A Traditional Feasibility Study of Gemcitabine, Cisplatin, and 90Y TARE for Unresectable Intrahepatic Cholangiocarcinoma
Phase: NA
Conditions: Intrahepatic Cholangiocarcinoma
Sponsor: Medical University of South Carolina

 
 
MUSC CTO # 102254 
NCT # 02512692 
 
 
A Traditional Feasibility study of Gemcitabine, Cisplatin, and 90Y TARE for 
Unresectable Intrahepatic Cholangiocarcinoma 
 
 
Principal Investigator 
S. Lewis Cooper, M.D. 
Medical University of South Carolina 
86 Jonathan Lucas Street 
P.O. Box 250955 
Charleston, SC 29425-2225 
TEL:  843-792-9300 
FAX: 843-792-0644 
Email: coopersl@musc.edu 
 
Co-Investigators: 
Graham Warren, M.D., Ph.D. – Radiation Oncology 
David T. Marshall, M.D., M.S. – Radiation Oncology 
Marcelo Guimaraes, M.D. –Radiology 
Bret Anderson, M.D. – Radiology 
Carolyn Britten, M.D. - Oncology 
Elizabeth Garrett-Mayer Ph.D. - Division of Biostatistics and Epidemiology 
Andrew D. Hardie, M.D. – Radiology 
Cynthia Schandl, M.D., Ph.D - Pathology 
 
Coordinating Office:   
Hollings Cancer Center, Sponsor-Investigator Support Unit 
Medical University of South Carolina 
86 Jonathan Lucas Street 
Charleston, SC 29425-2225 
 
Protocol Version History: 
Version 2.1 dated November 14, 2016 
Version 2 dated October 31, 2016 
Version 1.3 dated June 25, 2015 
Version 1.2 dated June 8, 2015 
Version 1.1 dated April 27, 2015 
Version 1 dated March 12, 2015 
 
 

Protocol version date: November 14, 2016 
1 
 
 
TABLE OF CONTENTS 
 
DEFINITIONS OF TERMS USED ....................................................................................... 3 
PROTOCOL SUMMARY ..................................................................................................... 5 
1 
OBJECTIVES ................................................................................................................. 6 
1.1 
PRIMARY OBJECTIVE: ..................................................................................................... 6 
1.2 
SECONDARY OBJECTIVES: .............................................................................................. 6 
2 
BACKGROUND ............................................................................................................. 7 
2.1 
CHEMOTHERAPY IN BILIARY TRACT TUMORS ............................................................... 7 
2.2 
ESTABLISHMENT OF CISPLATIN AND GEMCITABINE AS FIRST LINE THERAPY ................ 7 
2.3 
YTTRIUM-90 RADIOEMBOLIZATION IN ICC .................................................................... 7 
2.4 
YTTRIUM-90 TARE AND CHEMOTHERAPY ..................................................................... 8 
2.5 
ASSESSMENT OF RESPONSE IN ICC ................................................................................. 8 
2.6 
MOLECULAR SUBTYPES OF ICC...................................................................................... 8 
2.7 
SUMMARY ....................................................................................................................... 8 
3 
PATIENT SELECTION ................................................................................................ 9 
3.1 
INCLUSION CRITERIA ...................................................................................................... 9 
3.2 
EXCLUSION CRITERIA ...................................................................................................... 9 
3.3 
INCLUSION OF WOMEN AND MINORITIES ..................................................................... 10 
3.4 
PATIENT REGISTRATION ............................................................................................... 10 
4 
TREATMENT PLAN ................................................................................................... 11 
4.1 
AGENT ADMINISTRATION ............................................................................................. 11 
4.2 
90Y TARE ..................................................................................................................... 12 
4.3 
DEFINITION OF DOSE-LIMITING TOXICITY ................................................................... 13 
4.4 
DOSE ESCALATION RULES ............................................................................................ 13 
5 
DOSING DELAYS/DOSE MODIFICATIONS ......................................................... 14 
5.1 
HEMATOLOGIC .............................................................................................................. 14 
5.2 
NON-HEMATOLOGIC TOXICITY .................................................................................... 15 
6 
STUDY assessments ...................................................................................................... 16 
6.1 
GUIDELINES FOR STUDY ASSESSMENTS ....................................................................... 16 
6.2 
STUDY CALENDAR ........................................................................................................ 17 
7 
Concomitant Therapy ................................................................................................... 18 
7.1 
GENERAL CONSIDERATIONS ......................................................................................... 18 
7.2 
90Y TARE ..................................................................................................................... 18 
7.3 
CISPLATIN AND GEMCITABINE ..................................................................................... 18 
8 
Patient discontinuation ................................................................................................. 19 
8.1 
DURATION OF FOLLOW UP ........................................................................................... 19 
9 
PHARMACEUTICAL INFORMATION ................................................................... 20 
9.1 
GEMCITABINE HCL ....................................................................................................... 20 
9.2 
CISPLATIN ..................................................................................................................... 20 
9.3 
SIRTEX (YTTRIUM-90 MICROSPHERES) ........................................................................ 21 
10 CORRELATIVE STUDIES ......................................................................................... 23 
10.1 
COLLECTION: ................................................................................................................ 23 
10.2 
HANDLING: ................................................................................................................... 23 
10.3 
SHIPPING: ...................................................................................................................... 23 
10.4 
CORRELATIVE STUDY: .................................................................................................. 23 
11 STATISTICAL CONSIDERATION .......................................................................... 24 
11.1 
PRIMARY ENDPOINT: .................................................................................................... 24 

Protocol version date: November 14, 2016 
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11.2 
SECONDARY ENDPOINT(S): ........................................................................................... 24 
11.3 
STUDY DESIGN ............................................................................................................. 24 
11.4 
SAMPLE SIZE/ACCRUAL RATE ...................................................................................... 27 
11.5 
STRATIFICATION FACTORS ........................................................................................... 27 
11.6 
ANALYSIS OF SECONDARY ENDPOINTS ........................................................................ 27 
12 MEASUREMENT OF EFFECT ................................................................................. 28 
12.1 
ANTITUMOR EFFECT – SOLID TUMORS ........................................................................ 28 
12.2 
DEFINITIONS ................................................................................................................. 28 
12.3 
DISEASE PARAMETERS ................................................................................................. 28 
12.4 
METHODS FOR EVALUATION OF MEASURABLE DISEASE ............................................. 28 
12.5 
RESPONSE CRITERIA ..................................................................................................... 29 
12.6 
DURATION OF RESPONSE .............................................................................................. 30 
12.7 
PROGRESSION-FREE SURVIVAL .................................................................................... 30 
13 DATA REPORTING/REGULATORY REQUIREMENTS .................................... 31 
14 ADVERSE EVENTS: REPORTING REQUIREMENTS ........................................ 32 
14.1 
PURPOSE ....................................................................................................................... 32 
14.2 
DEFINITION OF ADVERSE EVENT ................................................................................... 32 
14.3 
DEFINITION OF SERIOUS ADVERSE EVENT .................................................................... 33 
14.4 
SERIOUS ADVERSE EVENT REPORTING ........................................................................ 33 
14.5 
DEFINITION OF SEVERITY ............................................................................................. 33 
14.6 
ATTRIBUTION OF THE AE ............................................................................................. 33 
14.7 
ADVERSE EVENT “EXPECTEDNESS” ............................................................................. 34 
15 Monitoring ..................................................................................................................... 35 
15.1 
PROTOCOL DEVIATIONS ................................................................................................ 35 
15.2 
SAFETY REPORTING ...................................................................................................... 35 
15.3 
DATA SAFETY MONITORING COMMITTEE ..................................................................... 35 
16 Appendices ..................................................................................................................... 36 
17 REFERENCES: ............................................................................................................ 49 
 
 

Protocol version date: November 14, 2016 
3 
 
DEFINITIONS OF TERMS USED 
 
2HG 
 
 
2-hydroxyglutarate 
5FU 
 
 
5-fluorouracil 
ADC 
 
 
apparent diffusion coefficient 
AE 
 
       
adverse event 
ALT 
 
 
alanine aminotransferase 
AST 
 
 
aspartate aminotransferase 
ANC 
 
 
absolute neutrophil count 
BSA 
 
 
body surface area 
BMP 
 
 
basic metabolic panel 
CBC 
 
 
complete blood count 
CMP 
 
 
complete metabolic panel 
CR 
 
 
complete response 
CRF 
 
 
case report form 
CT 
 
 
computer-assisted tomography 
CTCAE 
 
Common Toxicity Criteria adverse event 
CTO 
 
 
Clinical Trials Office 
CTSA  
 
Clinical and Translational Science Award 
CTRC  
 
Clinical and Translation Research Center 
DLT 
 
 
dose limiting toxicity 
DSMC  
 
Data Safety Monitoring Committee 
EASL  
 
European Association for the Study of the Liver 
ECG 
 
 
electrocardiogram 
ECOG  
 
Eastern Cooperative Oncology Group 
FDA 
 
 
Food and Drug Administration 
GGT 
 
 
gamma-glutamyl transferase 
HCC 
 
 
Hollings Cancer Center 
HIV 
 
 
human immunodeficiency virus 
IB 
 
 
Investigator Brochure 
ICC 
 
 
intrahepatic cholangiocarcinoma 
ICH 
 
 
International Conference on Harmonisation 
INR 
 
 
international normalized ratio 
IRB 
 
 
Institutional Review Board 

Protocol version date: November 14, 2016 
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LTF 
 
 
liver function test 
MTD  
 
maximum tolerated dose 
MRI 
 
 
magnetic resonance imaging 
mRECIST 
 
Modified Response Evaluation Criteria in Solid Tumors 
MUSC  
 
Medical University of South Carolina 
NCI 
 
 
National Cancer Institute 
NYHA  
 
New York Heart Association 
OS 
 
 
overall survival 
PI 
 
 
Principal Investigator 
PFS 
 
 
progression free survival 
PLT 
 
 
platelet count 
PPI 
 
 
proton pump inhibitor 
PR 
 
 
partial response 
RECIST 
 
Response Evaluation Criteria in Solid 
REDCap 
 
Research Electronic Data Capture 
SAE 
 
 
serious adverse event 
SD 
 
 
stable disease 
SIS Unit 
 
Sponsor-Investigator Support Unit 
TACE  
 
transarterial chemoembolization 
TiTE-CRM 
 
time-to-event continual reassessment method 
ULN 
 
 
upper limit of normal 
90Y TARE 
trans-arterial embolization with Yttrium-90 
 
 

Protocol version date: November 14, 2016 
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PROTOCOL SUMMARY 
Patient Eligibility:                                                                Required Laboratory Values:                               
• Histologic diagnosis of ICC that is deemed 
unresectable by a multidisciplinary team that includes a 
hepatobiliary surgeon.   
• ANC ≥ 1.5K/CUMM 
• PLT ≥ 100K/CUMM 
• AST, ALT, and Alk Phos < 5 x ULN 
• Total Bilirubin < 2.0mg/dL 
• Creatinine < 1.5mg/dL 
• No prior liver radiation therapy or immunotherapy for 
ICC. 
• Only previous single agent chemotherapy for ICC 
allowed. 
• Child-Pugh A 
• Age > 18 
• ECOG performance status 0-2  
• Patients must not have any grade III/IV cardiac disease 
as defined by the NYHA Criteria, unstable angina 
pectoris, or myocardial infarction within 6 months of 
registration.  Patients with a history of myocardial 
infarction or irregular heart rate within 6 months prior 
to registration should be evaluated by a cardiologist 
prior to trial entry. 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
                  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R
E
G
I
S
T
E
R 
Cycles 1-2,  
Days 1 and 8**   
Standard dose 
cisplatin and 
gemcitabine based 
on dose level  
Cycles 3-8 
Standard dose 
cisplatin and 
gemcitabine  
Cycle 1,  
Day 3 or 4 
90Y TARE 
Follow-
up 
Informed Consent 
/Patient Decline 
Questionnaire 
Hepatic 
Arteriography & 
Scintigraphy with 
Tc 99-labeled 
MAA 

Protocol version date: November 14, 2016 
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1 OBJECTIVES 
1.1 PRIMARY OBJECTIVE: 
To determine the safety and MTD of 90Y TARE in combination with gemcitabine and cisplatin in 
patients with unresectable intrahepatic cholangiocarcinoma.  The MTD is defined as the dose with dose 
limiting toxicity probability of no more than 0.25. 
1.2 SECONDARY OBJECTIVES: 
• To determine progression free survival. 
• To determine if changes in ADC on MR predict overall survival in patients   treated with 
chemotherapy and 90Y TARE. 
• To determine the response to the combination of chemotherapy and 90YTARE based on 
molecular subtype of ICC. 
• To determine if GGT level at diagnosis and after treatment is predictive of overall 
survival. 
 
 

Protocol version date: November 14, 2016 
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2 BACKGROUND 
Intrahepatic cholangiocarcinoma is an uncommon malignancy affecting between 5000 to 8000 individuals 
a year in the United States with an age-adjusted incidence of 0.73 per 100,000 (1,2).  Complete surgical 
resection is the only established curative treatment for ICC, but most patients present with locally 
advanced disease and only a third are candidates for resection.  Even among patients who undergo 
resection, two thirds will have a recurrence with the predominate pattern of recurrence being in the 
remnant liver (3).  Five year survival in surgical series reporting outcomes for resection of ICC range 
from 25-40% (4).  Therapeutic options are limited in patients who have unresectable disease at 
presentation or recurrence not amenable to further surgery.   
2.1 CHEMOTHERAPY IN BILIARY TRACT TUMORS 
Different chemotherapy regimens were used for cholangiocarcinoma in the 1980’s, 1990’s and early 
2000’s, but no randomized controlled trial showed a survival benefit.  The majority of these regimens 
contained 5FU with response rates typically from 20 to 30% and median survival from 6 to 9 months 
(5-11).  Gemcitabine also began to be used in biliary tract cancer due to its activity in pancreatic cancer 
in which an overall survival benefit was seen when compared to 5FU(12).  Two small phase II trials 
suggested that gemcitabine may have activity in biliary tract tumors.  Response rates were modest at 15 
to 20% with overall survival of 6.5 to 7.5 months (11,13).   
2.2 ESTABLISHMENT OF CISPLATIN AND GEMCITABINE AS FIRST LINE THERAPY 
Cisplatin and gemcitabine were known to be effective together in several tumor types, including head 
and neck, lung, and bladder cancers (14-16).  For this reason, the Upper Gastrointestinal Cancer 
Clinical Studies Group of the United Kingdom National Cancer Research Institute designed a 
randomized phase II trial comparing cisplatin and gemcitabine to gemcitabine alone (the Advanced 
Biliary Cancer [ABC]-01 trial).  Eighty-six patients were enrolled with improvement in 6 month 
progression-free survival from 47.7% to 57.1% (17).  This study was then extended into a randomized 
phase III study, the ABC-02 trial.  This trial established cisplatin plus gemcitabine as the standard 
frontline therapy for locally advanced or metastatic biliary cancer with a median overall survival 11.7 
months compared to 8.1 months in the gemcitabine alone arm.  Median progression-free survival was 
improved from 5 to 8 months in the cisplatin and gemcitabine arm.  Grade 3 to 4 toxic effects were 
similar in both arms at 70%, but the combination arm had significantly less liver toxicity at 16% versus 
27%.  This was thought to be due to better control of the disease in the liver (18).  There were eighty 
patients with intrahepatic cholangioarcinoma on this trial and the hazard ration for death was 0.57 in the 
combined arm.  In addition, a small randomized phase III trial with eighty-four patients was also 
performed in Japan comparing gemcitabine and cisplatin to gemcitabine alone in patients with biliary 
tract cancer.  Median survival was improved from 7.7 to 11.2 months with no significant increase in 
toxicity (19). 
2.3 YTTRIUM-90 RADIOEMBOLIZATION IN ICC 
Liver directed intra-arterial therapies have also been investigated in unresectable ICC.  Trans-arterial 
embolization with Yttrium-90 tagged to glass or resin microspheres were initially used in unresectable 
colorectal cancer liver metastases as well as for the palliative treatment of hepatocellular carcinoma.  
An initial pilot study of 24 patients with ICC treated with 48 administrations of Y90 to hepatic 
segments or lobes demonstrated that the therapy was well-tolerated with a response rate of 86% and 
median survival of 14.9 months (20).  Grade 3 liver toxicity was seen in 21% of patients, all in patients 
who had progression and one patient (4%) developed grade 4 gastrointestinal toxicity with a bleeding 
gastroduodenal ulcer requiring surgery.  Several other series have found a median survival of 9.3 
months to 22 months after Y90 for ICC (21-24). 

Protocol version date: November 14, 2016 
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2.4 YTTRIUM-90 TARE AND CHEMOTHERAPY 
Combination chemotherapy and 90Y TARE has also been investigated for colorectal cancer liver 
metastases.  A phase I study combined FOLFOX4 chemotherapy with 90Y TARE in patients with 
colorectal liver metastases who had not received chemotherapy for metastases.  Oxaliplatin was dose 
reduced for the first three cycles and 90Y TARE was given on the third or fourth day of the first cycle.  
The starting oxaliplatin dose was then increased in cohorts and 60mg/m2 was found to be the 
maximum-tolerated dose for the first three cycles (25).  One phase III trial randomized 44 patients with 
liver-limited metastatic colorectal cancer refractory to standard chemotherapy to protracted infusion 
5FU alone versus in combination with 90Y TARE on cycle 1, day 1.  There was no increased toxicity 
with the addition of 90Y TARE and time to liver progression was significantly improved from 2.1 
months to 5.5 months (26).  The SIRFLOX trial is evaluating FOLFOX6m chemotherapy alone versus 
in combination with 90Y TARE on cycle 1, day 3 or 4 in patients with colorectal liver metastases as 
front line therapy and has completed accrual with over 500 patients.  Analysis is pending, but safety 
data on the first 120 patients have shown no increased toxicity over FOLFOX6m chemotherapy alone.  
In addition, the FOXFIRE trial is investigating 5FU, oxaliplatin, and folinic acid chemotherapy alone 
versus in combination with90Y TARE for patients with colorectal liver metastases in the United 
Kingdom.   
2.5 ASSESSMENT OF RESPONSE IN ICC 
Response rates to 90Y TARE are 50% to 88%, but there are multiple criteria that have been used to 
assess response.  RECIST does not correlate with survival in patients treated with Y90, but the 
mRECIST and EASL criteria do correlate with survival (27,28).  In ICC patients treated with TACE, 
percent tumor necrosis and volumetric changes in ADC on MRI have been noted to correlate with 
survival, but these have not been assessed in patients receiving 90Y TARE (28,29). 
2.6 MOLECULAR SUBTYPES OF ICC 
Little is known about the molecular pathogenesis of ICC and no molecular targeted agents have been 
approved for cholangiocarcinoma.  Recently, genomic profiling of surgical specimens from patients 
with ICC has allowed some characterization of this malignancy with two distinct groups with different 
prognosis, the proliferation and inflammation classes.  Mutations are common and can be found in 
KRAS, BRAF, IDH1, IDH2, EGFR among others (30,31).  These genomic classifications have largely 
been performed on surgical samples from patients undergoing resection so there is no prospective data 
on how the genetic profile impacts response to chemotherapy or TARE.  There are currently no 
standard serum markers to assess response to treatment in patients with ICC.  One recent study found 
that serum GGT elevation was correlated with poor prognosis, but it is unknown if tumor response can 
be followed by GGT serum levels or if they are elevated in specific molecular subtypes (32).  An 
additional study found that serum 2HG was elevated in patients with IDH1/2 mutations and that the 
serum level seemed to be correlated with disease burden in a small cohort (33). 
2.7 SUMMARY 
Gemcitabine and cisplatin chemotherapy is the current standard for the treatment of unresectable 
intrahepatic cholangiocarcinoma.  90Y TARE combined with the current standard may be an ideal way 
to improve disease control in the liver as almost all patients die from their disease in the liver.  The data 
from this trial would then be used to move to a phase II trial to determine efficacy to see if a phase III 
trial would be warranted.  In addition, assessment of the molecular classification of intrahepatic 
cholangiocarcinoma could determine if there is difference in survival with chemotherapy and 90Y 
TARE.  Finally, MRI before and after treatment will be used to determine if utilizing the percent 
increase of mean ADC correlates with survival.   
 

Protocol version date: November 14, 2016 
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3 PATIENT SELECTION 
3.1 INCLUSION CRITERIA 
1. Histologic Documentation:  Core needle biopsy or surgical specimen that confirms ICC.  
Patients must be determined to be unresectable by a multidisciplinary team that includes 
a hepatobiliary surgeon. 
2. Prior treatment:   
• No prior liver radiation therapy or immunotherapy for cholangiocarcinoma.   
• Only one previous single agent chemotherapy for ICC allowed.  
• Patient may have prior liver resection.   
3. Age > 18 years of age.   
4. ECOG performance status < 2 (see Appendix E) 
5. Child- Pugh score of A (see Appendix F) 
6. Life expectancy of greater than 4 months 
7. Patients must have normal organ and marrow function as defined below: 
ANC 
> 1.5 K/CUMM 
PLT 
> 100 K/CUMM 
Bilirubin 
< 2.0 mg/dL 
Creatinine 
< 1.5 mg/dL 
AST, ALT, & Alk phos 
< 5 X ULN 
INR 
< 2.0 
8. All patients must be informed of the investigational nature of this study and must have 
the ability to understand and the willingness to sign a written informed consent 
document. 
9. Willingness to use effective contraceptive methods during the study.  Female patients 
may participate if patient is either not of childbearing potential (defined as 
postmenopausal for > 1 year or surgically sterile) or is practicing two forms of 
contraception.  Sexually active male participants must agree to use a physical barrier 
method (male latex rubber condom with or without spermicide). 
10. Patients with well controlled HIV infection are eligible if their CD4 count is >499/cu mm 
and viral load is < 50 copies/ml.   
11. Pre-certification for the 90Y TARE should be performed prior to enrollment on this study. 
3.2 EXCLUSION CRITERIA 
1. Patients who have had major surgery within 4 weeks prior to study registration or those 
who have not recovered from complications from a surgery more than 4 weeks prior to 
registration.   
2. Patients may not be receiving any other investigational and/or anti-cancer agents.   
3. Patients must not have any grade III/IV cardiac disease as defined by the NYHA Criteria 
(See Appendix G) unstable angina pectoris, or myocardial infarction within 6 months of 
registration.  Patients with a history of myocardial infarction or irregular heart rate within 
6 months prior to registration should be evaluated by a cardiologist prior to registration. 
4. Patients must NOT have liver disease such as cirrhosis or sever hepatic impairment as 
defined by Child-Pugh Class B or C (See appendix F) 
5. Pregnant women are excluded from this study because 90Y TARE is a radioisotope agent 
with the potential for teratogenic or abortifacient effects.  Because there is an unknown 

Protocol version date: November 14, 2016 
10 
 
but potential risk for adverse events in nursing infants secondary to treatment of the 
mother with cisplatin and gemcitabine, breastfeeding should be discontinued.  
3.3 INCLUSION OF WOMEN AND MINORITIES 
Both men and women of all races and ethnic groups are eligible for this trial.   
3.4 PATIENT REGISTRATION 
The SIS Unit will provide patient registration services for the study.  The SIS Unit will conduct a 
patient eligibility audit review of all eligibility source documents prior to patient registration.  These 
procedures are outlined in the Investigator Initiated Trial Operations Manual.  After obtaining signed 
informed consent and completion of required baseline assessments, eligible subjects will be registered.  
A unique subject number will be assigned to each patient.  The SIS Unit will issue a patient registration 
confirmation email to the enrolling study team at the time of registration.  This confirmation will 
include the patient’s assigned cohort dose level and study ID number.  Patient registrations may occur 
between 8AM and 5PM EST, Monday through Friday. 
 
Prior to any study specific activities, the patient must be aware of the nature of his/her disease and 
willingly consent to the study after being informed of study procedures, the experimental therapy, 
possible alternatives, risks and potential benefits.  IRB approval of this protocol and accompanying 
consent is required.   
 
Following registration, patients should begin protocol treatment within 14 days.  Issues that would 
cause treatment delays should be discussed with the PI.  If a patient does not receive protocol therapy 
following registration, the patient’s registration on the study may be canceled.  The SIS Unit should be 
notified of cancellations as soon as possible. 
 
 

Protocol version date: November 14, 2016 
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4  TREATMENT PLAN 
4.1 AGENT ADMINISTRATION 
This is a traditional feasibility study of 90Y TARE, cisplatin, and gemcitabine for unresectable ICC.  
Treatment will be administered on an outpatient basis.  Reported adverse events and potential risks 
for 90Y TARE and cisplatin and gemcitabine are described in Section 9.  Appropriate dose 
modifications for cisplatin and gemcitabine are described in Section 5.  No investigational or 
commercial agents or therapies other than those described below may be administered with the intent to 
treat the patient's malignancy. 
 
Cohorts of at least 2 patients will be treated with 90Y TARE, cisplatin and gemcitabine.  The 90Y TARE 
will be given on day 3 or 4 of cycle 1 and start at 75% (dose level 1) of the dose calculated by the body 
surface area formula and escalated by 25% per cohort in combination with cisplatin and gemcitabine at 
the dose levels described in the dose-escalation schedule table below.  A TiTE-CRM design will be 
used to guide dose escalation (see section 11.3 for more details).   
 
 
Dose-Escalation Schedule 
  
(During Cycle 1) 
Cycle 1 and 2 
Cycle 3 + 
  
Day 3 or  4 
Days 1 and 8 
Days 1 and 8 
Dose Level 
90Y TARE 
Cisplatin 
Gemcitabine 
Cisplatin 
Gemcitabine 
0 
50% 
25 mg/m2 
300 mg/m2 
25 mg/m2 
1000 mg/m2 
1 
75% 
25 mg/m2 
300 mg/m2 
25 mg/m2 
1000 mg/m2 
2 
100% 
25 mg/m2 
300 mg/m2 
25 mg/m2 
1000 mg/m2 
3 
100% 
25 mg/m2 
600 mg/m2 
25 mg/m2 
1000 mg/m2 
4 
100% 
25 mg/m2 
1000 mg/m2 
25 mg/m2 
1000 mg/m2 
 
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
90Y TARE 
Patient should be on 
PPI (i.e., Nexium 40 
mg) 
 
** in D5 
Intra-arterial 
during hepatic 
angiography 
Days 3 or 4 
of cycle 1 
21 days  
(3 weeks) 
Cisplatin 
Patient should have 
anti-emetic prophylaxis 
as indicated in section 
7.3 
1L NS prehydration 
followed by 
25mg/m2 in 250 mL 
NS over 1 hr (+/- 15 
minutes)a 
IV  
Days 1 and 8 
of each cycle 
Gemcitabine 
 
** in NS given over 
30 min (+/- 15 
minutes)a 
IV after 30 min 
NS infusion 
following cisplatin  
Days 1 and 8 
of each cycle 
** Doses as appropriate for assigned dose level. 
aInfusion times may be prolonged due to infusion reactions. 
 
 
 
 

Protocol version date: November 14, 2016 
12 
 
4.2 90Y TARE 
• 
The following premedications are suggested: 
o PPI for gastrointestinal prophylaxis prior to 90Y TARE administration.  If the patient is on 
a PPI they can continue their current medication if it is equivalent to Nexium 40 mg 
daily.  If the patient is not on a PPI, they should be started on Nexium 40 mg daily prior 
to the procedure.  Gastrointestinal prophylaxis should continue for 3 months after 90Y 
TARE.   
 
o For patients who have had biliary intervention in the past 30 days prior to registration, 
levaquin 500 mg daily and flagyl 500 mg twice daily starting 3 days before 90Y TARE 
and continue for 7 days post treatment. 
 
• 
Selective angiography will be used to deliver the microspheres as selectively as possible.  If both 
lobes are involved then at least two vials will be used to deliver the dose. 
 
• 
Angiography may be performed via femoral or radial access based on evaluation by the 
Interventional Radiologist. 
 
• 
During the initial angiogram, the Interventional Radiologist will determine the hepatic vascular 
anatomy and coil any vessels that could result in microsphere migration.  Tc-99 will be injected 
and scintography performed to determine lung shunt. 
 
• 
The Liver CT and/or MRI at registration will be used for planning.  The total liver volume, right 
and left lobes, and tumor volume in each lobe will be contoured.  If a more selective delivery will 
be performed then the appropriate segments and tumor therein will be contoured.  The below 
equation will be used to calculate the dose for each vial to be delivered.  The Pre-Implantation 
Written directive (Appendix B) should be completed and submitted per institutional standards at 
least one day prior to 90Y TARE.  A copy of the directive will also be submitted to the PI. 
 
BSA[m2] = 0.20247 * height[m]0.725 * weight[kg]0.425  
 
A[GBq] = BSA – 0.2 + (Tumor Volume Targeted /  Liver Volume Targeted) 
 
• 
On day 3 or 4 of cycle 1, angiography will be performed and the dose delivered to the appropriate 
vessel as follows: 
 
• 
The Delivery Set will be primed with 5% dextrose for injection.  
• 
5% dextrose for injection is injected through the D-line to suspend the SIR-Spheres 
microspheres in the V-Vial.  
• 
An aliquot of SIR-Spheres microspheres is loaded into the A-line that leads to the 
patient. 
• 
Non-ionic CM is injected through the B-line to flush the SIR-Spheres microspheres 
into the patient, while at the same time enabling the assessment of microcatheter 
position, direction and velocity of hepatic arterial blood flow, and confirming the 
delivery of SIR-Spheres microspheres to the target tissue  
• 
These steps are repeated until the prescribed activity is delivered to the patient. 
 
• 
After the delivery of 90Y TARE, radiation safety will perform surveys to ensure no contamination 
as well as determine the remaining activity in the Delivery Set to calculate the delivered dose.  
The Post-Implantation Written Directive (Appendix C) should be submitted per institutional 

Protocol version date: November 14, 2016 
13 
 
standards no later than 7 days after 90Y TARE.  A copy of the directive will also be submitted to 
the PI. 
 
4.3 DEFINITION OF DOSE-LIMITING TOXICITY  
Toxicities will be graded according to the NCI CTCAE scale version 4.0.  If multiple toxicities are 
seen, the presence of DLT should be based on the most severe toxicity grade experienced.  DLT will be 
defined as any of the following events occurring within six weeks from treatment with 90Y TARE. 
• 
Any documented ≥ grade 4 non-hematologic toxicity. 
• 
Any documented grade 3 or 4 neutropenic fever. 
• 
Grade 4 thrombocytopenia or neutropenia > 7 consecutive days. 
• 
Grade 3 non-hematologic toxicity delaying chemotherapy > 21 days. 
4.4 DOSE ESCALATION RULES 
A CRM design will be used to guide dose escalation of 90Y TARE and gemcitabine due to the long 
period of evaluation for dose-limiting toxicities.  The MTD is defined as the dose with DLT probability 
of no more than 0.25.  By using a weighted likelihood, patients will be enrolled continuously 
throughout the trial.  The following dose escalation rules will be used: 
 
• 
The first patient will be treated at the second dose level as the first dose is included only as a 
“fall-back” in the event DLT occurs in the first or second patient. 
• 
The dose assigned to each patient has an estimated DLT rate closest to, but not greater than 
the target probability.   
• 
Dose escalation is restricted to one level between adjacent patients.    
• 
Escalation from the current dosage is not allowed until both patients assigned to the current 
dose reach 6 weeks from the start of therapy.   
• 
Discontinue the trial when the probability of DLT at the lowest dose is larger than 25%. 
• 
DLT will be evaluated during the first six weeks from the start of therapy.  After a DLT is 
observed in a cohort, the trial will pause to accrual of the next cohort.  The model will be 
updated to obtain the dose for the next cohort.  The updated model, including the proposed 
dose level for the next cohort, will be sent to the HCC DSMC for approval before restarting 
accrual.  Note that if the first patient in a cohort has a DLT, the 2nd patient will still enroll at 
the current dose level.  The model will be updated after results from both patients have been 
observed and enrollment will continue after the 2nd patient in the cohort has been followed for 
6 weeks.   
 
 
 

Protocol version date: November 14, 2016 
14 
 
5 DOSING DELAYS/DOSE MODIFICATIONS 
For all study drugs, if a dose is missed or held, the dose will not be made up. 
5.1 HEMATOLOGIC  
The following dose modifications should be made for febrile neutropenia and blood counts obtained 
within 2 days prior to each subsequent week. If more than one of these applies, use the most stringent 
(i.e., the greatest dose reduction).   
 
5.1.1 
Cisplatin:  
Toxicity 
Level 
Dose Modification 
ANC 
< 1000/mm3 
Hold cisplatin 
Once ANC recovers to > 1.0 K/CUMM , give at full 
dose at next study treatment day in the current cycle 
or the first day of the next subsequent cycle. 
Platelets 
< 75,000/mm3 
Hold cisplatin 
Once PLT recovers to > 75 K/CUMM, give at full 
dose at next study treatment day in the current cycle 
or the first day of the next subsequent cycle. 
 
If cisplatin is held for greater than 21 days then it will be discontinued.  There are no dose 
reductions for Cisplatin. 
 
5.1.2 
Gemcitabine:  
Dose Level 
Gemcitabine 
Full Dose 
1,000 mg/m2 
-1 
750 mg/m2 
-2 
500 mg/m2 
 
For Day 1 and 8 of each cycle, the dose of gemcitabine to be given will depend on the patient’s 
blood counts on that day according to the following table.   
 
ANC (K/CUMM): 
Day 1 
PLT (K/CUMM):   
Day 1 
 
DOSE MODIFICATION 
> 1.5 AND 
> 100 
No dose modification 
< 1.5 OR 
< 100 
Hold treatment until recovery of blood counts.   
 
If held for > 3 weeks, patient will be removed 
from study 
Day 8 
Day 8 
DOSE MODIFICATION   
≥1.0AND  
≥100 
No dose modification  
0.75-0.999 AND 
≥75 
Decrease by 1 dose level. This dose reduction is 
not permanent. 
≥1.0 AND 
75 -99.999 
Decrease by 1 dose level.  This dose reduction is 
not permanent  
0.5-0.749 OR 
20-74.999 
Omit gemcitabine 
<0.5 OR 
<20 
Omit gemcitabine and reduce by 1 dose level on 
Day 1 of the next cycle.  This dose reduction is 
permanent    
 
If patients had a non-permanent dose reduction on day 8 and their ANC ≥1.5 K/CUMM and PLT 
≥100K/CUMM by day 1 of the next cycle, they will return to full dose (the dose prior to the non-
permanent dose reduction).   

Protocol version date: November 14, 2016 
15 
 
5.2 NON-HEMATOLOGIC TOXICITY 
5.2.1 
Cisplatin 
Toxicity 
Level 
Modification 
Creatinine Clearance 
< 50ml/min 
Hold Cisplatin 
Administer fluids and repeat creatinine as clinically 
indicated. 
 
Administer cisplatin if CrCl > 50 ml/min  at full dose at 
next study treatment day in the current cycle or the first 
day of the next subsequent cycle. 
 
Discontinue if < 50ml/min. after one week 
Creatinine Clearance 
< 30ml/min 
Hold Gemcitabine 
Administer fluids and repeat creatinine as clinically 
indicated. 
 
Administer gemcitabine if CrCl > 50 ml/min  at full dose 
at next study treatment day in the current cycle or the 
first day of the next subsequent cycle. 
Nausea and/or vomiting 
> Grade 3, despite 
maximum antiemetics 
Hold cisplatin 
  
If improved, cisplatin should be resumed at full dose at 
next study treatment day in the current cycle or the first 
day of the next subsequent cycle., if possible 
 
If cisplatin is held for > 21 days, discontinue 
Neurotoxicity (peripheral) 
Grade 1 
Full dose 
> Grade 2 
Hold until improved to grade 1 or better, then resume at 
full dose at next study treatment day in the current cycle 
or the first day of the next subsequent cycle. 
 
If cisplatin is held for > 21 days, discontinue 
Ototoxicity 
> Grade 3 
Discontinue cisplatin 
 
5.2.2 
Gemcitabine   
General Guidelines: 
• 
Grade 3 or 4 nausea or vomiting only requires dose modifications if it persists > 24 hours 
despite adequate antiemetic medication.  
• 
There are no dose modifications for alopecia.   
• 
Grade 3 or 4 adverse events not related to treatment such as a thrombosis, pulmonary 
embolus or non-neutropenic infection do not require dose reductions when treatment is 
resumed.   
• 
For suspected > grade 2 pneumonitis consult with a medical oncology co- principal 
investigator. 
Toxicity 
Grade 
Dose Modifications 
Other non-hematological 
toxicities 
0-2 
Full Dose 
 
3-4 
Hold until resolution to ≤ Grade 2, then 
decrease by 1 dose level from current dose at 
next study treatment day in the current cycle or 
the first day of the next subsequent cycle.  If 
toxicity does not resolve within 3 weeks, 
discontinue gemcitabine treatment. 

Protocol version date: November 14, 2016 
16 
 
6 STUDY ASSESSMENTS   
6.1 GUIDELINES FOR STUDY ASSESSMENTS 
• 
Prior to any study specific activities, the patient must be aware of the nature of his/her disease and 
willingly consent to the study after being informed of study procedures, the experimental therapy, 
possible alternatives, risks and potential benefits.   
• 
To be completed within 16 days before registration: 
o All blood work, including pregnancy test for WOCBP 
o History and Physical, Vital signs, height/BSA, performance status and Child-Pugh 
• 
To be completed within 28 days prior to registration: 
o CT of chest and pelvis, MRI of abdomen 
• 
Cycle = 21 days 
• 
Chemotherapy should start within 14 days of registration 
• 
To allow for scheduling or holiday issues, patient assessments and drug administration may be 
done +/- 3 days.  Radiographic assessments may be done +/- 7 days. 
• 
Patient assessments must be completed prior to administration of study treatment.  Labs obtained 
within 2 days prior to study treatment will not need to be repeated. 

Protocol version date: November 14, 2016 
17 
 
6.2 STUDY CALENDAR 
a. 
If available, tissue from previous biopsy or surgical specimen will be obtained for the mutation analysis.  No biopsy will be performed as part of this study.  If tissue is not available, the 
patient is still eligible to participate in the study.  Specimen should be submitted within 30 days of registration.   
b. 
Vital Signs include: temperature, blood pressure, heart rate, respiratory rate, and weight 
c. 
CMP is a BMP with the addition of LFTs 
d. 
Ιf contraindication to MRI then 4 phase liver CT will be obtained.  Imaging must be completed at MUSC. 
e. 
See section 4 for details regarding treatment administration. 
f. 
Performed according to CTCAE version 4.0. 
g. 
Q 3 months for 2 years after initiation of treatment and then Q 6 months for 4 years until progression.  After progression, patients will enter long term follow up 
h. 
After progression, patients will be followed for overall survival and second malignancy until the follow up period is completed. 
i. 
Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. 
j. 
Radiographic assessments & GGT should be repeated at the end of treatment visit, unless progression was previously documented. 
k. 
Baseline labs may be used for 90Y evaluation.
Tests & Observations 
Pre- 
Study 
Patient Registration 
90Y 
Eval 
Cycle 1 
Cycle  
2-4 
Post 
cycle 4 
Cycle  
5-8 
Post Cycle 8/ 
End of 
Treatment 
Follow 
upg 
Long Term 
Follow Uph 
 
 
 
Day 
Day 
Day 
Day 
Day 
 
Day 
Day 
 
 
 
 
 
 
1 
3 or4 
8 
1 
8 
 
1 
8 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Y90 Precertification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PHYSICAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical Exam 
X 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
Vital Signsb 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
Height/BSA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Performance Status 
X 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
Child’s Pugh Classification 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Toxicity Assessmentf 
 
 
X 
 
 
X 
 
 
X 
 
X 
Xh 
 
Concomitant Medications 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
CMP 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Coagulation Panel 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
GGT 
X 
 
 
 
 
 
 
X 
 
 
Xi 
 
 
Serum Pregnancy test for WOCBP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SPECIMEN SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mutation analysisa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT of chest & pelvis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI of Abdomend 
X 
 
 
 
 
 
 
X 
 
 
Xi 
X 
 
Hepatic Angiography 
 
Xk 
 
X 
 
 
 
 
 
 
 
 
 
TREATMENTe 
 
 
 
 
 
 
 
 
 
 
 
 
 
90Y TARE 
 
 
 
X 
 
 
 
 
 
 
 
 
 
PPI premedication 
 
 
 
X ---------------------------------------------------------------------------------------------X 
 
Gemcitabine 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
Cisplatin 
 
 
X 
 
X 
X 
X 
 
X 
X 
 
 
 
FOLLOW UP 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 

Protocol version date: November 14, 2016 
18 
 
7 CONCOMITANT THERAPY 
7.1 GENERAL CONSIDERATIONS 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the patient 
are allowed, including drugs given prophylactically (e.g. anti-emetics), with the following exceptions: 
 
• 
No other investigational therapy may be given to patients. 
• 
No other anticancer agents other than the study medications administered as part of this study 
protocol must be given to patients.  If such agents are required for a patient then the patient 
must be withdrawn from protocol treatment.   
• 
Growth factors (e.g. G-CSF, G-GM-CSF, erythropoietin, platelets growth factors, etc.) are 
not to be administered prophylactically but may be prescribed by the treating physician for 
rescue from severe hematologic events.   
7.2 90Y TARE  
The following medications are suggested after 90Y TARE: 
 
• 
Medrol dose pack for nondiabetics 
• 
Zofran 8 mg to fill if needed 
• 
Percocet 5/325 mg to fill if needed. 
7.3 CISPLATIN AND GEMCITABINE  
Anti-emetic prophylaxis will be administered as needed as outlined below: 
 
• 
To reduce the risk of acute emesis, give Zofran 8 mg (IV), aprepitant 125 mg (PO), and 
Dexamethasone 12 mg (IV) prior to cisplatin. 
• 
An alternative to reduce the risk of acute emesis would be to give Zofran 8 mg, fosaprepitant 
150 mg, and Dexamethasone 12 mg (all IV) prior to cisplatin. 
• 
To reduce the risk of delayed emesis give dexamethasone 8 mg daily for days 2-4 and 
apripetant 80 mg for days 2-3. 
• 
To reduce the risk of delayed emesis if fosaprepitant is given for acute emesis, then give 
dexamethasone 8 mg once on day 2 and 8 mg bid on days 3 and 4. 
• 
Prehydration, potassium chloride 10 mEq; magnesium sulfate 1 g in NaCl 0.9% 1000 mL 
infusion 
 
 
 
 

Protocol version date: November 14, 2016 
19 
 
8 PATIENT DISCONTINUATION 
Patients may discontinue study treatment at any time.  Any patient who discontinues treatment will be 
asked to return to the study center to undergo end of treatment assessments as outlined within Study 
Calendar (Section 6).  The primary reason for discontinuation should be recorded.  
In the absence of treatment delays due to adverse events, treatment may continue for 8 cycles or until one 
of the following criteria applies: 
 
• 
Clinical or radiographic disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Estimated lung dose > 30 Gy, 
• 
Uncorrectable extrahepatic deposition on Tc 99 scintography, 
• 
90Y TARE unable to be given to all disease in one procedure as determined by the Interventional 
Radiologist or Radiation Oncologist after the initial angiography. 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
8.1  
DURATION OF FOLLOW UP 
Patients will be followed for progression every 3 months for a maximum of 2 years after initiation of 
treatment and then every 6 months for 4 years. After progression, patients will be followed for survival 
and second malignancy.  
 
 

Protocol version date: November 14, 2016 
20 
 
9 PHARMACEUTICAL INFORMATION 
9.1 GEMCITABINE HCL  
To supplement the toxicity information contained in this document, see package insert for 
comprehensive pharmacologic and safety information.  
 
9.1.1 
Description 
Gemcitabine is an antineoplastic agent that is a cell cycle specific pyrimidine analogue.  
Gemcitabine kills cells undergoing DNA synthesis and blocks the progression of cells through the 
G1/S-phase boundary. Gemcitabine is metabolized by nucleoside kinases to diphosphate 
(dFdCDP) and triphosphate (dFdCTP) nucleosides.  Gemcitabine diphosphate inhibits 
ribonucleotide reductase.  Gemcitabine triphosphate competes with dCTP for incorporation into 
DNA.  Gemcitabine is available commercially as a lyophilized powder in sterile vials containing 
200 mg or 1 gram of gemcitabine as the hydrochloric salt (expressed as the free base) formulated 
with mannitol and sodium acetate. 
9.1.2 
Availability 
The commercially available gemcitabine in 200 mg (10 mL vial) or 1 g (50 mL vial) per vial must 
be prepared for intravenous infusion.  Drug vials will be reconstituted with normal saline added to 
the vial to make a solution ideally containing 10 mg/mL.  The concentration for 200 mg and 1g 
vials should be no greater than 40 mg/mL.   
 
9.1.3 
Storage and Stability 
The lyophilized product should be stored at controlled room temperature (20-25°C or 68-79° F). 
Once the drug has been reconstituted, it should be stored at controlled room temperature and used 
within 24 hours. The manufacturer recommends solutions of gemcitabine not be refrigerated as 
crystallization may occur. 
9.1.4 
Administration 
An appropriate amount of drug will be prepared with normal saline and administered as a 30-
minute intravenous infusion. 
9.1.5 
Toxicity 
The major side effects observed with gemcitabine include leukopenia, thrombocytopenia, anemia, 
and a collection of signs and symptoms referred to collectively as a flu-like syndrome with fever, 
headache, rigors, nausea, diarrhea, itchy skin rash, myalgia, and anorexia.  Other side effects have 
included fatigue, peripheral edema, and proteinuria. Less likely side effects include abnormal 
renal and liver function tests, vomiting, constipation, malaise, and anorexia.  Rare side effects 
include Stevens-Johnson syndrome (severe skin reaction) and shortness of breath, cough, 
inflammation or scarring of the lung.  Rare side effects have also included hemolytic uremic 
syndrome/renal failure and liver failure have occurred following therapeutic gemcitabine therapy.  
Cardiac dysfunction (myocardial infarction, congestive heart failure, and atrial fibrillation) have 
been infrequently reported. 
9.2 CISPLATIN  
To supplement the toxicity information contained in this document, see package insert for 
comprehensive pharmacologic and safety information.  
 
9.2.1 
Description 
Cisplatin is a heavy metal complex containing a central atom of platinum surrounded by two 
chloride atoms and two ammonia molecules in the cis position. It is soluble in water or saline at 1 
mg/mL and in dimethylformamide at 24 mg/mL.  Cisplatin is an antineoplastic agent whose 
mechanism of action appears to be inhibition of the incorporation of DNA precursors, although 

Protocol version date: November 14, 2016 
21 
 
protein and RNA synthesis are also inhibited.  Although this drug seems to act as an alkylating 
agent, there are data to indicate that its mode and sites of action are different from those of 
nitrogen mustard and the standard alkylating agents. 
 
9.2.2 
Availability 
Each vial contains 10 mg of DDP, 19 mg of sodium chloride, 100 mg of mannitol, and 
hydrochloric acid for pH adjustment. One vial is reconstituted with 10 ml of sterile water. The pH 
range will be 3.5 to 4.5. Cisplatin injection also is available from the manufacturer in aqueous 
solution, each ml containing 1 mg cisplatin and 9 mg NaCl and HCL or NaOH to adjust pH. 
Cisplatin also is available in vials containing 50mL or 100mL of a 1mg/mL solution. 
 
9.2.3 
Storage and Stability 
Reconstituted solution of cisplatin is stable for 20 hours when stored at 27°C and should be 
protected from light if not used within 6 hours. The vials and injection should not be refrigerated. 
Cisplatin has been shown to react with aluminum needles, producing a black precipitate within 30 
minutes. 
 
9.2.4 
Administration 
After administering appropriate antiemetics, cisplatin will be infused intravenously over 1-2 
hours along with vigorous hydration. 
 
9.2.5 
Toxicity 
Human toxicity includes nausea, vomiting, renal toxicity (with an elevation of BUN and 
creatinine and impairment of endogenous creatinine clearance, as well as renal tubular damage, 
which appears to be transient), ototoxicity (with hearing loss that initially is in the high-frequency 
range, as well as tinnitus), and hyperuricemia. Much more severe and prolonged toxicity has been 
observed in patients with abnormal or obstructed urinary excretory tracts.  Myelosuppression, 
often with delayed erythrosuppression, is expected. 
9.3 SIRTEX (YTTRIUM-90 MICROSPHERES)  
 
9.3.1 
Description 
SIR-Spheres microspheres consist of biocompatible microspheres containing yttrium-90 with a 
size between 20 and 60 microns in diameter.  Yttrium-90 is a high-energy pure beta- emitting 
isotope with no primary gamma emission. 
 
9.3.2 
Availability 
SIR-Spheres microspheres are provided in a vial with water for injection.  Each vial contains 
3GBq of yttrium-90 (at the time of calibration) in a total of 5 cc water for injection.  Each vial 
contains 40 - 80 million microspheres.  The vial is shipped within a 6.4mm thick, lead pot.  The 
package consists of a crimp-sealed SIR-Spheres microspheres glass vial within a lead pot, and a 
package insert within Type A packing bucket. 
 
9.3.3 
Storage and Stability 
The vial and its contents should be stored inside its transportation container at room temperature 
(15-25° C, 59-77° F).    The useful life of the SIR-Spheres microspheres is 24 hours from the time 
of calibration.   
 
9.3.4 
Dose Preparation (in nuclear pharmacy) 
• 
Unpack SIR-Spheres microspheres, leaving shipping vial in lead pot.   
• 
Place on the bench top in a lead or acrylic shielded box if available.  

Protocol version date: November 14, 2016 
22 
 
• 
Remove the center of aluminum seal from sterile v-vial with forceps, and clean the septum 
with an alcohol swab.  
• 
Place the v-vial in an empty lead pot (10 cm x 6 cm) for stability and shielding. 
• 
Insert a short 25 gauge needle through the septum of the v- vial until it just pierces the septum 
to create a vent.  
• 
Remove the SIR-Spheres microspheres shipping vial from the lead pot and shake vigorously 
to disperse the SIR- Spheres microspheres.  
• 
Using a dose calibrator, determine the activity in the shipping vial and return it to the lead 
pot.  
• 
Remove partially the aluminum seal of the SIR-Spheres microspheres shipping vial, clean 
with alcohol swab.  
• 
Insert a 25 gauge needle through the septum of the shipping vial to create a vent, ensuring the 
needle is well clear of the contents in the shipping vial.  
• 
Use a shielded 5ml syringe with a 21 gauge hypodermic needle at least 50mm long to 
puncture the septum of the SIR-Spheres microspheres shipping vial, and quickly draw back 
and forth several times in order to mix the SIR- Spheres microspheres thoroughly.  
• 
Quickly withdraw the pre-calculated patient radiation dose, and transfer into the vented v-vial 
in the other lead pot.  Withdraw the required amount quickly before the contents of the 
shipping vial start to settle.  
• 
Verify the patient dose in the v-vial by re-measuring the activity in the shipping vial with 
dose calibrator, and correct, if necessary.  
• 
Put the v vial, containing the confirmed patient dose into the dedicated acrylic shield. 
 
9.3.5 
Administration 
• 
The Delivery Set may be primed with either 5% dextrose or sterile water for injection.  
• 
5% dextrose or sterile water for injection is injected through the D-line to suspend the SIR-
Spheres microspheres in the V-Vial.  
• 
An aliquot of SIR-Spheres microspheres is loaded into the A-line that leads to the patient. 
• 
Non-ionic CM is injected through the B-line to flush the SIR-Spheres microspheres into the 
patient, while at the same time enabling the assessment of microcatheter position, direction 
and velocity of hepatic arterial blood flow, and confirming the delivery of SIR-Spheres 
microspheres to the target tissue  
• 
These steps are repeated until the prescribed activity is delivered to the patient. 
 
9.3.6 
Toxicity 
When the patient is treated with proper technique, without excessive radiation to any organ, the 
common adverse events after receiving the SIR-Spheres microspheres are fever, transient 
decrease of hemoglobin, mild to moderate abnormality of liver function tests (mild increase in 
AST, alkaline phosphatase, bilirubin), abdominal pain, nausea, vomiting, and diarrhea.  Severe 
side effects can include acute pancreatitis, radiation pneumonitis, acute gastritis, radiation 
hepatitis, and acute cholecystitis.  
 
 

Protocol version date: November 14, 2016 
23 
 
10 CORRELATIVE STUDIES 
If available, tissue from the diagnostic biopsy or previous surgery should be submitted for mutation 
analysis.   
10.1 
COLLECTION:  
The tissue from the most recent biopsy or surgery should be submitted.  Tissue submitted will be 
formalin-fixed paraffin embedded specimen.  The following shall be obtained: 
 
• 
One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide (block) 
or can be the diagnostic slide itself).  If a core is sent instead of the block, the region from 
where the core was punched must be circled by the submitting pathologist. 
• 
A corresponding paraffin-embedded tissue block of the primary tumor (the block must match 
the H&E being submitted) preferably also containing normal tissue (NOTE: Tissue block that 
includes normal tissue is encouraged).   
• 
If the institution is not able to release the block, a 5 mm diameter core of tissue, punched from 
the tissue block containing the tumor with a punch tool and submitted in a plastic tube (such as 
an Eppendorf or similar) labeled “tumor” with the surgical pathology number. The punch must 
come from the same block as the H&E being submitted.  Cores should be received for 
processing within 5 working days of coring. 
10.2 
HANDLING:   
• 
Storage Conditions:  Store at ambient temperature (25C) until ready to ship.  Formalin-fixed 
paraffin-embedded samples should NOT be frozen.   
• 
Ship all samples overnight in a Styrofoam container in order to prevent extreme temperatures 
during shipping.  Please document the storage conditions used and time stored. 
10.3 
SHIPPING:   
Ship the labeled package according to IATA shipping regulations to the following address: 
 
Department of Pathology and Laboratory Medicine 
ATTN:  Norma Evans/Dr. Schandl (CTO 102254) 
165 Ashley Avenue, Suite 309, MSC 908 
Charleston, South Carolina 29425 
Phone: (843) 792-3500 
Samples at MUSC may be delivered to 165 Ashley Ave, Suite 309.  Please contact Dr. Schandl 24 hour in 
advance of drop-off. 
10.4 
CORRELATIVE STUDY:   
The Medical University of South Carolina will perform mutation analysis utilizing the 50-gene 
RainDance Technologies Thunderbolts Cancer panel. 

Protocol version date: November 14, 2016 
24 
 
11 STATISTICAL CONSIDERATION 
11.1 
PRIMARY ENDPOINT:  
Presence or absence of a DLT of 90Y TARE in combination with gemcitabine and cisplatin.  All 
patients who receive any amount of 90Y TARE will be evaluable for toxicity.  DLT will be assessed 
during the first 6 weeks of study treatment and is defined in section 4.3 of this protocol. 
 
11.2 
SECONDARY ENDPOINT(S): 
• 
Progression-free survival as defined from the time of enrollment to death or progression 
utilizing mRECIST criteria. 
• 
Overall survival as defined from time to enrollment to death. 
• 
Percent change in mean volumetric ADC of the index lesion between baseline MRI and at 12 
and 24 weeks.   
• 
Classification of diagnostic biopsy or surgical specimen material as proliferative or 
inflammatory class according to the Illumina TruSight 26 gene test panel.   
• 
GGT obtained from plasma at enrollment and at 12 and 24 weeks. 
11.3 
STUDY DESIGN 
 
11.3.1 Description of CRM study design 
A continual reassessment method (CRM) design will be used to identify the maximum-
tolerated dose (MTD) (34).  The CRM has been shown to have better properties than the 
more commonly employed ‘3+3” design (35).   Briefly, it assumes the probability of a 
DLT at dose j is equal to 𝜋𝜋𝑗𝑗(𝛼𝛼) = 𝑝𝑝𝑗𝑗
exp (𝛼𝛼) where the pj values (j = 0,1,2,3,4 doses which 
correspond to dose levels listed in dose level table in Section 4.1 and in Figure 11.3.1A) 
are the “skeleton” for the model.  It is an adaptive dose-finding approach where a model-
based estimate of the dose is used to determine where the next cohort of patients should 
be treated based on the accumulated toxicity information from patients already treated on 
the trial.  The R package dfcrm (36) will be used to implement the design in the trial.  
The prior on α has been chosen to be normal with mean 0 and variance 1.34.   The dose 
which has an estimated DLT rate closest to 0.25 will be selected as the MTD. 
 
Our CRM assumes the following characteristics: 
• a target DLT rate of 0.25 
• cohorts of size 2,  
• starts at dose level 1 (75% Y-90; 300 mg/m2 gemcitabine’ 25 mg/m2 cisplatin),  
• includes  restrictions such that  
a. dose levels cannot be skipped (e.g., dose level 2 must be visited before dose 
level 3 in this case),  
b. dose escalation will not occur immediately following a toxic outcome.  
• Our skeleton is 𝑝𝑝= {0.05, 0.15,0.20,0.30,0.40} which is also our prior.   
• The trial will terminate after: 
(a) a total of 24 patients have been treated, or  
(b) 10 patients have been treated at a dose which is recommended by the CRM as 
the dose for the next cohort. 
(c) the estimated DLT rate at the lowest dose level is 0.35 or greater.   
 

Protocol version date: November 14, 2016 
25 
 
Whichever of (a), (b) or (c) occurs first will determine the sample size, which 
could be as large as 24. 
 
Figure 11.3,1A:  Proposed dose levels.  The first cohort of 2 patients will be treated at dose level 
1 (y-90 at 75%, Gemcitabine at 300 mg/m2.  Escalation decisions will be made using the CRM 
design.  
 
 
11.3.2 CRM Operating Characteristics 
 
Figure 11.3.2A shows four different true dose-response relationships considered to 
evaluate the behavior of the proposed CRM, labeled 1 through 4. 
• Scenario 1: low toxicity, dose level 4 is optimal 
• Scenario 2: moderate toxicity, dose level 2 is optimal 
• Scenario 3: synergistic toxicity (ie high toxicity at high dose levels).  Optimal 
dose is 1 or 2. 
• Scenario 4: synergistic toxicity with very high toxicity at dose levels 2-4..  
Optimal dose is level 0.  
 
Figure 11.3.2A:  Four 
dose-toxicity association 
scenarios (1 through 4) 
considered for simulating 
operating characteristics 
of CRM design are shown 
in black. Skeleton is 
shown in red, and 
horizontal blue line 
indicates the target DLT 
rate (0.25). Scenario 
numbers (1-4) correspond 
to the scenarios described 
in the text and in Table in 
Section 4.1.  
 
 

Protocol version date: November 14, 2016 
26 
 
Table 11.3.2A:  Operating characteristics of proposed CRM design for Scenario 1.  Optimal 
dose is Dose level 4, shown in bold.  
 
Dose 0 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
 
 
 
 
 
 
True DLT rate 
0.01 
0.05 
0.07 
0.10 
0.20 
Probability dose selected 
<0.01 
<0.01 
0.02 
0.13 
0.85 
Expected number of pts treated at dose 
0.2 
2.6 
2.7 
4.0 
8.7 
Expected number of toxicities observed at 
dose  
<0.01 
0.1 
0.2 
0.4 
1.7 
 
 
 
 
 
 
Expected Sample Size 
18.2 
Expected Number of DLTs 
2.4 
Expected percent of trials that stop early 
due to toxicity 
<1% 
Expected percent of trials that stop early 
due to reaching max of 10 at one dose 
87% 
 
Table 11.3.2B:  Operating characteristics of proposed CRM design for Scenario 2.  Optimal 
dose is Dose level 2, shown in bold.  
 
Dose 0 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
 
 
 
 
 
 
True DLT rate 
0.07 
0.13 
0.25 
0.35 
0.45 
Probability dose selected 
0.03 
0.24 
0.34 
0.27 
0.10 
Expected number of pts treated at dose 
1.3 
5.5 
6.0 
4.6 
2.2 
Expected number of toxicities observed at 
dose  
0.1 
0.7 
1.5 
1.6 
1.0 
 
 
 
 
 
 
Expected Sample Size 
19.7 
Expected Number of DLTs 
4.8 
Expected percent of trials that stop early 
due to toxicity 
2% 
Expected percent of trials that stop early 
due to reaching max of 10 at one dose 
72% 
 
Table 11.3.2C:  Operating characteristics of proposed CRM design for Scenario 3.  Optimal 
doses are dose levels 1 or 2, shown in bold.  
 
Dose 0 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
 
 
 
 
 
 
True DLT rate 
0.10 
0.20 
0.30 
0.61 
0.80 
Probability dose selected 
0.10 
0.48 
0.33 
0.03 
<0.01 
Expected number of pts treated at dose 
2.5 
7.5 
5.7 
2.4 
0.2 
Expected number of toxicities observed at 
dose  
0.3 
1.5 
1.7 
1.4 
0.2 
 
 
 
 
 
 
Expected Sample Size 
18.4 
Expected Number of DLTs 
5.1 
Expected percent of trials that stop early 
due to toxicity 
6% 
Expected percent of trials that stop early 
due to reaching max of 10 at one dose 
78% 
 
 
 
 

Protocol version date: November 14, 2016 
27 
 
Table 11.3.2D:  Operating characteristics of proposed CRM design for Scenario 4.  Optimal 
dose is dose level 1, shown in bold.  
 
Dose 0 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
 
 
 
 
 
 
True DLT rate 
0.25 
0.40 
0.60 
0.70 
0.85 
Probability dose selected 
0.36 
0.21 
<0.01 
<0.001 
<0.001 
Expected number of pts treated at dose 
5.5 
5.1 
1.5 
0.3 
<0.1 
Expected number of toxicities observed at 
dose  
1.4 
2.1 
0.9 
0.2 
<0.1 
 
 
 
 
 
 
Expected Sample Size 
12.4 
Expected Number of DLTs 
4.5 
Expected percent of trials that stop early 
due to toxicity 
43% 
Expected percent of trials that stop early 
due to reaching max of 10 at one dose 
53% 
 
11.3.3 Phase I Analysis Plans 
The CRM design will guide us to a dose to select for expansion in the Phase II portion of 
the study.  For each dose level, the DLT rate with a 95% confidence interval will be 
reported. 
11.4 
SAMPLE SIZE/ACCRUAL RATE 
HCC is a hepatobiliary referral center and treats 10 patients with ICC per year.  All patients are 
discussed at our multi-disciplinary tumor board where they are considered for eligibility for clinical 
trials with a dedicated gastrointestinal research coordinator.  We expect to enroll up to 24 patients.  
Based on historic numbers (10 eligible patients per year) and competing protocols (currently none), we 
estimate an accrual rate of 1 patient every two months.  At this rate we would expect to meet the overall 
accrual goals of the trial within 3 to4 years. A Patient Decline Questionnaire will be utilized to identify 
barriers to enrollment with the expectation of amending the protocol as needed to address accrual 
deterrents.  
11.5 
STRATIFICATION FACTORS 
There will be no stratification factors.   
11.6 
ANALYSIS OF SECONDARY ENDPOINTS 
Progression-free survival and overall survival will be determine by Kaplan-Meier analysis and defined 
from the time of enrollment to death or progression utilizing mRECIST criteria.  Cox regression will be 
used to determine if percent change in mean volumetric ADC of the index lesion between baseline MR 
and at 12 and 24 weeks are related to overall survival.  
 
The log rank test will be used to compare the overall survival for the inflammatory and proliferative 
classes. 
 
Cox regression will be used to determine if baseline GGT or change in GGT at 12 and 24 weeks are 
related to overall survival.  
 
 

Protocol version date: November 14, 2016 
28 
 
12 MEASUREMENT OF EFFECT 
Although response is not the primary endpoint of this trial, patients will be assessed by standard criteria.  
For the purposes of this study, patients should be re-evaluated after four cycles.  In addition to a baseline 
scan, confirmatory scans will also be obtained after 4 cycles following initial documentation of an 
objective response. 
12.1 
ANTITUMOR EFFECT – SOLID TUMORS 
Response and progression will be evaluated in this study using the modified mRECIST criteria 
endorsed by the American Association for the Study of Liver Disease (AASLD) (37) Changes in only 
the largest diameter (unidimensional measurement) of the tumor enhancing component are used in the 
mRECIST criteria. 
12.2 
DEFINITIONS 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first treatment 
with 90Y TARE 
 
Evaluable for objective response.  All patients will have measurable disease present at baseline.  If they 
have received at least one cycle of therapy and have had their disease re-evaluated, they will be 
considered evaluable for response.  These patients will have their response classified according to the 
definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to the end of 
cycle 1 will also be considered evaluable.) 
12.3 
DISEASE PARAMETERS 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, x-
ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters). 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <20 mm with conventional techniques or <10 mm using spiral CT scan), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by CT or 
MRI), and cystic lesions are all non-measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and measured 
at baseline.  Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically).  A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD.  The baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 10 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up.  
12.4 
METHODS FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and never 
more than 4 weeks before the beginning of the treatment.  The same method of assessment and the 
same technique should be used to characterize each identified and reported lesion at baseline and during 
follow-up.  
 

Protocol version date: November 14, 2016 
29 
 
Conventional CT and MRI:  These techniques should be performed with cuts of 10 mm or less in slice 
thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and neck tumors and those 
of extremities usually require specific protocols. 
12.5 
 RESPONSE CRITERIA 
Disease response will be documented using mRECIST. 
 
12.5.1 Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesion enhancing component, 
taking as reference the baseline sum LD 
Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target 
viable lesions, taking as reference the smallest sum LD 
recorded since the treatment started or the appearance of 
one or more new lesions 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference 
the smallest sum LD since the treatment started 
 
12.5.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits 
 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
12.5.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
 
 
 
 

Protocol version date: November 14, 2016 
30 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
Category Also 
Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-
CR/Non-PD 
No 
PR 
 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once 
>4 wks. from baseline 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
12.6 
DURATION OF RESPONSE 
Duration of overall response:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria 
for progression are met, taking as reference the smallest measurements recorded since the treatment 
started.  
12.7 
PROGRESSION-FREE SURVIVAL 
PFS is defined as the duration of time from start of treatment to time of progression. 
 
 

Protocol version date: November 14, 2016 
31 
 
13 DATA REPORTING/REGULATORY REQUIREMENTS 
Electronic and hard copy CRF’s will be provided for the recording of data.  With the exception of hard 
copy case report forms utilized for expedited reporting requirements, such as the reporting of SAE’s, the 
remainder of patient data will be collected and submitted via electronic CRFs. All data should be 
substantiated by clinical source documents organized within a patient research record. ICH Good Clinical 
Practices are to be followed.  
 
Electronic data for on study and follow-up patient data is submitted via the electronic system called 
REDCap. REDCap is managed from MUSC as a consortium partner under their CTSA. REDCap is a 
secure, Web-based application designed to capture and manage research study data. 
 
The system has been reviewed for 21CFR Part 11 compliance and has been deemed “21CFR 11 
Capable.” Users of the REDCap system are limited to members of the IRB approved research team who 
are delegated data management responsibilities, typically the study coordinator and data manager. A 
report with compliance information is available upon request. 
 
 

Protocol version date: November 14, 2016 
32 
 
14 ADVERSE EVENTS: REPORTING REQUIREMENTS   
The descriptions and grading scales found in the revised NCI CTCAE version 4.0will be utilized for AE 
reporting.  In addition, SAEs have special reporting requirements. AE and SAE criteria and reporting 
requirements are outlined in this section. For both serious and non-serious adverse events, the investigator 
must determine the severity of the event, “expectedness” of the event, and the relationship of the event to 
study treatment administration. 
 
The study period during which all AEs and SAEs must be reported begins after initiation of study 
treatment and ends at end of cycle 8 or end of treatment. After this period, investigators should only 
report AEs that are attributed to 90Y TARE. SAEs should be monitored until they are resolved or 
are clearly determined to be due to the patient’s stable or chronic condition or intercurrent 
illness(es) 
 
All AEs and SAEs whether volunteered by the subject, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study 
treatment, and actions taken.  All AEs should be recorded and described in the AE database in 
REDCap.   
14.1 
PURPOSE 
AE data collection and reporting, which are required as part of every clinical trial, are done to ensure 
the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents. AEs are reported in a routine manner during a trial. Additionally, certain AEs must be 
reported in an expedited manner to allow for more timely monitoring of patient safety and care. The 
following guidelines prescribe routine and expedited adverse event reporting for this protocol.  
 
Throughout the study, the Investigator will be required to provide appropriate information concerning 
any findings that suggest significant hazards, contraindications, side effects, or precautions pertinent to 
the safety of the drug under investigation.  
 
Note:  All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause must be provided. 
14.2 
DEFINITION OF ADVERSE EVENT 
An adverse event will be considered any undesirable sign, symptom or medical or psychological 
condition even if the event is not considered to be related to the investigational 
drug/device/intervention. Medical condition/diseases present before starting the investigational 
drug/intervention will be considered adverse events only if they worsen after starting study 
treatment/intervention.  An adverse event is also any undesirable and unintended effect of 
research occurring in human subjects as a result of the collection of identifiable private 
information under the research.  Adverse events also include any problems associated with the 
use of an investigational device that adversely affects the rights, safety or welfare of subjects All 
toxicities, serious and non-serious, > grade 2 that were not present at baseline will be reported in 
the REDCap AE database.  Only clinically significant grade 3 or 4 abnormal lab values that were 
not noted during the screening phase should be recorded; however, any clinical consequences of 
the abnormality, regardless of grade, should be reported as AEs.   
 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency, duration or severity, or a change in the quality, of the disease or condition.  Hospitalization 
for elective surgery or routine clinical procedures that are not the result of an AE (e.g., surgical 
insertion of central line) need not be considered AEs and should not be recorded as an AE.  Progression 
of cancer also will not be considered an AE. 

Protocol version date: November 14, 2016 
33 
 
14.3 
DEFINITION OF SERIOUS ADVERSE EVENT 
An SAE is defined as any event that results in one of the following outcomes: 
• 
death 
• 
life threatening (places the subject at immediate risk of death) 
• 
inpatient hospitalization or prolongation of existing hospitalization.  Emergency room visits 
that do not result in admission to the hospital should be evaluated for one of the other serious 
outcomes  
• 
disability or permanent damage.  Report is the event resulted in a substantial disruption of a 
person’s ability to conduct normal life functions. 
• 
congenital anomaly/birth defect.  
• 
requires intervention to prevent permanent impairment or damage 
• 
important medical important events.  Report when the event does not fit the other outcomes, but 
the event may jeopardize the patient and may require medical or surgical intervention 
(treatment) to prevent one of the other outcomes.  Examples include allergic bronchospasm (a 
serious problem with breathing) requiring treatment in an emergency room, serious blood 
dyscrasias (blood disorders) or seizures/convulsions that do not result in hospitalization. The 
development of drug dependence or drug abuse would also be examples of important medical 
events. 
14.4 
SERIOUS ADVERSE EVENT REPORTING 
The Investigator must report all SAEs to the SIS Unit within 24 hours of first becoming aware of the 
event. This report will be accomplished by completing the 102254 SAE form in REDCap 
(redcap.musc.edu).  Any missing or additional relevant information concerning the SAE should be 
provided in a written follow-up report.  SAE reporting for this study will follow FDA guidelines for 
Medical Device Reporting. 
 
All SAEs should be monitored until they are resolved or are clearly determined to be due to the 
patient’s stable or chronic condition or intercurrent illness(es). 
14.5 
DEFINITION OF SEVERITY 
Adverse events will be graded according to the revised NCI Common Toxicity Criteria.  If toxicities are 
not defined by the NCI CTCAE v. 4.0, the intensity of each adverse event should be graded as either 
Mild (grade 1), Moderate (grade 2), Severe (grade 3), or Life-threatening (grade 4) by the Investigator.   
 
GRADE 1 
MILD:  Sign or symptom noticeable, but does not interfere with normal daily 
activities. 
GRADE 2 
MODERATE:  Sign or symptom sufficient to interfere with normal daily activities. 
GRADE 3 
SEVERE:  Sign or symptom is incapacitating, with inability to perform daily activities. 
GRADE 4 
LIFE-THREATENING:  sign or symptom poses immediate risk of death to this 
patient. 
14.6 
ATTRIBUTION OF THE AE 
Definite:      
AE is clearly related in time and a direct association can be 
demonstrated to the study intervention 
Possible: 
AE may be reasonably related in time and the AE can be 
explained equally well by causes other than the study 
intervention 
Unrelated: 
AE is clearly not related to intervention and can be fully 
explained by another cause. This other cause should be provided. 
 

Protocol version date: November 14, 2016 
34 
 
14.7 
ADVERSE EVENT “EXPECTEDNESS” 
Expected adverse events are those adverse events that are listed or characterized in the Package 
Insert. 
 
Unexpected adverse events are those not listed in the package Insert. This includes adverse events 
for which the specificity or severity is not consistent with the description in the Package Insert. 
(For example, under this definition, hepatic necrosis would be unexpected if the Package Insert 
only referred to elevated hepatic enzymes or hepatitis.) 

Protocol version date: November 14, 2016 
35 
 
15  MONITORING 
The SIS Unit will be responsible for the monitoring of study patient data and records. All patients’ 
eligibility criteria will be audited by the SIS Unit prior to patient registration.  During the course of the 
study, each site will be selected for an audit approximately twice a year. The number of cases reviewed 
will be commensurate with the site’s rate of enrollment.  
15.1 
PROTOCOL DEVIATIONS  
A Protocol Deviation is any variance from the protocol involving a subject or subjects that is not 
approved by the IRB prior to its initiation or implementation, and occurs when a member of the study 
team departs from the IRB-approved protocol in any way without the investigator first obtaining IRB 
approval.  Any protocol deviation will be reported by the site within 10 days of notification.  
15.2 
SAFETY REPORTING 
All toxicities, serious and non-serious, that represent a new side effect or toxicity greater than baseline 
will be reported by the sub-site via the REDCap electronic case report form.  In addition, SAEs have 
special reporting requirements. SAE criteria and reporting requirements are outlined in section 14. 
15.3 
DATA SAFETY MONITORING COMMITTEE 
The HCC DSMC will have oversight of the protocol. The HCC DSMC will meet, at a minimum, on a 
semi-annual basis to discuss this investigator-initiated trial. Also, this study will be audited by the HCC 
DSMC auditor) approximately two times per year. 
 
In addition, all protocol deviations and SAEs as defined above will be reviewed by the HCC DSMC at 
monthly meetings. As new protocol deviations or serious adverse events are reported to the SIS Unit, 
the SIS Unit will review these reports for form completion and follow up if more information is 
warranted. The SIS Unit will forward the event report to the HCC DSMC so that the information can be 
reviewed at the next available HCC DSMC meeting. During the HCC DSMC review, the HCC DSMC 
can make recommendations for any further study action.    
 
 

Protocol version date: November 14, 2016 
36 
 
16 APPENDICES 
 
 

Protocol version date: November 14, 2016 
37 
 
 
  APPENDIX A 
National Cancer Institute Common Toxicity Criteria, Version 4.0 
 
HTTP://WWW.EORTC.BE/SERVICES/DOC/CTC/CTCAE_4.03_2010-06-
14_QUICKREFERENCE_5X7.PDF 
 
 

Protocol version date: November 14, 2016 
38 
 
APPENDIX B 
 
Pre-implantation Written Directive 
See next page 
 
 

Protocol version date: November 14, 2016 
39 
 
PRE-IMPLANTATION WRITTEN DIRECTIVE 
Patient Name: 
Last, First  
Study ID 
Treatment Site: Liver 
Scheduled Treatment Time: 
 
  
  
  
Eq. 1 
Mass of Target Liver (Kg)= 
(Density * Volume -> 1.03gm/cc * 1kg/1000gm*Volume (cc)) 
  
  
  
Eq 
.2: 
Estimated Dose to Perfuse Liver Tissue (Gy)= 
50*[Injected Activity (GBq) * [1-LSF]*[1-R]  
  
  
Mass of Target Liver, Kg 
  
  
  
Eq 
.3: 
Est. Dose to Lung(Gy)= 
     50*[Injected Activity (GBq) * [LSF]*[1-R] 
  
  
  
Maximum acceptable dose to lungs: 
30Gy 
(from all administrations) 
  
  
Right 
Left 
Radiopharmaceutical: 
SIR-Tex Y-
90  
  
Radiopharmaceutical: SIR-Tex Y-90  
Target Tissue/Tx. Site (Rt., Lt. Lobe, or Whole): 
  
  
Target Tissue/Tx. Site (Rt., Lt. Lobe, or Whole): 
  
% Lung Shunting 
(LSF): 
  
  
% Lung Shunting (LSF): 
  
Desired Activity:  
  
mCi   
Desired Activity:  
  
mCi   
Accep. Act. Range(+ 10%): 
  
to 
  
Accep. Act. Range(+ 10%): 
  
to 
  
  
 
  
Volume of target/infused liver: 
  
cc 
Volume of target/infused liver: 
  
cc 
Mass of target liver 
: 
  
Kg 
Mass of target liver : 
  
Kg 
Est. dose to be del. to perfused 
liver*: 
  
Gy 
Est. dose to be del. to perfused liver*: 
  
Gy 
Est. dose to be delivered to 
lungs**: 
  
  
Gy 
Est. dose to be delivered to lungs**: 
  
Gy 
*Eq. 3 Assumed no residual 
**Eq. 2 Assumed no residual 
Est. Total dose to be delivered to lungs(Gy): 
0.0 
  
Number of Vials  
  
  
  
  
Right 
  
mCi 
dose 
  
  
Left 
  
mCi 
  
Radiation Oncologist: 
  
  
  Radiation Oncology Physicist: 
  
Radiopharmacy Meas. Activity:  
Right  
  
mCi 
  
  
Left 
  
mCi 
Time of measurement: 
  
  

Protocol version date: November 14, 2016 
40 
 
Nuclear Pharmacist 
  
  
  
  
  
  
Desired Activity is within acceptable range 
  
Yes 
  
No 
  
Note: 
  
  
  
  
  
  
  
  
  
  
  
Radiation Oncologist: 
  
  
  
Radiation Oncology Physicist: 
 
 
 

Protocol version date: November 14, 2016 
41 
 
 
APPENDIX C 
 
Post-Implantation Written Directive 
See next page 
 
 

Protocol version date: November 14, 2016 
42 
 
 
POST-IMPLANTATION WRITTEN DIRECTIVE 
Patient Name: 
Last, First 
Study 
ID 
Treatment Site: Liver 
Scheduled Treatment Time: 
 
  
  
  
Prescribed Activity Left: 
mCi 
 
GBq 
 
 
 
 
 
Prescribed Activity Right: 
mCi 
 
GBq 
 
 
 
 
 
Eq. 1 
Mass of Target Liver (Kg)= 
(Density * Volume -> 1.03gm/cc * 1kg/1000gm*Volume (cc)) 
  
  
  
Eq .2: 
Estimated Dose to Perfuse Liver Tissue (Gy)= 
50*[Injected Activity (GBq) * [1-LSF]*[1-R]  
  
  
Mass of Target Liver, Kg 
  
  
  
Eq .3: 
Est. Dose to Lung(Gy)= 
     50*[Injected Activity (GBq) * [LSF]*[1-R] 
  
  
  
Maximum acceptable dose to lungs: 
30Gy 
(from all administrations) 
 
 
 
 
 
 
 
 
Estimated % Delivered(Left): 
 
 
 
 
 
 
Estimated % Delivered(Right): 
 
 
 
 
 
 
Delivered Activity(Left) : 
 
 
mCi 
 
GBq 
 
Delivered Activity(Right) : 
 
 
mCi 
 
GBq 
 
 
 
 
 
 
 
 
 
 Total Delivered Activity: 
mCi 
GBq 
  
 
 
 
 
Estimated dose delivered to perfused Left liver: 
 
Gy    Eq 2 
 
Estimated dose delivered to perfused Right liver: 
Gy    Eq 2 
Estimated dose delivered to lung: 
 
Gy    Eq 3 
 
 
 
 
 
Pt. Identification: (@ least 2 criteria ) 
 
YES 
 
NO 
 
Dose was not stopped due to decreased flow/stasis/other 
clinical factors: 
 
 
 
 
 
 
YES 
 
NO 
 
Injected Act. is within acceptable 
range 
 
 
 
YES 
 
NO 
 
Highest Exposure Rate Measured by 
RSO: 
 
 
 
mR/hr 
at 1meter from patient 
surface 
 
 
 
 
 
 
 
  
Note: 
  
  
  
  
  
  
  
  
 
 
 

Protocol version date: November 14, 2016 
43 
 
 
  
  
  
Radiation Oncologist: 
  
  
  
Radiation Oncology 
Physicist: 
 
 
 
 
 
 

Protocol version date: November 14, 2016 
44 
 
 
APPENDIX D 
 
Patient Decline Questionnaire 
 
See next page 
 
 

Protocol version date: November 14, 2016 
45 
 
 
Thank you for thinking about participating in the Yttrium 90 intrahepatic cholangiocarcinoma 
trial.  It would be helpful if you could tell us the reasons you have decided not to participate.  
This will help us to develop trials that future patients might find more agreeable to join. Your 
response will be completely anonymous. 
Please complete the following questionnaire and either leave it at the clinic front desk, or drop it 
in the mail.   
 
Date: __________________________________________  
 
I have decided not to sign the informed consent document.  
 
The reasons for my decision include the following (check all that apply): 
 I decided against being in any clinical trial  
 I had concerns about fitting this into my life  
  The trial involves too many extra clinic visits 
  The trial is too far from home 
  I want to be treated by local doctor 
  I have family and/or job issues 
 I had concerns about the procedures I would have to do 
 Too many MRIs 
 I had concerns about the treatment I would receive 
 Yttrium 90 microspheres 
 Gemcitabine and cisplatin chemotherapy  
 Frequency of when I would be getting treatment 
 I had concerns about my insurance and/or financial concerns 
 Other (please specify):_______________________________ 
_________________________________________________ 
 
Coordinator—CTO 102254 
Hollings Cancer Center, Medical University of South Carolina 
86 Jonathan Lucas Street, Suite 373 
P.O. Box 250955 
Charleston, SC 29425-2225 
 
 

Protocol version date: November 14, 2016 
46 
 
APPENDIX E 
 
Performance Status Scale 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 

Protocol version date: November 14, 2016 
47 
 
 
 
APPENDIX F 
 
ASSESSMENT OF THE CHILDS-PUGH CLASSIFICATION 
Clinical and Biochemical  
Measurements  
Points Scored for 
Increasing Abnormality  
  
Check box below 
Refer to points 
scored columns 
on right 
1 
2 
3 
Hepatic 
encephalopathy 
(grade)* 
1    
2   
3 
None 
1 and 2 
3 and 4 
Date hepatic encephalopathy was assessed: _______________________ 
 
Ascites 
1    
2   
3 Absent 
Mild 
Moderate 
Date ascites was assessed: _______________________ 
 
Total bilirubin (mg/dl) 
1    
2   
3 
< 2.0 
2.0 - 3.0 
> 3.0 
Date Total bilirubin was assessed: _______________________ 
 
Serum albumin (g/dl) 
1    
2   
3 
> 3.5 
2.8 - 3.5 
< 2.8 
Date Serum Albumin was assessed: _______________________ 
 
Prothrombin time 
(sec. prolonged) or 
Prothrombin time 
INR** 
1    
2   
3 
< 4 
or 
< 1.7  
4 - 6 
or 
1.7 - 2.3  
> 6 
or 
>2.3  
Date Prothrombin time or Prothrombin time INR was assessed: 
________________ 
 
 
TOTAL POINTS: _________________  
CHILD-PUGH GRADE: ___________    
 
Grade A (well-compensated disease) = Total score 5-6 
Grade B (significant functional compromise) = Total score 7-9 
Grade C (decompensated disease) = Total score 10-15 
 
 
 
Investigator Signature: ________________________________  Date: _______________ 
 
 

Protocol version date: November 14, 2016 
48 
 
APPENDIX G 
 
NEW YORK HEART ASSOCIATION CLASS 
 
Class 
Cardiac Symptoms Limitations 
Need for 
Additional Rest* 
Physical Ability 
to Work 
I 
None 
None 
None 
Full time 
II 
Only moderate 
Slight 
Usually only 
slight or 
occasional 
Usually full time 
III 
Defined, with less 
than ordinary 
activity 
Marked 
Usually moderate 
Usually part time 
IV 
May be present 
even at rest, & any 
activity increases 
discomfort 
Extreme 
Marked 
Unable to work 
*     To control or relieve symptoms, as determined by the patient, rather than as 
advised by the physician. 
**   At accustomed occupation or usual tasks. 
 
 
 

Protocol version date: November 14, 2016 
49 
 
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