 Mar; 30(1): 21-7. 
61. Gray B, Van Hazel G, Hope M, et al.  Randomised trial of SIR-Spheres plus chemotherapy vs. 
chemotherapy alone for treating patients with liver metastases from primary large bowel 
cancer.  Ann Oncol.  2001 Dec; 12(12): 1711-20. 
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62. Hendlisz A, Van den Eynde M, Peeters M, et al.  Phase III trial comparing protracted intravenous 
fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-
limited metastatic colorectal cancer refractory to standard chemotherapy.  J Clin Oncol.  2010 
Aug 10; 28(23): 3687-94. 
63. Van Hazel G, Blackwell A, Anderson J, et al.  Randomised phase 2 trial of SIR-Spheres plus 
fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in 
advanced colorectal cancer.  J Surg Oncol.  2004 Nov 1; 88(2): 78-85. 
64. Sharma RA, Van Hazel GA, Morgan B, et al.  Radioembolization of liver metastases from 
colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, 
fluorouracil, and leucovorin chemotherapy.  J Clin Oncol.  2007 Mar 20; 25(9): 1099-106. 
65. Chua TC, Bester L, Saxena A, Morris DL.  Radioembolization and systemic chemotherapy 
improves response and survival for unresectable colorectal liver metastases.  J Cancer Res Clin 
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66. Kosmider S, Tan TH, Yip D, Dowling R, Lichtenstein M, Gibbs P.  Radioembolization in 
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67. Martin RC 2nd, Scoggins CR, Schreeder M, et al.  Randomized controlled trial of irinotecan drug-
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68. Lin M, Pellerin O, Bhagat N, et al.  Quantitative and volumetric European Association for the 
Study of the Liver and Response Evaluation Criteria in Solid Tumors measurements: feasibility of 
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69. Chapiro J, Lin M, Duran R, Schernthaner RE, Geschwind JF.  Assessing tumor response after loco-
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199-205. 
70. Tacher V, Lin M, Duran R, et al.  Comparison of Existing Response Criteria in Patients with 
Hepatocellular Carcinoma Treated with Transarterial Chemoembolization Using a 3D 
Quantitative Approach.  Radiology.  2016 Jan; 278(1): 275-84. 
71. Duran R, Chapiro J, Frangakis C, et al.  Uveal Melanoma Metastatic to the Liver: The Role of 
Quantitative Volumetric Contrast-Enhanced MR Imaging in the Assessment of Early Tumor 
Response after Transarterial Chemoembolization.  Transl Oncol.  2014 Aug; 7(4): 447-55. 
 
 
 
 
 
 
 
 
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15. Appendices 
 
 
Appendix A – ECOG Performance Status 
 
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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Appendix B – Child-Pugh Classification 
 
 
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 (seconds over control or INR), 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. 
 
 
 
 
 
 
 
 
 
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Appendix C – New York Heart Association Classification 
 
 
Class 
Description 
I 
Subjects with cardiac disease but without resulting limitations of physical activity.  
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or 
angina pain. 
II 
Subjects with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, 
or angina pain. 
III 
Subjects with cardiac disease resulting in marked limitations of physical activity.  They 
are comfortable at rest.  Less than ordinary physical activity causes fatigue, 
palpitation, dyspnea, or angina pain. 
IV 
Subjects with cardiac disease resulting in inability to carry on physical activity without 
discomfort.  Symptoms of cardiac insufficiency or of the angina syndrome may be 
present even at rest.  If any physical activity is undertaken, discomfort is increased. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix D – Tables for Dose Modifications 
 
Table 1: Suggested Dose Modifications for Non-hematological Toxicities 
1. Toxicity 
Grade 
Management/Next Dose 
Gemcitabine 
Management/Next Dose Cisplatin 
Peripheral 
neuropathy 
Grade 1-2, 
tolerable 
No change in dose 
No change in dose 
Grade 2, 
intolerable 
No change in dose 
Hold until ≤ tolerable G2.  Resume 
at dose reduction. 
Grade 3-4 
No change in dose 
Hold until ≤ G2.  Resume at dose 
reduction. 
Elevated creatinine 
≤ 0.4 above 
baseline 
No change in dose 
No change in dose 
0.5-1.0 above 
baseline 
No change in dose 
Hold until ≤ 0.4 above baseline.  
Resume at same dose, increase pre 
and post cisplatin hydration. 
≥ 1.1 above 
baseline 
No change in dose 
Hold until ≤ 0.4 above baseline.  
Resume at dose reduction. 
Other non-
hematologic 
toxicities* 
≤ Grade 1 
No change in dose 
No change in dose 
Tolerable 
Grade 2 
No change in dose 
No change in dose 
Grade 3 or 4 
Hold until ≤ tolerable G2.  
Resume at dose 
reduction. 
Hold until ≤ tolerable G2.  Resume 
at dose reduction. 
 
* Asymptomatic non-hematological laboratory abnormalities will not be cause for dose reduction, but 
will be corrected as per standard clinical practice. 
 
 
 
 
 
 
 
 
 
 
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Table 2: Suggested Dose Modifications for Hematologic Toxicities 
Toxicity 
Grade/Laboratory 
Value 
Management/Next Dose 
Gemcitabine 
Management/Next Dose 
Cisplatin 
Neutropenia* 
Day 8 of a cycle: 
< 900/mcL 
Hold until ≥ 900, resume at 
reduced dose, if indicated 
Hold until ≥ 900, resume at 
reduced dose, if indicated 
Thrombocytopenia** Day 8 of a cycle: 
< 70 x 109/L 
Hold until ≥ 70, resume at 
reduced dose, if indicated 
Hold until ≥ 70, resume at 
reduced dose, if indicated 
 
* Use of growth factors is permitted 
** A platelet goal of 50K should be considered for those on anticoagulation 
 
 
 For patients who are noted to have new onset Grade 3 or higher increases in AST, ALT, and/or bilirubin, 
an evaluation for obstruction and cholangitis will be performed; the presence of either obstruction or 
cholangitis will necessitate withholding of treatment until resolution to baseline.  To administer Day 8 
chemotherapy, these liver associated biochemical abnormalities must resolve to ≤ Grade 2 or baseline. 
Supportive care use of transfusion for symptomatic anemia or hemoglobin < 8 g/dL and colony-
stimulating factors (CSFs) for neutropenia is encouraged per established guidelines. 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix E – Study Calendar 
 
Screening 
Phase 
Treatment Phase 
Follow-up 
Phase 
Cycle 1, 3, 5, 7 
Cycle 2, 4, 6, 8 
Day -30 to 0 
Day 1 
Day 8 
Day 15 
Day 1 
Day 8 
Day 8-14 
Day 15-21 
Q3 mo post 
treatment 
Inf. Consent 
X 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
 
 
 
 
 
 
 
 
Medical 
History, H&P 
X 
 
 
 
 
 
X 
 
X 
ECOG-PS 
X 
 
 
 
 
 
X 
 
X 
CMP labs 
X 
X 
X 
 
X 
X 
X* 
 
X 
CBC w/ diff 
X 
X 
X 
 
X 
X 
X* 
 
X 
PT/INR 
X 
 
 
 
 
 
X* 
 
X 
Tumor 
marker: CEA, 
CA 19-9, etc 
X 
 
 
 
 
 
X 
 
X 
Serum/urine 
pregnancy 
X* 
 
 
 
 
 
 
 
 
MRI liver 
with contrast 
X 
 
 
 
 
 
X 
 
X 
CT chest w/o  
contrast 
X 
 
 
 
 
 
 
 
 
cTACE 
procedure 
 
 
 
 
 
 
 
X* 
 
Gemcitabine, 
Cisplatin 
 
X 
X 
 
X 
X 
 
 
 
AE 
Assessment 
X 
X 
X 
 
X 
X 
X 
 
X 
Concomitant 
Medications 
X 
X 
X 
 
X 
X 
X 
 
X 
* if required.  First cTACE is mandatory for continued enrollment. 
 
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