A Phase III Clinical Trial Evaluating TheraSphere® in Patients With Metastatic Colorectal Carcinoma of the Liver Who Have Failed First Line Chemotherapy
Phase: NA
Conditions: Colorectal Cancer Metastatic
Sponsor: Boston Scientific Corporation

mCRC Phase III Protocol TS-102 
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Protocol Number: 
TS-102 
Protocol Short Title: 
EPOCH 
Protocol Name: 
A Phase III Clinical Trial Evaluating TheraSphere® in Patients with 
Metastatic Colorectal Carcinoma of the Liver who have Failed First Line 
Chemotherapy 
US Sponsor: 
Frances Harrison 
BTG International Inc. 
Five Tower Bridge, Suite 800 
300 Barr Harbor Drive 
West Conshohocken, PA 19428, USA 
(P) 610 943 3643 (F) 610 943 6018 
Global Sponsor: 
Biocompatibles UK Ltd. 
Chapman House 
Farnham Business Park 
Weydon Lane, Farnham 
Surrey GU9 8QL, UK 
Global Co- Principal 
Investigator: 
Mary F. Mulcahy, MD 
Associate Professor, Division of Hematology/Oncology 
Robert H. Lurie Comprehensive Cancer Center of Northwestern 
University; Galter Pavilion 
675 N. St. Clair, 21st Floor, Chicago, Illinois 60611, USA 
m-mulcahy@northwestern.edu 
(P) (312) 695-6180 (F) (312) 695-6189 
Global Co- Principal 
Investigator: 
Professor Ricky Sharma, MA MB BChir FRCP FRCR PhD 
Honorary Consultant in Clinical Oncology 
Department of Oncology, University of Oxford 
Old Road Campus Research Building 
Oxford OX3 7DQ, UK  
Ricky.sharma@oncology.ox.ac.uk 
(P) +44 (0) 1865 617322 
US Medical 
Monitor: 
Jac Jaroslaw M.D., Medical Director 
Chiltern 
King of Prussia, PA 19046, USA 
(P) (978) 697-9099    (F) (855) 349-6664 
Protocol Medical 
Monitor: 
Beata Paluchowska, MD, PhD, Medical Director 
Chiltern 
35 Nieklanska St. 
03-954 Warszawa, Poland 
+48 22 514 1817 (mobile) 
Device:   
TheraSphere, Yttrium-90 Glass Microspheres 
FDA File #: 
IDE G100324 
Protocol Date 
Activated: 
2011-03-07 (YYYY/MM/DD)  
Amendment Date 
Activated: 
Version 2.0, 2012/01/10 
Version 3.1, 2013/04/08 
Version 4.0, 2013/09/06 
Version 5.0, 2014/03/05 

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Version 5.1, 2014/05/30 
Version 6.1 2016/01/08 
Version 7.0 2017/05/10 
TheraSphere® is a trademark of Theragenics Corporation used under license by Biocompatibles UK Ltd a BTG International group 
company. BTG and the BTG roundel logo are trademarks of BTG International Ltd, and are registered trademarks in the US, EU and 
certain other territories. All rights reserved. 
This document is the confidential property of the Sponsor. No part of it may be transmitted, reproduced, published, or used by other 
persons without prior written authorization. 

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INVESTIGATOR’S PROTOCOL REVIEW STATEMENT 
 
By my signature, I confirm that my staff and I have carefully read and understand the protocol, A Phase III 
Clinical Trial Evaluating TheraSphere® in Patients with Metastatic Colorectal Carcinoma of the Liver who 
have Failed First Line Chemotherapy, and agree to conduct the trial in accordance with the protocol, the 
appropriate regulations specified in the protocol, and the stipulations of the clinical study agreement. 
 
 
 
 
 
 
__________________________________________ 
 
________________ 
Investigator  
 
 
 
 
 
Date 
 
__________________________________________ 
 
 
Print Investigator Name 
 
 
 

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TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS .............................................................................................................................................................. 8 
2. 
TRIAL SCHEMA ...................................................................................................................................................................... 18 
3. 
SCHEDULE OF EVENTS ........................................................................................................................................................... 19 
4. 
LIST OF ABBREVIATIONS ....................................................................................................................................................... 21 
5. 
BACKGROUND AND RATIONALE ............................................................................................................................................ 23 
5.1 
GENERAL DEVICE DESCRIPTION ......................................................................................................................... 23 
5.2 
GLOBAL REGULATORY STATUS OF THERASPHERE ............................................................................................. 23 
5.3 
US CLINICAL EXPERIENCE WITH THERASPHERE IN PATIENTS WITH METASTATIC LIVER CANCER ..................... 23 
5.4 
RATIONALE FOR TREATMENT OF LIVER METASTASES SECONDARY TO COLORECTAL CANCER .......................... 24 
6. 
STUDY OBJECTIVE ................................................................................................................................................................. 27 
7. 
STUDY DESIGN ...................................................................................................................................................................... 27 
8. 
STUDY POPULATION AND ELIGIBILITY CRITERIA .................................................................................................................... 28 
8.1 
PATIENT POPULATION ......................................................................................................................................... 28 
8.2 
ELIGIBILITY CRITERIA ......................................................................................................................................... 28 
9. 
STUDY VISITS, EVALUATIONS AND PROCEDURES .................................................................................................................. 30 
9.1 
STUDY VISITS...................................................................................................................................................... 30 
9.2  STUDY EVALUATIONS AND PROCEDURES ................................................................................................................. 32 
10. STATISTICS ............................................................................................................................................................................ 45 
10.1 
SAMPLE SIZE ESTIMATE ...................................................................................................................................... 45 
10.2 STATISTICAL ANALYSIS PLAN ................................................................................................................................. 45 
11. ELECTRONIC DATA COLLECTION AND MANAGEMENT ........................................................................................................... 53 
11.1 
ELECTRONIC DATA COLLECTION (EDC) ............................................................................................................. 53 
11.2 
DATA MANAGEMENT .......................................................................................................................................... 53 
12. ADVERSE EVENTS .................................................................................................................................................................. 53 
12.1 
ADVERSE EVENT DEFINITIONS ............................................................................................................................ 53 
12.2 
RECORDING ADVERSE EVENTS ........................................................................................................................... 55 
12.3 
SUBMITTING EXPEDITED SAFETY REPORTS ......................................................................................................... 56 
12.4 
PERIODIC SAFETY REPORTING ............................................................................................................................ 57 
12.5 
EXPECTED ADVERSE EVENTS .............................................................................................................................. 57 
13. INVESTIGATOR AND SITE QUALIFICATION AND OBLIGATIONS ............................................................................................... 59 
13.1 
STUDY SITE AND INVESTIGATOR QUALIFICATION ............................................................................................... 59 
13.2 
INSTITUTIONAL APPROVAL AND DOCUMENTATION OF THE PROTOCOL ............................................................... 60 
13.3 
REGULATORY DOCUMENTS ................................................................................................................................. 60 
13.4 
SOURCE RECORDS AND STUDY DOCUMENTATION .............................................................................................. 62 
13.5 
ETHICAL CONDUCT OF THE STUDY ...................................................................................................................... 62 
13.6 
RESPONSIBLE CONDUCT OF RESEARCH ............................................................................................................... 63 
13.7 
INFORMED CONSENT ........................................................................................................................................... 63 
13.8 
PATIENT MEDICAL RECORDS ............................................................................................................................... 64 
13.9 
PATIENT PRIVACY AND CONFIDENTIALITY ......................................................................................................... 64 
13.10 
ADDITIONAL INVESTIGATOR RESPONSIBILITIES .............................................................................................. 64 

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14. PROTOCOL DEVIATIONS ........................................................................................................................................................ 65 
15. STUDY MONITORING ............................................................................................................................................................ 65 
16. STUDY TERMINATION ........................................................................................................................................................... 66 
17. APPENDICES .......................................................................................................................................................................... 66 
18. REFERENCES .......................................................................................................................................................................... 67 
 
 
 

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1. PROTOCOL SYNOPSIS 
Protocol Number 
TS-102 
Protocol Short Title 
EPOCH 
Protocol Title 
A Phase III Clinical Trial Evaluating TheraSphere in Patients with Metastatic 
Colorectal Carcinoma of the Liver who have Failed First Line Chemotherapy 
Device 
TheraSphere, Yttrium-90 glass microspheres 
In the European Union, TheraSphere has been CE marked for the treatment of 
hepatic neoplasia. 
TheraSphere is currently approved in Canada for treatment of hepatic 
neoplasia in patients who have appropriately positioned arterial catheters. 
TheraSphere is currently approved for commercial distribution in the United 
States under a Humanitarian Device Exemption (HDE) for use in radiation 
treatment or as a neoadjuvant to surgery or transplantation in patients with 
unresectable hepatocellular carcinoma (HCC) who can have placement of 
appropriately positioned hepatic arterial catheters.  The device is also indicated 
for HCC patients with partial or branch portal vein thrombosis/occlusion, when 
clinical evaluation warrants the treatment. 
Standard-of-Care 
Chemotherapy 
All patients will be treated with standard-of-care second line chemotherapy 
consisting of either an irinotecan-based regimen, or an oxaliplatin-based 
regimen.  The addition of biological agents approved for use  in the second-line 
setting of mCRC treatment to date (bevacizumab, cetuximab,  panitumimab, 
aflibercept, ramucirumab) is permitted.  
The biological agents  are administered at the investigator discretion, per local 
practices and according to the approved labels which determine the target  
patient population and define the full prescribing information.      
Type of Protocol 
Phase III 
Protocol Design 
This is an open-label, prospective, multi-center, randomized clinical trial.   
Study Objective 
The objective of this study is to evaluate the efficacy and safety of TheraSphere 
in patients with metastatic colorectal cancer of the liver who have progressed 
with first line chemotherapy.  
Primary Endpoints 
Progression-Free Survival (PFS) according to RECIST Criteria v.1.1 from time of 
randomization 
Hepatic Progression-Free Survival (HPFS), defined as the time from 
randomization to the date of disease progression in the liver according to 
RECIST 1.1, or death. 
The study will be considered to have met its objective if at least one of the 
primary endpoints is statistically significant. 
Secondary Endpoints 
• 
Overall Survival (OS) Time, calculated from randomization to death. 
 
• 
Time to symptomatic progression (TTSP) from the time of randomization 
to assessment of ECOG performance status >2. Deterioration in 
performance status is to be confirmed at one subsequent evaluation 8 
weeks later. 
• 
Objective Response Rate (ORR): per RECIST criteria v 1.1  
• 
Disease Control Rate (DCR): per RECIST criteria v 1.1  

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•  Quality of Life Assessment: Functional Assessment of Cancer Therapy – 
colorectal cancer (FACT-c).  
• 
Adverse events and reportable serious adverse events as defined by the 
study protocol (NCI Common Toxicity Criteria for Adverse Events; CTCAE 
v. 4.0).   
Trial Population 
Patients with metastatic colorectal carcinoma (mCRC) of the liver who have 
disease progression with first line chemotherapy either; 1) an oxaliplatin-based 
regimen, or 2) an irinotecan-based regimen, and who are eligible for second 
line chemotherapy with the alternate chemotherapy regimen. 
Number of Patients 
Approximately 420 randomized patients are planned . 
Number of Sites 
Up to 100 sites in the United States, Canada, Europe and Asia 
Treatment Groups 
For all patients, all chemotherapy, including biological agents (i.e. VEGF 
inhibitors or others), must be stopped at least 14 days prior to starting 2nd line 
chemotherapy and 28 days prior to the administration of TheraSphere. 
Patients randomized to the Treatment Group must initiate 2nd line 
chemotherapy, within a maximum of 21 days of randomization. TheraSphere is 
to  be administered in place of the second chemotherapy cycle.  Biological 
therapy can be added for patients randomized to the Treatment Group, 2 
weeks after the TheraSphere administration ( i.e. with the next cycle of the 
standard-of –care chemotherapy). 
(Note: For the purpose of this study, one cycle is defined as a chemotherapy 
infusion.) 
Patients randomized to the Control Group will initiate 2nd line chemotherapy 
within 21 days of randomization. Biological agents can start with the first cycle 
of second line chemotherapy for patients randomized to the control group. 
Trial Duration 
Approximately 60 months of accrual and 1 year additional follow-up are 
planned.  
Note: the sample size calculation, in terms of the number of patients, is based 
on an accrual period of 36 months and 12 months of additional follow-up.  
However, since the timing of the interim and final analyses is based on the 
number of PFS events, the increase in the forecasted accrual period to 60 
months, does not increase the number of patients required, or affect the 
statistical power of the study.  

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Eligibility Criteria 
 
Patients must meet all eligibility criteria: 
1. Must be male or female, 18 years of age or older, and of any ethnic or 
racial group 
2. If primary tumor has not been resected, it must be clinically stable  
3. Must have colorectal cancer with unresectable metastatic disease to  
the liver (unresectable unilobar or bilobar disease) who have disease 
progression in the liver  with oxaliplatin or irinotecan based first-line 
chemotherapy;  
4. Must be eligible to receive second-line standard-of-care 
chemotherapy with either: 1) an oxaliplatin-based chemotherapy 
regimen, or 2) an irinotecan-based chemotherapy regimen  
5. Must have baseline efficacy images with measurable target tumors in 
the liver according to RECIST 1.1 using standard imaging techniques 
taken within 28 days prior to randomization. Images must be taken 
after, or at the time of completion of first line chemotherapy  
6. Tumor replacement <50% of total liver volume  
7. Current Eastern Cooperative Oncology Group (ECOG) Performance 
Status score of 0-1 through screening to first treatment on study 
8. Will have completed the first line chemotherapy regimen at least 14 
days prior to the initiation of 2nd line chemotherapy under the 
protocol 
9. Patient is willing to participate in the study and has signed the study 
informed consent 
10. Serum creatinine <2.0 mg/dL 
11. Serum bilirubin up to 1.2 x upper limit of normal 
12. Albumin >3.0 g/dL 
13. Must not have a history of hepatic encephalopathy 
14. Must not have any contraindications to angiography and selective 
visceral catheterization such as bleeding diathesis or coagulopathy 
that is not correctable by usual therapy of hemostatic agents (e.g. 
closure device) 
15. No history of severe peripheral allergy or intolerance to contrast 
agents, narcotics, sedatives or atropine that cannot be managed 
medically 
16. Must have neutrophil count >1200/mm3 (1.2x109/L) 
17. No presentation of pulmonary insufficiency or clinically evident 
chronic obstructive pulmonary disease 
18. No cirrhosis or portal hypertension 
19. Must not have received any prior external beam radiation treatment 
to the liver  
20. Must not have received any prior intra-arterial liver-directed therapy, 
including TACE or Y-90 microsphere therapy   

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21. Must not have any planned liver-directed therapy or radiation therapy 
22. Must not have planned treatment with biological agents within 28 
days prior to receiving TheraSphere  
23. Must not have undergone any intervention for, or compromise of, the 
Ampulla of Vater 
24. Must not have any clinically evident ascites (trace ascites on imaging is 
acceptable) 
25. Must not have any toxicities due to prior cancer therapy that have not 
resolved before the initiation of study treatment,  if the Investigator 
determines that the continuing complication will compromise the safe 
treatment of the patient  
26. Must not have any significant life-threatening extra-hepatic disease, 
including patients who are on dialysis, have unresolved diarrhea, have 
serious unresolved infections including patients who are known to be  
HIV positive or  have acute HBV or HCV 
27. Must not have any confirmed extra-hepatic metastases. Limited, 
indeterminate extra-hepatic lesions in the lung and/or lymph nodes 
are permitted (up to 5 lesions in the lung, with each individual lesion 
<1 cm; any number of lymph nodes with  each individual node <1.5 
cm) 
28. Must not have any contraindications to the planned second line 
standard-of-care chemotherapy regimen 
29. Women of childbearing potential must have a negative serum 
pregnancy test within 14 days prior to randomization, must not be 
breastfeeding, and must agree to use contraceptive for duration of 
study. 
30. Must not have participated in a clinical trial with an investigational 
therapy within 30 days prior to randomization 
31. Must not have any co-morbid disease or condition that would place 
the patient at undue risk and preclude safe use of TheraSphere 
treatment, in the Investigator’s judgment 
 
Imaging Requirements 
The primary efficacy endpoints progression free survival (PFS) and hepatic 
progression-free survival (HPFS), and secondary efficacy endpoint of disease 
control rate (DCR) will be based on imaging evidence of disease progression.  
Patients will have baseline images for disease assessment taken within 28 days 
prior to randomization and every 8 weeks from randomization (+/- 1 week) 
during the study to evaluate disease progression.  A confirmatory image at the 
next subsequent visit following progression is required  and may be scheduled 
outside of the 8-week window. In addition  to the confirmatory scan,  all 
images performed according to the local standard practices should be collected 
until hepatic progression is confirmed. These images do not have to conform to 
an 8-week schedule. All disease assessment images including the baseline 
images must be assessable according to RECIST 1.1. Baseline images conducted 
in the course of standard-of-care clinical management may be used if the 
images conform to RECIST 1.1 and are taken after, or at the time of completion 
of first line chemotherapy. All imaging studies from baseline to  progression 

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will require a duplicate set of images in DICOM format to be submitted to the 
sponsor for blinded independent central image review analysis.  
• 
CT scans for the assessment of liver metastases must include a portal 
venous phase  
• 
Spiral CT/MRI abdomen/pelvis –performed with cuts of 5 mm or less in 
slice thickness contiguously in the axial plane to assess hepatic and extra-
hepatic lesions according to the RECIST criteria v1.1. 
• 
Spiral CT/MRI Chest –performed with cuts of 5 mm or less in slice thickness 
contiguously in the axial plane to assess extra-hepatic lesions according to 
the RECIST criteria v 1.1. 
Other Variables 
Labs – Blood will need to be drawn for the following labs to test liver function 
and pregnancy as part of standard-of-care clinical management with results 
documented in the electronic case report form.  Progression of disease will be 
monitored through tumor markers:   
• 
Hematology (WBC with differential, Hgb, Hct, Platelet) 
• 
Coagulation (PT, PTT, INR) 
• 
Chemistry Panel, Liver function tests 
• 
Serum Pregnancy test (as appropriate)  
• 
CRC Tumor Marker: Serum CEA 
ECOG Performance Status  
Statistical Plan and 
Sample Size Calculation 
This study is an adaptive trial using a group sequential design with PFS and 
HPFS as the primary endpoints.  The study could be stopped early for efficacy 
at an interim analysis based on superiority in PFS but not HPFS.  
The study is designed to detect a 2.5 month increase in median PFS time, from 
6 months in the control arm to 8.5 months in the TheraSphere arm (ie, hazard 
ratio [HR]  = 0.71), and a 3.5 month increase in median HPFS time, from 6.5 
months in the control arm to 10 months in the TheraSphere arm (ie, HR = 
0.65), using log rank tests.   
The analysis of PFS will be based on a group sequential design with 2 interim 
analyses and rho family error spending function stopping boundary with 
rho=1.5. It is estimated that approximately 420 patients will need to be 
recruited over 36 months, with a 1 year additional follow-up period, allowing 
for 10% of patients lost to follow-up and for whom a date of progression or 
death is not recorded.  Although the forecasted accrual period has been 
increased to 60 months, this does not increase the number of patients 
required, or affect the statistical power of the study since both the power and 
the timing of the interim and final analyses are based on the number of PFS 
events rather than the number of patients.  The Hochberg procedure 
(Hochberg, 1988) will be used to control Type I error for the two primary 
endpoints at the final analysis.   
A simulation study, assuming that PFS and HPFS have a correlation between 
0.3 and 0.8, showed that the power to detect the target difference in either 
median PFS (ie, HR=0.71) or median HPFS (ie, HR=0.65) is >90%, and the power 

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to detect the target difference in PFS or HPFS alone is >80%.   The simulation 
study also demonstrated control of Type I error. 
Analysis of primary endpoints:  
PFS and HPFS will be compared between treatment arms using log-rank tests at 
an overall one-sided alpha level of 0.025, to test the null hypothesis that the 
hazard rates for the treatment and control arms are equal versus the 
alternative hypothesis that the hazard rate for the TheraSphere arm is less 
than the hazard rate for the control arm, ie,  
H0: λT = λC   versus H1:  λT < λC,  
where λT and λC represent the PFS or HPFS hazard rates for the TheraSphere 
and control arms respectively.  The hazard ratio and two-sided 95% confidence 
limits for the treatment effect will be computed.  Kaplan-Meier curves will also 
be produced.  Log rank tests converted to z-scores will be used to compare the 
primary endpoints between the treatment arms. 
Interim Analyses of primary endpoint of PFS:  
The first interim analysis is planned at 172 PFS events.  PFS will be compared 
between treatment arms using a log rank test converted to a z-score and 
compared to the nominal critical value of 2.372 based on the rho family error 
spending function corresponding to a one-sided p-value ≤0.0088 allowing the 
study to be stopped early for efficacy, in which case HPFS will be tested at the 
same boundary as PFS  using a log rank test converted to a z-score.  
A second interim analysis is planned at 241 PFS events, where PFS will be 
compared between treatment arms using a log rank test converted to a z-score 
and compared to the nominal critical value of 2.330 based on the rho family 
error spending function corresponding to a one-sided p-value ≤0.0099 allowing 
the study to be stopped early for efficacy.  If the study is stopped early for PFS 
at the second interim analysis, HPFS will be tested using the boundary derived 
based on an incremental alpha of 0.0057.  This boundary will account for the 
correlation between the z-score for HPFS at the first interim analysis and the z-
score for HPFS at the second interim analysis, which is determined by the 
observed number of HPFS events at the first interim analysis and the 
cumulative number of HPFS events observed at the second interim analysis.    
At each of the interim analyses, if the conditional power for both PFS and HPFS 
is less than 15% the study could be stopped early for futility. 
 
 
 

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Final Analysis of primary endpoints of PFS and HPFS:   
The final analysis is planned at 344 PFS events. The Hochberg procedure 
(Hochberg, 1988) will be used to control Type I error for the two primary 
endpoints.  Whichever of PFS or HPFS that has the larger p-value, will be 
compared between treatment arms using a log rank test converted to a z-score 
and compared to the nominal critical value of 2.312 with a corresponding one-
sided p-value ≤0.0104 required to declare a statistically significant 
improvement in hazard rate for this endpoint.  To ensure that Type I error is 
controlled for both primary endpoints, this boundary is based on the 
incremental alpha of 0.0104 instead of the p-value scale boundary of 0.0168, 
using the rho family error spending function with rho=1.5.  
According to the Hochberg procedure, if the primary endpoint with the larger 
p-value is statistically significant then the other primary endpoint is also 
statistically significant.  However, if the primary endpoint with the larger p-
value is not statistically significant then the other primary endpoint will be 
compared between treatment arms using a log rank test converted to a z-score 
and compared to the nominal critical value of 2.562 based on the rho family 
error spending function, with a corresponding one-sided p-value ≤0.0104/2 = 
0.0052 required to declare a statistically significant improvement in hazard rate 
for this endpoint.   
 
Analysis of secondary efficacy endpoints: Comparison between treatment 
groups for all secondary endpoints will be conducted at the final analysis at 
α=0.025 (one-sided), only if both of the primary endpoints are statistically 
significant, with study-wise Type I error controlled using a sequential 
hierarchical approach, according to the following ordering of secondary 
endpoints: OS→ TTSP→ORR→DCR→TTDQoL. 
Time to event endpoints (ie, OS, TTSP, TTDQoL) will be compared between 
treatment arms using a log-rank test.  Disease control rates and ORR will be 
compared between treatment arms using the continuity adjusted Newcombe-
Wilson test.  The FACT-c score will be compared between treatment arms using 
a mixed linear model with baseline score and the relative time from baseline as 
covariates. 
Safety Analysis: All patients who received study treatments at least once will be 
included in the safety analysis. All adverse events will be reported according to 
the NCI grades and coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of treatment emergent adverse events (events which 
were not present at baseline or worsened in severity following the start of 
treatment) will be summarized according to MedDRA primary system-organ 
class (SOC) and preferred term (PT). Laboratory values will be summarized by 
treatment group over time and overall.  
A feasibility safety assessment will be conducted after the first 20 patients in 

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the Treatment group have received both TS and chemotherapy. 
Poolability: As a sensitivity analysis, to address the poolability of data across 
regions, study sites and gender, a Cox regression analysis of the primary 
efficacy endpoints, PFS and HPFS, will be conducted including additional factors 
of region, study site and gender, and to determine the impact of these factors 
on PFS and HPFS.  If the poolability of PFS and HPFS results is in direct question 
as a result of this sensitivity analysis, the primary endpoints (PFS and HPFS) will 
also be analyzed separately by region, site or gender.  In addition, the primary 
endpoints (PFS and HPFS) will be analyzed separately by US and non-US region. 
Screening/Baseline 
Test Period  
Patients with colorectal cancer liver metastases who have progressed with a 
first line chemotherapy regimen (either oxaliplatin-based or irinotecan-based 
regimen), and are eligible for a standard-of-care second line regimen may be 
screened for inclusion into this study.  The baseline tests should be performed 
within 14 days prior to randomization. Results of tests conducted in the course 
of standard-of-care clinical management taken within the baseline period may 
be used.  
Evaluations include:  
• 
Baseline images for efficacy assessment will be taken within 28 days 
prior to randomization.  The baseline disease assessment images must 
also have been taken after, or at the time of completion of first line 
chemotherapy.  Baseline disease assessment images must have 
measurable target tumors in the liver and be assessable according to 
RECIST 1.1.  Informed Consent (before any study required tests are 
performed),  
• 
Physical examination,  
• 
Medical history,  
• 
ECOG assessment of performance status,  
• 
Quality of Life Questionnaire (FACT-C), 
• 
Laboratory blood tests, including serum CEA 
• 
Baseline chest/abdomen/pelvis images to assess liver tumor 
presentation and assess tumor burden 
Randomization  
Upon meeting eligibility for trial participation in accordance with the Eligibility 
criteria, patients will be randomized 1:1 between the Treatment and Control 
groups.  
Prior to randomization, the investigator will decide which chemotherapy 
regimen, including drugs, doses and biological agents, is to be given as second-
line treatment. This planned treatment is to be administered regardless of the 
arm to which the patient is randomized (Control or Treatment). The only 
exception being that the addition of biological agents for those randomized to 
the Treatment Group may only begin with the chemotherapy cycle following 
the treatment with TheraSphere. 
In order to ensure that the treatment groups are balanced, patients will be 
stratified at randomization according to; the presence of unilobar or bilobar 
disease; oxaliplatin or irinotecan based first-line chemotherapy; and KRAS 

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status.  
Patients randomized to the Control group or the Treatment group who are 
unable to receive their planned study treatment will continue to be followed 
under their assigned study group for the purpose of the intent-to-treat 
analysis. 
The date of screening is the date all screening procedures are completed. 
Initiation of Study 
Treatment and Early 
Treatment Cycles 
The chemotherapy regimen, including dose and type of biological agent, must 
be decided and documented prior to randomization. 
Patients randomized to the Control group must begin standard-of-care second-
line chemotherapy within 21 days of randomization Biological agents can start 
along with the first cycle of second-line chemotherapy for patients randomized 
to the Control group. 
Patients randomized to the Treatment group must begin standard-of-care 
second-line chemotherapy within 21 days of randomization.  Biological agents 
can be added for patients randomized to the Treatment Group, a minimum of 
2 weeks (+/- 2 days) after the TheraSphere administration ( i.e. with the next 
cycle of the standard-of–care chemotherapy).   
TheraSphere 
Treatment Procedure 
For patients randomized to the Treatment group, hepatic angiography will be 
performed to assess hepatic vascular anatomy and tumor hypervascularity, 
followed by a 99mTc-MAA scan to rule-out gastrointestinal flow or unacceptable 
lung shunting.  Embolization may be performed, if necessary, to close off 
gastrointestinal flow. These evaluations should be scheduled as soon as 
possible after randomization, but TheraSphere treatment can only take place 
at least 28 days after the discontinuation of biological agents. 
Patients will not be eligible to receive TheraSphere infusion if the potential 
radiation dose to the lungs exceeds 30 Gy for a single treatment or cumulative 
50 Gy or embolization cannot be performed to effectively block GI blood flow 
from the hepatic arterial system. In this case, patients should continue with 
their planned standard-of-care second line chemotherapy treatment. 
In patients with bilobar disease, TheraSphere treatment should be 
administered to both lobes on the same day. In patients with unilobar disease, 
TheraSphere should be administered to the lobe where disease is present. The 
number of infusions required will be determined by the Investigator, based on 
the hepatic vascular anatomy. TheraSphere treatment can be performed in the 
inpatient or outpatient setting. 
Patients will receive a target dose of 120 ± 10% Gy of TheraSphere. An interval 
of two weeks  after the previous cycle of chemotherapy and two weeks before 
the next cycle is required.  
For patients randomized to the Treatment Group, subsequent TheraSphere 
administration to newly observed liver lesions following disease progression is 
permitted in patients who are amenable to further TheraSphere treatment. 
Second line 
Chemotherapy 
The chemotherapy regimen, including dose and type of biological agent, must 
be decided and documented prior to randomization. 
All randomized patients will follow their planned second-line treatment 
regimen until disease progression, death or intolerable toxicity in accordance 
with standard medical practice, including any adjustments to the planned 

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treatment doses and schedule for reasons of toxicity.  
Trial Visits and  
Follow-up  
• 
Screening and Randomization 
• 
Every 2 Weeks following randomization:  Patients return to the clinic for 
chemotherapy administration and safety assessment.  Visit activities 
include standard-of-care clinical management laboratory evaluations, 
performance status, recording and assessment of adverse events, and 
administration of chemotherapy.   
• 
Every 8 Weeks following randomization until hepatic progression:  imaging 
for disease assessment (see above) 
• 
Every  8 Weeks following progression until death or end of study: clinic 
visits for safety assessment 
Central Image Review 
CT/MRI images will be reviewed centrally prior to the interim and final 
analyses.  The central image reader will be qualified by training and experience.  
The analysis for the interim and final reports will be based upon the readings of 
the central reviewer.  In cases of dispute between the site and the central 
reviewer, the central reviewer will prevail. 
Independent Data 
Monitoring Committee 
This study will have oversight by an Independent Data Monitoring Committee 
(IDMC) who will meet as determined to review the enrollment, protocol 
deviations, and safety events.  They will evaluate the data at interim analyses 
for consideration of stopping the study for overwhelming efficacy or futility. 
The IDMC will evaluate the final study report. 

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2. TRIAL SCHEMA 
Treatment Arm 
Control Arm 
Patients with 
metastatic CRC of 
the liver  
14 day screening period   
Randomization (Takes place ≥14 days from end of 1st 
line CTX and biological agent) 
 
Study Visit Q 8 
weeks until 
progression 
Study Visit 
Q 8 weeks 
until death 
or end of 
study 
Hepatic Progression: 
Best Alternative Care 
Continue 2nd 
line CTX 
Initiate 2nd line CTX ≥14 days from 
last administration of all first line 
agents 
 
Initiate 2nd line CTX ≥14 days from 
last administration of all first line 
agents 
Primary 
Endpoints 
PFS and HPFS
Secondary Endpoint OS 
Administer TS to both lobes (pts with bilobar 
disease) or single lobe (pts with unilobar disease) 
on the same treatment day in place of  2nd cycle of 
chemo. 
Hepatic Progression: 
Subsequent TS work-up and 
administration  
TS treatment replaces 1 cycle 
of  CTX; biological agent 
washout required 
Legend 
CTX: chemotherapy  
CRC: colorectal cancer 
HPFS: Hepatic Progression Free Survival 
OS: Overall Survival 
PFS: Progression Free Survival 
Pts: patients 
TS: TheraSphere 
*Note –one cycle of chemotherapy is given prior to treatment with TheraSphere. 

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3. SCHEDULE OF EVENTS 
Evaluation/Test 
 
 
Timing of Visit(s) 
Screen 
 
 
 
 
Day 
-14 to 
0 
Rand-
omize 
 
 
 
Study 
Day 0 
Chemo-
therapy 
 
 
 
Q 2  
1st TS work 
up & 
Admin-
istration 
 
(replaces 
second cycle) 
Study Visits 
to Progress-
ion 
 
 
Q 8 weeks from  
randomization 
(+/- 1 week) 
Additional 
TS work up  
& Admin-
istration 
 
Post hepatic 
progression, 
TS Replaces a 
cycle of 
chemo 
Study 
Visits  
Until 
Death or 
End of 
Study 
 
Q 8 weeks 
(+/- 1 
week) 
Informed Consent 
x 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Physical Exam (PE) 
x 
 
 
 
 
 
 
ECOG Performance 
Status 
x 
 
x7 
x 
x 
x 
x7 
Medication & Prior 
Treatment History 
x 
 
 
 
 
 
 
Review Eligibility 
Criteria 
x 
 
 
 
 
 
 
Hematology:  WBC 
with Diff Hgb, Hct, 
platelet 
x 
 
x 
 
x 
x 
 
Coagulation:  PT, PTT, 
INR 
x 
 
x1 
 
 
x 
 
Chemistry panel, liver 
function tests 
x 
 
x 
 
x 
x 
 
Serum Pregnancy2 
x 
 
 
x 
 
x 
 
Tumor markers for 
CRC (CEA) 
x 
 
 
 
x 
 
 
Liver Volume/Mass 
Calculation 
 
 
 
x 
 
x 
 
Estimation of Tumor 
Burden3 
x 
 
 
 
 
 
 
                                                                
1 Only required at chemo visits as clinically indicated (i.e. if patient is being followed for coagulopathy) 
2   Required for female patients of childbearing potential 
3  Required for Screening Purposes, may be visual or volumetric assessment 
4 TS patients only 
5All randomized patients: all patients must receive a study treatment (Chemo) within 21 days of randomization 

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Evaluation/Test 
 
 
Timing of Visit(s) 
Screen 
 
 
 
 
Day 
-14 to 
0 
Rand-
omize 
 
 
 
Study 
Day 0 
Chemo-
therapy 
 
 
 
Q 2  
1st TS work 
up & 
Admin-
istration 
 
(replaces 
second cycle) 
Study Visits 
to Progress-
ion 
 
 
Q 8 weeks from  
randomization 
(+/- 1 week) 
Additional 
TS work up  
& Admin-
istration 
 
Post hepatic 
progression, 
TS Replaces a 
cycle of 
chemo 
Study 
Visits  
Until 
Death or 
End of 
Study 
 
Q 8 weeks 
(+/- 1 
week) 
Documentation of 
Type and dose of 
chemo and biologics 
x 
 
 
 
 
 
 
Randomize Patient 
 
x 
 
 
 
 
 
Hepatic Angiogram, 
99mTc-MAA scan, TS 
Dose Calculation 
 
 
 
x 
 
x 
 
Order TS4 
  
  
  
x 
  
x 
  
Administer TS 4 
  
  
  
x 
  
x 
  
Administer  2nd line 
Chemotherapy2 
  
  
x 
  
  
  
 
Record/Administer 
any Chemotherapy 
following 2nd line5 
  
  
  
  
 
  
x 
QOL questionnaire 
x 
  
  
  
x 
 
 x7 
Spiral CT /MRI of 
abdomen/pelvis/chest
8 
x 
  
  
  
x 
 x 
  
Assess/Report Adverse 
Events 
 
  
x 
x 
x 
x 
x 
Review/Record 
Concurrent 
Medication 
x 
 
x 
x 
x 
x 
x 
Final Endpoint 
Efficacy/Safety 
documentation  & exit 
patient 
  
 
  
  
 
  
x 
                                                                
6 Additional approved chemotherapy for CRC may be administered only after progression of 2nd line chemotherapy 
7Can be done remotely if patient is not coming in for clinic visit 
8 all attempts should be made to image every 8 weeks until hepatic progression, plus confirmatory scan (see main 
text) 

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4. LIST OF ABBREVIATIONS 
AE - Adverse Event 
ALT – Alanine Transaminase 
AST – Aspartate Transaminase 
BUN – Blood Urea Nitrogen 
CBC – Complete Blood Count 
CEA – Carcinoembryonic Antigen – CRC tumor marker 
CRC – Colorectal Cancer 
Cr - Chromium 
CT – Computed Tomography 
CTCAE – Common Toxicity Criteria for Adverse Events 
DCR – Disease Control Rate 
DSMB – Data Safety Monitoring Board 
ECOG – Eastern Cooperative Oncology Group 
eCRF – Electronic Case Report Form 
EGFR – Epidermal Growth Factor Receptor 
FACT-c – Functional Assessment of Cancer Therapy - colorectal 
FDA – Food and Drug Administration (United States) 
FOLFIRI – irinotecan-based chemotherapy  
FOLFOX – oxaliplatin-based chemotherapy 
GBq - GigaBecquerel 
GI – Gastrointestinal 
Gy – Gray, a measure of irradiation dose 
HCC – Hepatocellular Carcinoma 
HDE – Humanitarian Device Exemption 
HPFS – Hepatic Progression Free Survival 
ICF – Informed Consent Form 
IDMC – Independent Data Monitoring Committee 
INR – International Normalized Ratio for prothrombin time 
IRB – Institutional Review Board 

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ITT – Intent–to-Treat 
KRAS - V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LFT – Liver Function Tests 
mCRC – metastatic colorectal carcinoma 
MR, MRI – Magnetic Resonance, Magnetic Resonance Image 
NCCN – National Comprehensive Cancer Network (United States) 
NCI – National Cancer Institute 
ORR – Objective Response Rate 
OS – Overall Survival 
QoL – Quality of Life 
PE – Physical Exam 
PFS – Progression Free Survival 
PP-Per Protocol 
PT - Prothrombin Time 
PTT – Partial Thromboplastin Time 
RECIST – Response Evaluation Criteria in Solid Tumor 
SAE – Serious Adverse Event 
SOC – Standard of Care 
99mTc-MAA – Technetium-99m Magroaggregated albumin 
TS - TheraSphere 
TTP – Time-to-Progression 
TTSP- Time to symptomatic progression 
UADE – Unanticipated Adverse Device Effect 
UPFS – Untreatable Progression-Free Survival 
VEGF inhibitor – Vascular Endothelial Growth Factor inhibitor 
WBC – White Blood Cells 
Y-90 (Y-88, Y-91) – Ytrium-90 and isotopes 
 
 

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5. BACKGROUND AND RATIONALE 
5.1 GENERAL DEVICE DESCRIPTION 
TheraSphere® (TS) consists of insoluble glass microspheres in which yttrium-90 (Y-90) is an integral 
component of the glass. The sphere diameter ranges from 20 to 30 µm with 22,000 to 73,000 
microspheres per milligram. TheraSphere is available in dose sizes ranging from 3 to 20 GBq 
(typically 3 GBq, 5 GBq, 7 GBq, 10 GBq, 15 GBq and 20 GBq) each supplied in 0.6 mL of sterile, 
pyrogen-free water contained in a 1.0 mL vial secured within a clear acrylic vial shield. A pre-
assembled single-use TheraSphere Administration Set is provided for each dose. Each user site is 
provided with a re-useable TheraSphere Administration Accessory Kit that provides both radiation 
protection for the user and physical support of the dose vial and Administration Set during 
administration of the product. 
Yttrium-90 is a pure beta emitter which decays to stable zirconium-90 with a physical half-life of 
64.1 hours. The average energy of the beta emissions from yttrium-90 is 0.9367 MeV with mean 
tissue penetration of approximately 2.5 mm.  
TheraSphere is administered through the hepatic artery which supplies blood to tumor tissue (the 
portal vein supplies blood to the normal hepatic tissue). The microspheres are trapped in the 
vasculature of the tumor due to arteriolar capillary blockage where they exert a local 
radiotherapeutic effect. In clinical use, the glass microspheres remain permanently trapped in the 
vasculature where the isotope decays to infinity leaving background radiation with no therapeutic 
value.  
5.2 GLOBAL REGULATORY STATUS OF THERASPHERE 
TheraSphere received a Humanitarian Device Exemption (HDE) from the United States Food and 
Drug Administration (FDA) in 1999 (HDE H980006) and is currently approved for use in radiation 
treatment or as a neoadjuvant to surgery or transplantation in patients with unresectable 
hepatocellular carcinoma (HCC) who can have placement of appropriately positioned hepatic 
arterial catheters. The device is also indicated for HCC patients with partial or branch portal vein 
thrombosis/occlusion, when clinical evaluation warrants the treatment. The current package insert 
approved by the United States Food and Drug Administration (FDA) is provided in Appendix 1a. 
TheraSphere is approved for use in Europe for the treatment of hepatic neoplasia. TheraSphere is 
approved in Canada for the treatment of hepatic neoplasia in patients who have appropriately 
positioned arterial catheters. In addition, TheraSphere is available in South Africa, Turkey, Saudi 
Arabia, Singapore, Hong Kong and South Korea for the treatment of hepatic neoplasia. The current 
package inserts from Canada and Europe are provided in Appendix 1b and 1c respectively. 
5.3 US CLINICAL EXPERIENCE WITH THERASPHERE IN PATIENTS WITH 
METASTATIC LIVER CANCER 
Since 2004, more than 500 patients in the United States with metastatic liver cancer have been 
treated with TheraSphere under a named-patient compassionate use process.  This program was 
terminated in late 2009.  As of October 2009, follow-up information for more than 400 patients in 

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this program has been reported to the FDA with data for a subset of more than 190 patients 
published in the literature.  
In addition, an open-label, single group, Phase II clinical trial in patients with metastatic liver cancer 
was initiated in 2007.  The primary outcome measure of this Phase II study was safety.  Enrollment 
in this study was completed at 151 patients.  The last patient exited this study on March 30th 2011 
and the data was submitted to the FDA as part of a Clinical Study Report in September 2011. The 
safety results from this Phase II trial are consistent with those reported under the named-patient 
compassionate use program and include fatigue, pain, nausea/vomiting and transient laboratory 
abnormalities.  
Early reports of serious adverse events possibly associated with the use of TheraSphere included 
death, hepatorenal failure, liver abscess, hepatic encephalopathy, hepatic decompensation, 
radiation hepatitis, radiation pneumonitis, duodenal ulcer, gastrointestinal bleeding and 
cholecystitis. As clinical experience with TheraSphere increased, the pre-treatment risk factors 
associated with these early serious adverse events were identified, leading to improved patient 
selection criteria, and thereby lowering the risk of these events occurring. Patients in whom 
TheraSphere should be used with caution include those with infiltrative tumor type, bulk disease 
(tumor volume >70% or nodules too numerous to count), AST (aspartate transaminase) or ALT 
(alanine transaminase) > five times the upper limit of normal, bilirubin > 2 mg/dL, tumor volume 
>50% in the presence of an albumin < 3 g/dL and those in whom extra-hepatic shunting to the 
lungs or gastrointestinal tract cannot be managed through standard angiographic techniques. 
For those patients without the pre-treatment high risk factors noted above, TheraSphere is very 
well tolerated, with treatment administered in an outpatient setting. Hospitalization for treatment 
effects is rarely required. The most commonly reported adverse events associated with 
TheraSphere are fatigue, abdominal pain, nausea/vomiting and transient laboratory values 
including elevated bilirubin, AST, ALT, alkaline phosphatase, decreased platelets and lymphocyte 
depression with no clinical sequelae. 
5.4 RATIONALE FOR TREATMENT OF LIVER METASTASES SECONDARY TO 
COLORECTAL CANCER 
Colorectal cancer (CRC) is the third most common cancer diagnosed among both men and women 
in the US. The American Cancer Society1 estimates that approximately 148,810 new cases of 
colorectal cancer and 49,960 deaths were expected in 2008. Approximately 72% of new diagnoses 
are colon cancer and 28% are rectal cancer.  
Because the liver is the most frequent site of metastases, an estimated 60% of patients who are 
diagnosed with CRC eventually will experience liver disease as a predominant site2. Consequently, 
much of the morbidity and mortality in patients with CRC3 is due to unresectable liver metastases. 
A median overall survival of 44 months and a 5-year survival rate of 35%4 are associated with 
surgical resection of liver-confined disease for patients with no evidence of disseminated disease 
with a resection strategy encompassing all liver disease with adequate remnant liver for recovery 
and medical fitness for laparotomy. However, patients who have liver metastases amenable to 
resection are less than 20% of the population with metastatic liver disease5, a rate that may 
improve with current chemotherapy. For the majority of patients without resectable disease, the 

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median overall survival is 22 months and rarely is associated with survival beyond 5 years6.  
Targeted non-surgical approaches for liver-confined CRC metastases may offer survival advantages 
beyond that of systemic therapy alone.  
TheraSphere was evaluated in a cohort of seventy-two patients7 with unresectable hepatic 
colorectal metastases who were treated at a targeted absorbed dose of 120 Gy with a median 
delivered dose of 118 Gy. The safety and toxicity of TheraSphere was assessed using version 3 of 
the National Cancer Institute Common Terminology Criteria. Response was assessed radio-
graphically and survival estimated using the Kaplan-Meier method from the diagnosis of hepatic 
metastases and first treatment. Treatment-related toxicities included fatigue (61%), nausea (21%), 
and abdominal pain (25%) with Grade 3 and 4 bilirubin toxicities observed in 9 of 72 patients 
(12.6%). The tumor response rate was 40.3%. The median time to hepatic progression was 15.4 
months, and the median response duration was 15 months. Overall survival from the first 
TheraSphere treatment was 14.5 months. Based on sub-stratification analyses, tumor replacement 
(≤25% vs >25%) was associated with significantly greater median survival (18.7 months vs 5.2 
months). The presence of extrahepatic disease was associated negatively with overall survival (7.9 
months vs 21 months). Overall survival from the date of initial hepatic metastases was 34.6 
months. A subset analysis of patients who had an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 demonstrated a median survival of 42.8 months and 23.5 months from 
the time of hepatic metastases and TheraSphere treatment, respectively.  The data from this study 
also suggests that patients who have been exposed to fewer than three cytotoxic agents may have 
a better outcome than patients who have received all chemotherapy options prior to treatment 
with TheraSphere.   
Based on the subset analyses of this study, it appears patients with good performance status, no 
extrahepatic metastases, liver disease limited to ≤25% of liver volume, who have not received all 
available lines of chemotherapy may benefit most from treatment with TheraSphere.  We 
therefore propose to evaluate the outcome of these patients when TheraSphere is added to 
second line standard-of-care chemotherapy.  
The most recent National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in 
Oncology8(NCCN - Colon Cancer V.3.2015 - COL-C – Appendix 3) note that current 
chemotherapeutic options for the treatment of colorectal cancer, may include but are not limited 
to, fluoropyrimidines, irinotecan, oxaliplatin, tyrosine kinase inhibitors, as well as vascular 
endothelial growth factor- and epidermal growth factor-targeting agents. Section COL-7 of these 
guidelines recommends the various combinations of these agents that should be used in the first 
or second line treatment of colorectal cancer.  Typically, patients with metastatic colorectal cancer 
are treated with either an Oxaliplatin or Irinotecan based regimen as first line chemotherapy, with 
or without the addition of bevacizumab, cetuximab or panitumumab.  On progression, patients are 
treated with the regimen they did not receive during first line chemotherapy. Epidermal growth 
factor receptor (EGFR) inhibitors may be added in patients with wildtype KRAS (V-Ki-ras2 Kirsten 
rat sarcoma viral oncogene homolog).  
The result of a recent Phase III clinical trial demonstrated that continuing treatment with 
bevacizumab into second line chemotherapy results in improvements in both PFS and overall 
survival, as compared to second line chemotherapy alone, if the patient progressed while receiving 
a bevacizumab containing regimen during first line chemotherapy. 9 

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A radioembolization device similar to TheraSphere but composed of resin microspheres has also 
been evaluated in the treatment of metastatic colorectal cancer. Jakobs10 et al confirmed the mild 
to moderate toxicity profile of Y-90 microsphere radioembolization when they reported no severe 
toxicities, except for one grade 4 treatment-associated cholecystitis and two grade 2 gastric ulcers, 
using resin-microsphere radioembolization administered as single-session, whole liver treatment in 
41 patients with metastatic colorectal cancer refractory to chemotherapy.  In dose escalation 
studies reporting use of the resin microspheres in combination with oxaliplatin11 based 
chemotherapy and in combination with irinotecan12 based chemotherapy, the authors concluded 
respectively that the maximum-tolerated dose of oxaliplatin was 60 mg/m2 during the first three 
cycles of chemotherapy and a maximum-tolerated dose of irinotecan was not reached. In both 
trials, radioembolization treatment was administered within a cycle of chemotherapy with the 
majority of patients experiencing mild to moderate transient toxicities.   
In this clinical trial, TheraSphere will be administered in place of the second cycle of 
chemotherapy, ensuring a 2 week period between the radioembolization and chemotherapy. 
In this clinical trial, patients with metastatic colorectal cancer and liver only metastases in whom 
second line chemotherapy treatment is planned using either an oxaliplatin-based or irinotecan-
based chemotherapy regimen, will be randomized (1:1) to either the Treatment Group, where 
TheraSphere will be administered in place of the second cycle of the planned standard-of care-
second line chemotherapy, or the Control Group, where patients will be treated with only their 
planned standard-of-care second line chemotherapy. Patients in both groups must receive a study 
treatment, either chemotherapy or TheraSphere, within 21 days of randomization. 
One of the primary endpoints for this clinical trial is progression free survival (PFS).  The outcome 
assumptions in the Control group are from the Phase III study13 that investigated second-line 
FOLFIRI (5-fluorouracil, leucovorin and irinotecan) with or without panitumumab in 1,186 
metastatic colorectal cancer patients.   
This study met its primary endpoint, with the addition of panitumumab to FOLFIRI showing a 
statistically significant increased progression-free survival in wild-type KRAS patients of 5.9 months 
versus 3.9 months for FOLFIRI alone (p=0.004). Panitumumab also resulted in slightly longer  
overall survival in wild-type KRAS patients with 14.5 months in comparison with 12.5 months for 
chemotherapy alone (p=0.115), although this was not statistically significant. Overall response rate 
was higher in the panitumumab arm at 35% compared with 10% in the chemotherapy alone arm.  
In contrast, between the two treatment arms for mutant KRAS, there was only a negligible 
difference in progression-free survival (5.0 months for panitumumab versus 4.9 months for 
chemotherapy alone), overall survival (11.8 months for panitumumab versus 11.0 months for 
chemotherapy alone).  There is a wide variation in the outcomes14,15 reported with second line 
chemotherapy in metastatic colorectal cancer, and outcomes in patients with liver only metastases 
have not been reported.   
We have also taken into consideration the recent Phase III trial data by Arnold et al, demonstrating 
a significant improvement in PFS and overall survival when bevacizumab treatment is continued 
into second line chemotherapy.  In the Arnold study, the median PFS was 5.7 months in patients 
who progressed on a bevacizumab containing regimen in first line chemotherapy and continued 
with bevacizumab in combination with their second line chemotherapy regimen as compared to a 

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median PFS of 4.1 months in patients who continued into second line chemotherapy without 
bevacizumab.11   
For our proposed trial, we assume a median PFS of 6 months in the control group, and 8.5 in the 
treatment group (hazard ratio [HR]=0.71).    We also assume a median hepatic PFS (HPFS) of 6.5 
months in the control group and 10 months in the treatment group (HR=0.65).  The assumption of 
a median HPFS of 10 months in the treatment group is based on a median HPFS of 9.2 months in a 
study of 23 patients who received second line yttrium-90 resin microspheres16. 
6. STUDY OBJECTIVE  
The objective of this study is to evaluate the efficacy and safety of TheraSphere in the treatment of 
patients with metastatic colorectal cancer of the liver.  
7. STUDY DESIGN 
This is an open-label, prospective, multi-center, randomized, clinical trial. 
Patients with metastatic colorectal carcinoma of the liver, who have disease progression with first line 
chemotherapy, and in whom the administration of standard-of-care second line chemotherapy with 
either an oxaliplatin-based regimen, or an irinotecan-based regimen is planned, are eligible to participate.  
Most patients receive an oxaliplatin-based regimen during first line chemotherapy, therefore it is 
expected most patients will be receiving an irinotecan-based regimen as their standard-of-care second 
line regimen while they participate in this trial.  However some patients are expected to receive an 
oxaliplatin-based regimen as their second-line regimen. 
Prior to randomization the investigator will decide which chemotherapy regimen, including drugs, doses 
and type of biological agent is to be given as part of the second line treatment.  This planned treatment is 
to be administered regardless of the treatment arm to which the patient is randomized (control or 
treatment).  The only exception being that the addition of biological therapy for those randomized to the 
Treatment Group may only begin at the chemotherapy cycle following the treatment with TheraSphere. 
Eligible patients will be randomized (1:1) to either the Control Group or the Treatment Group, defined as 
follows:   
Treatment Group:  Patients randomized to the Treatment Group will be treated with TheraSphere 
administered in place of the second cycle of their standard-of-care second line chemotherapy regimen.    
Subsequent chemotherapy must not begin until a minimum of two weeks (+/- 2 days) after the 
TheraSphere has been administered. Treatment with first cycle of chemotherapy must begin within 21 
days of randomization. 
Control Group:  Patients randomized to the Control Group will receive only their planned standard-of-care 
second line chemotherapy regimen. Treatment with chemotherapy must begin within 21 days of 
randomization. 
The addition of approved biological agents (bevacizumab, cetuximab, panitumimab, aflibercept, 
ramucirumab) is permitted and should be administered at the investigator discretion per local practices, 
to the  approved targeted population per label.  Biological agents can be resumed for patients randomized 
to the Treatment Group 2 weeks after the TheraSphere administration (i.e. with cycle 2 of the standard-

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of-care chemotherapy).  Standard of care biological agents can start along with the first cycle of second 
line chemotherapy for patients randomized to the Control group. 
Patients will have regular clinical study visits as long as they participate in the trial.  During these visits, 
safety and efficacy data will be collected and recorded.   
The primary efficacy endpoints of the trial will be PFS and HPFS.  Once a patient has progressed, he/she 
will have reached the primary efficacy endpoints of the trial, but the patient will be encouraged to remain 
on the trial for evaluation of the secondary endpoint of survival.   
Following disease progression, patients in either group may receive the Best Alternative Therapy or Care 
for further treatment of their disease.  For patients randomized to the Treatment Group, TheraSphere will 
be provided to patients amenable to further treatment with TheraSphere.   
8. STUDY POPULATION AND ELIGIBILITY CRITERIA 
8.1 PATIENT POPULATION 
Patients with metastatic colorectal carcinoma (mCRC) to the liver who have disease progression with 
first line chemotherapy, either an oxaliplatin-based regimen or an irinotecan-based regimen and who 
are eligible for second line chemotherapy with the alternative chemotherapy regimen. 
8.2 ELIGIBILITY CRITERIA 
Patients must meet all of the following inclusion criteria: 
1. Must be a male or female, 18 years of age or older, and of any ethnic or racial group  
2. If primary tumor has not been resected, it must be clinically stable  
3. Must have colorectal cancer with unresectable metastatic disease to  the liver (unresectable 
unilobar or bilobar disease) who have disease progression in the liver with oxaliplatin or 
irinotecan based first line chemotherapy 
4. Must be eligible to receive second-line standard-of-care chemotherapy with either 1) an 
oxaliplatin-based chemotherapy regimen, or 2) an irinotecan-based chemotherapy regimen  
5. Must have baseline efficacy images with measurable target tumors in the liver according to 
RECIST 1.1 using standard imaging techniques taken within 28 days prior to randomization. , 
Images must be taken after, or at the time of completion of first line chemotherapy  
6. Tumor replacement <50% of total liver volume  
7. Current ECOG Performance Status score of 0-1 through screening to first treatment on study. 
8. Will have completed the first line chemotherapy regimen at least 14 days prior to the initiation of 
2nd line chemotherapy under the protocol 
9. Patient is willing to participate in the study and has signed the study informed consent. 
10. Serum creatinine <2.0 mg/dL 

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11. Serum bilirubin up to  1.2 x upper limit of normal 
12. Albumin >3.0 g/dL 
13. Must not have a  history of hepatic encephalopathy 
14. Must not have any contraindications to angiography and selective visceral catheterization such 
as bleeding diathesis or coagulopathy that is not correctable by usual therapy of hemostatic 
agents (e.g. closure device) 
15. No history of severe peripheral allergy or intolerance to contrast agents, narcotics, sedatives or 
atropine that cannot be managed medically 
16. Must have neutrophil count >1200/mm3 (1.2x109/L) 
17. No presentation of pulmonary insufficiency or clinically evident chronic obstructive pulmonary 
disease 
18. No cirrhosis or portal hypertension 
19. Must not have received prior external beam radiation treatment to the liver  
20. Must not have received any prior intra-arterial liver directed therapy, including TACE, or Y-90 
microsphere therapy  
21. Must not have any planned liver directed therapy or radiation therapy 
22. Must not have planned treatment with biological agents within 28 days prior to  receiving 
TheraSphere 
23. Must not have undergone any intervention for, or compromise of, the Ampulla of Vater 
24. Must not have any clinically evident ascites (trace ascites on imaging is acceptable) 
25. Must not have any toxicities due to prior cancer therapy that have not resolved before the 
initiation of study treatment, if the Investigator determines that the continuing complication will 
compromise the safe treatment of the patient 
26. Must not have any significant life-threatening extra-hepatic disease, including patients who are 
on dialysis, have unresolved diarrhea, have serious unresolved infections including patients who 
are known to be  HIV positive or have acute HBV or HCV 
27. Must not have any confirmed extra-hepatic metastases. Limited, indeterminate extra-hepatic 
lesions in the lung and/or lymph nodes are permitted (up to 5 lesions in the lung, with each 
individual lesion <1 cm; any number of lymph nodes  with each individual node <1.5 cm) 
28. Must not have any contraindications to the planned second line standard-of-care chemotherapy 
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29. Women of childbearing potential must have a negative serum pregnancy test within 14 days 
prior to randomization, and must not be breastfeeding; and must agree to use contraceptive for 
duration of study. 
30. Must not have participated in a clinical trial with an investigational therapy within 30 days prior 
to randomization 
31. Must not have any co-morbid disease or condition that would place the patient at undue risk and 
preclude the safe use of TheraSphere Treatment, in the investigator’s judgment   
9. STUDY VISITS, EVALUATIONS AND PROCEDURES 
9.1 STUDY VISITS 
Study treatment visits should occur at the time intervals outlined below and in the study visit 
schedule in Section 3. All study visits that take place after the screening/randomization period should 
occur within +/- 7 days of the designated time interval for that study visit. 
9.1.1 
SCREENING/RANDOMIZATION (DAYS -14 TO DAY 0) 
All screening and baseline evaluations must be completed within 14 days prior to 
randomization except for KRAS test results.  There is no time limit prior to randomization for 
KRAS test results. Results from standard-of-care tests and examinations taken within 14 days 
prior to randomization may be used to determine the patient’s eligibility. Baseline images for 
disease evaluation must have measurable target tumors in the liver according to RECIST 1.1, 
be taken within 28 days prior to randomization, and be taken after, or at the time of 
completion of first line chemotherapy. CT scans obtained for clinical management may be 
used as baseline disease assessment images if they conform to the image requirements of 
the protocol.  All patients must discontinue first line chemotherapy agents and VEGF 
inhibitors during the screening period. The following activities will be completed during the 
screening period within 14 days prior to randomization.   
1. Informed Consent must be signed, as described in Section_Informed_Consent 13.7. 
2. Patient demographic information will be collected, as described in Section 9.2.2. 
3. Patient Medical History information will be collected, as described in Section 9.2.3. 
4. A physical examination as described in Section 9.2.4 will be done. 
5. ECOG Performance Status will be assessed as described in Section 9.2.5. 
6. Medication history & Prior treatment history will be obtained as described in 
Section 9.2.6. 
7. The estimation of liver tumor burden (must be less than 50%) will be completed as 
described in Section 9.2.7. 
8. Baseline clinical laboratory tests including blood chemistry, hematology and 
coagulation tests as described in Section 9.2.8 will be done. 
9. A serum pregnancy test as described in Section 9.2.9 will be administered for all 
female patients of childbearing potential. 
10. The patient’s eligibility to participate will be assessed as described in Section 9.2.10. 
11. A baseline CEA level will be drawn. 
12. Baseline images for disease assessment (Spiral CT/MRI of abdomen/pelvis and 
Spiral CT/MRI of chest) will be taken as described in Section 9.2.15. 

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13. Baseline Quality of Life assessments will be completed as described in Section 
9.2.12. 
14. Documentation of the intended second line chemotherapy regimen, including the 
use of biological agents and dosage. 
 
Following Screening, patients meeting the eligibility criteria will be randomized as described 
in Section 9.2.13.  The date of screening is the date all screening procedures are complete. 
9.1.2 
Q2 WEEKS FOLLOWING RANDOMIZATION  
The following clinical patient management activities will be completed every 2 weeks until 
disease progression or discontinuation of chemotherapy and documented on the eCRF: 
1. Complete appropriate clinical laboratory tests, except CEA and coagulation unless 
clinically required, as described in Section 9.2.8. 
2. Assess ECOG Performance Status as described in Section 9.2.5. 
3. Administer Chemotherapy as described in Section 9.2.14.2. 
4. Record details on the clinical assessments and administration of Chemotherapy as 
described in Section 9.2.16. 
5. Record any concurrent medications and any adverse events as described in Section 
9.2.17 and 12.2. 
 
9.1.3 
Q 8 WEEKS FOLLOWING RANDOMIZATION UNTIL DISEASE PROGRESSION 
(+/- 1 WEEK) 
Every 8 weeks following randomization until determination of disease progression, the 
following evaluations will be completed in addition to the activities described in 9.1.2: 
1. Complete appropriate clinical laboratory tests, as described in Section 9.2.8. 
2. Assess ECOG Performance Status as described in Section 9.2.5. 
3. CT/MRI images will be taken for efficacy assessment as described in Section 9.2.15. 
4. Quality of Life assessments will be obtained as described in Section 9.2.12. 
5. CEA 
 
9.1.4 
VISITS Q 8 WEEKS FOLLOWING DISEASE PROGRESSION (+/- 1 WEEK) 
Patients should continue to be followed for overall survival following disease progression.  
Patients remaining on the protocol following disease progression optimally should be seen 
at least once every 8 weeks, with the following procedures typically conducted. For those 
patients who are unable to come in to the clinic for routine visits, sites should maintain 
telephone contact or follow-up until death or the end of the study. The following procedures 
should be performed as clinically indicated. 
1. Administer Chemotherapy as appropriate in Section 9.2.14.2.1. 
2. Record details on the clinical assessments and administration of Chemotherapy as 
described in section 9.2.16. 
3. Record any concurrent medications and any adverse events as described in Section 
9.2.16 and 12.2. 
4. Assess ECOG Performance Status as described in Section 9.2.5. 
5. CT/MRI images will be taken for disease assessment, as described in Section 9.2.15, 
to support clinical care. Images taken according to standard clinical practices should 
be collected until liver progression  
6. Quality of Life assessments will be obtained as described in Section 9.2.12. 

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9.1.5 
PATIENT COMPLETION OR EARLY WITHDRAWAL 
When a patient completes the trial or withdraws early, the following end of study 
assessments will be completed, as appropriate, at the time the patient exits the trial:  
1. Record the date and reason for study completion or withdrawal, as listed in Section 
9.2.18. 
2. ECOG status as described in Section 9.2.5. 
3. Record any concurrent medications and any adverse events as described in Section 
9.2.17 and 12.2. 
4. CT/MRI images are taken, if appropriate, as described in Section 9.2.15. 
5. Quality of Life assessments will be taken as appropriate, as described in Section 
9.2.12. 
9.2  STUDY EVALUATIONS AND PROCEDURES 
9.2.1 
POTENTIALLY ELIGIBLE PATIENTS AND INFORMED CONSENT 
Any patient who appears to meet the eligibility criteria may be offered the opportunity to be 
evaluated for participation in this clinical trial. All such patients must sign an IRB approved 
informed consent form, and have the opportunity to ask the Investigator any questions 
regarding the trial and their rights and obligations as a trial participant before any protocol 
related evaluations can be performed. The details regarding informed consent are described 
in Section 13.7. 
9.2.2 
DEMOGRAPHICS 
Demographic data (date of birth, age, gender, childbearing potential, race, and ethnicity) will 
be obtained.  
9.2.3 
MEDICAL HISTORY 
Medical history deemed clinically significant by the Investigator will be collected per body 
system (allergy/immunology, auditory/ear, blood/bone marrow, cardiac arrhythmia, cardiac 
general, dermatology/skin, endocrine metabolic, gastrointestinal, hemorrhage/bleeding, 
Hepatobiliary/pancreatic, infection, musculoskeletal/soft tissue, neurologic, ocular/vision, 
psychiatric, pulmonary/upper respiratory, renal/genitourinary, sexual reproductive function, 
vascular). 
Diagnoses and medical history for colorectal cancer will be recorded separately from other 
medical history. 
All on-going medical conditions and adverse events arising from treatment of those 
conditions present for ≥ 30 days are generally considered a part of the patient’s medical 
history and must be recorded at baseline. 
9.2.4 
PHYSICAL EXAMINATION 
A physical examination will also be performed, which will cover the following: 
• 
Vital signs:  heart rate (HR), respiratory rate (RR), blood pressure (BP), and temperature 
(T) 

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• 
Height and weight 
• 
Head, eyes, ears, nose, and throat 
• 
Chest 
• 
Heart 
• 
Abdomen 
• 
Extremities 
• 
Brief neurological examination (level of consciousness, orientation, sensation, and 
motor function) 
• 
Genitourinary, endocrine and allergy/immunology systems 
 
9.2.5 
ECOG PERFORMANCE STATUS 
ECOG Performance Status17 will be assessed according to the following categories: 
Score 
Characteristics 
0 
Asymptomatic and fully active 
1 
Symptomatic; fully ambulatory; restricted in physically 
strenuous activity 
2 
Symptomatic; ambulatory; capable of self-care; more 
than 50% of waking hours are spent out of bed. 
3 
Symptomatic; limited self-care; more than 50% of 
waking hours are spent in bed 
4 
Completely disabled; no self-care; bedridden. 
 
ECOG assessments may be performed remotely for those patients receiving chemotherapy 
outside of the clinical study site and for those patients unable to come into clinic every 8 
weeks following progression. 
9.2.6 
MEDICATION AND PRIOR TREATMENT HISTORY 
The use of concurrent medications (medications taken within 30 days of screening and 
during the conduct of the study) will be obtained and documented on the relevant case 
report forms.  
Prior treatments for colorectal cancer will be recorded separately from treatments for other 
medical conditions.   
The start and stop dates for all such prior treatments for CRC or other cancer treatments as 
well as prior treatment of other medical conditions should be recorded.  
9.2.7 
LIVER TUMOR VOLUME DETERMINATION 
CT scans for the assessment of liver metastases- must include a portal venous phase. 
Accurate imaging and volume calculation are essential for calculation of TheraSphere 
dosimetry.   

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Using institutional standard equipment and techniques, lobar and tumor regions of interest 
will be drawn and the respective lobar and tumor volumes determined (a detailed discussion 
begins on page 1259 in Appendix 2).  
Tumor replacement, expressed as a per cent of total liver volume, must not exceed 50%. This 
may be done based on standard practice at the clinical site for assessment (either visual or 
volumetric assessment).  
9.2.8 
CLINICAL LABS 
The following clinical laboratory assessments will be completed at specified study visits 
during the trial. Laboratory assessments undertaken as part of standard-of-care clinical 
assessment may be used. 
• 
Hematology /coagulation panel: white blood cell (WBC) count with differential, 
platelet count, hematocrit, hemoglobin,  
• 
Coagulation: Prothrombin Time (PT), Partial Thromboplastin Time (PTT), 
International Normalized Ratio for prothrombin time (INR) 
• 
Chemistry panel: serum creatinine, blood urea nitrogen (BUN), glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), albumin, total bilirubin, 
and alkaline phosphatase. 
• 
Serum CEA 
9.2.9 
PREGNANCY TEST 
A serum pregnancy test for females of child-bearing potential will be performed at the 
screening visit and prior to any subsequent TheraSphere administration.  Patients 
determined to be pregnant are not eligible to participate in this clinical trial. 
Female patients of childbearing potential must be advised that they should not become 
pregnant while participating in this clinical trial. Adequate methods of contraception must 
be used by these patients while they are enrolled in this clinical trial. Patients should not be 
breastfeeding while participating on this trial. 
9.2.10 
REVIEW ELIGIBILITY CRITERIA 
Data detailing Demographic, Medical History, Physical Examination, ECOG Performance 
Status, Medication and Prior Oncologic Treatment, Tumor and Liver volume and Clinical Labs 
will be reviewed against eligibility criteria to determine eligibility. The determination will be 
recorded on the relevant case report form (eCRF). 
9.2.11 
CRC TUMOR BIOMARKERS 
Blood will be collected at the institution prior to and at visits following randomization to 
determine the baseline and subsequent CEA values.  
The date and results of the KRAS status will be recorded on the relevant eCRF during the 
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9.2.12 
QUALITY OF LIFE 
A Quality of Life (QOL) instrument suitable for patients being treated for metastatic 
colorectal cancer (FACT-c) will be administered at study visits every 8 weeks until 
progression then every 8 weeks throughout the trial. The baseline QOL assessment will be 
obtained after the Informed Consent is signed and before the first cycle of chemotherapy is 
administered. 
QOL assessments may be performed remotely for those patients unable or unwilling to come 
into clinic every 8 weeks following progression. 
9.2.13 
RANDOMIZATION (STUDY DAY 0) 
Patients will be randomized 1:1 to study treatment, either the Control group or the Study 
Treatment group.  Approximately 210 patients will be randomized to each protocol group.  
The date of screening is the date that all screening procedures are complete. 
If a patient is determined to be eligible to participate in the trial, the study site will contact 
the central randomization office where randomization will be determined using assignment 
by a computer-generated randomization scheme.  Upon randomization, each patient will be 
assigned a subject identity code consisting of the protocol number, the country code (e.g. 
01), the site number (e.g. 01) and a patient number (e.g. 001).   
In order to ensure that the study treatment groups are balanced, patients will be stratified at 
randomization based on the following:  
• 
Unilobar vs bilobar disease 
• 
Oxaliplatin vs Irinotecan based first-line chemotherapy 
• 
KRAS status (wildtype vs mutant) 
Prior to randomization, the investigator will decide the most appropriate treatment for 
his/her patient including the chemotherapy regimen, with or without biological agent that is 
to be given as second line treatment.  
Additional factors permitting covariate analysis will be captured at randomization but will 
not be stratification criteria. These factors will be defined based on the planned covariate 
analyses. 
Patients randomized to the Study Treatment group who are unable to receive their planned 
study treatment will continue to be followed under their assigned study group for the 
purpose of the intent-to-treat analysis. 
If a patient being screened is found ineligible for the study, the patient will not be 
randomized and the reason for treatment ineligibility should be documented on the Screen 
Failure Log.  
All patients deemed eligible for the study must have a minimum washout of 14 days from 
completion of treatment with their first line agents including any biological agents (such as 
VEGF inhibitors) prior to commencing their second line chemotherapy treatments. 
Additionally, patients in the Study Treatment arm must have a minimum washout period of 
28 days from any biological agent prior to receiving TheraSphere. 

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9.2.14 
STUDY TREATMENTS 
9.2.14.1    THERASPHERE  
TheraSphere will be administered in place of the second cycle of chemotherapy.  
Patients with unilobar disease will receive treatment of the diseased lobe. Patients with 
bilobar disease will receive treatment to both lobes separately, administered during the 
same treatment session. Any type of biological agent (such as VEGF inhibitors) must be 
discontinued for at least 28 days prior to treatment with TheraSphere. 
9.2.14.2 THERASPHERE PRE-TREATMENT EVALUATION 
Patients randomized to the Study Treatment group must undergo the following 
evaluations in order to determine eligibility to receive the TheraSphere.  These tests are 
described in detail in Appendix 2, pages 1254-1255 and include: 
• 
Hepatic Angiography: selective celiac and superior mesenteric arteriograms are 
needed to evaluate the hepatic arterial anatomy for the whole liver, as well as 
evaluation of potential sources of extra-hepatic blood supply to tumors.  The 
goal is to identify, within the hepatic vascular anatomy, a catheter placement 
location that allows a single TS infusion throughout the lobar tumor volume 
without administration of microspheres to extra-hepatic structures.  A 
technetium-99m macroaggregated albumin (99mTc-MAA) scan is used to assess 
the potential for shunting microspheres to the lungs as well as the potential for 
the deposition of microspheres to the gastrointestinal (GI) tract. Repeat 99mTc-
MAA may be needed for subsequent treatments to estimate cumulative lung 
shunt or re-asses GI flow.  Note that 3 technical factors, as discussed in 
Appendix 2 (time between administration of 99mTc-MAA and the scan, 99mTc-
MAA particle size and the presence of free 99mTc-MAA) can lead to an over-
estimation of shunting to the lungs and should be controlled. 
TheraSphere should not be administered to a patient randomized to the treatment 
group if: 
• 
Deposition of microspheres to the GI tract that cannot be corrected by 
placement of the catheter distal to collateral vessels or the application of 
standard angiographic techniques, such as coil embolization  to prevent 
deposition of microspheres in the GI tract. 
 
• 
Exposure of radiation to the lungs of 30 Gray (Gy) for a single infusion or a 
cumulative 50 Gy limit for all infusions of TheraSphere - estimated during 
TheraSphere dose calculation as described in Section 9.2.14.1.3. 
 
In the event that the patient is determined not to be suitable and/or cannot be safely 
treated with TheraSphere, that patient should continue with the planned second-line 
chemotherapy treatment as described in Section 9.2.14.2. 
 

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9.2.14.3 THERASPHERE ADMINISTRATION STRATEGY 
For patients eligible to receive TheraSphere, the administration strategy (choice of 
artery position to infuse the target vascular bed; selection of placement of coil 
embolization or other techniques used to prevent microsphere deposition to the GI 
tract) should be determined as discussed in Appendix 2, pages 1254 - 1257.  Dosimetry 
is based on the volume of the target vascular bed supplied by the artery selected for 
infusion.  Patients requiring coil embolization to prevent microsphere disposition to the 
GI tract should undergo this procedure during TheraSphere work-up.   
Since the treatment approach for TheraSphere is lobar or selective, proper imaging and 
volume calculation is essential for dosimetry purposes.  The ability to understand 
hepatic anatomy relies on the sound understanding of the Couinaud hepatic 
segments18.  Anatomically, the middle hepatic vein separates the right and left lobes.  
When drawing regions of interest and calculating lobar volumes, it is the middle hepatic 
vein that should be used as the anatomic delineator between the right and left lobes.  If 
the middle hepatic vein cannot be seen, then the gallbladder and its axis relative to the 
liver can be used.  This technique assumes standard arterial anatomy with single right 
and left hepatic arteries. If variants are observed angiographically, for example, an 
accessory right hepatic artery, then accurate angiographic correlations must be 
performed when drawing the regions of interest for lobar or segmental lobar volumes.  
This will ensure that accurate volumes are obtained and 3 or more infusions are 
administered.  The volume that needs to be used for TheraSphere dosimetry is that 
volume of liver that is perfused by the vessel that will be infused. 
Target liver mass is determined by the positioning of the delivery catheter in the hepatic 
vasculature and the resulting liver area (segments) infused.  Since there is considerable 
individual variation in hepatic vascular anatomy, the determination of target liver mass 
will depend on the variant encountered.  The Table below presents the most commonly 
encountered variants with the corresponding segments associated to them.   
 
 

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STANDARD AND VARIANT HEPATIC VASCULAR ANATOMY  
AND CORRESPONDING COUINAUD SEGMENTS 
Hepatic Vascular Anatomya: 
Angiographic Findings 
Target Segments: 
Infusion 1b,c 
Target Segments: 
Infusion 2 
Target Segments: 
Additional 
Infusion 
Standard right and left hepatic arteries 
1, 5, 6, 7, 8 
2, 3, 4 
 
Replaced right hepatic with flow to 
medial segment left lobe 
1, 4, 5, 6, 7, 8 
2, 3 
 
Replaced right hepatic artery without 
flow to middle lobe, left hepatic artery 
with flow to medial and lateral 
segments left lobe 
1, 5, 6, 7, 8 
2, 3, 4 
 
Replaced left hepatic artery without 
flow to medial lobe 
1, 4, 5, 6, 7, 8 
2, 3 
 
Replaced left hepatic artery with flow 
to medial lobe 
1, 5, 6, 7, 8 
2, 3, 4 
 
Accessory right hepatic artery 
6, 7 
2, 3, 4 
1, 5, 8 
Right hepatic artery in the presence of 
an accessory right hepatic 
5, 8 
2, 3, 4  
1, 6, 7 
Middle hepatic artery (irrespective of 
origin) 
1, 5 ,6, 7, 8 
4 
2, 3 
Notes: 
a) vascular anatomy subject to variation 
b) assumes caudate lobe (segment 1) derives blood supply from right hepatic artery 
c) caudate lobe (segment 1), right anterior lobe (segments 5/8), right posterior lobe (segments 6/7),  
left medial lobe (4), left lateral lobe (2, 3) 
9.2.14.4THERASPHERE DOSE DETERMINATION  
The screening angiogram and 99mTc-MAA scan are used to determine lobar liver volume 
from CT or MRI images, to identify vascular shunting to the gastrointestinal tract 
requiring use of angiographic occlusion techniques and to determine the lung shunt 
fraction. The target dose is 120 Gy ± 10%. 
Calculation of Lung Shunt Factor:  Lung shunt factor is determined from the 99mTc-MAA 
scan using the following equation: 
Lung shunt Fraction (F) = total lung counts/ (total lung+ liver counts) 
Calculation of Target Liver Mass: Convert the target liver volume to mass assuming a 
conversion factor of 1.03g/cm3.   
 
Calculation of Activity required to deliver the desired dose of 120 Gy: 

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The amount of radioactivity required to deliver the desired target dose (120 Gy) to the 
selected liver target, adjusted for the estimated fraction that will be shunted to the lung, 
is calculated using the following formula:  
Activity Required (GBq) = [Desired Dose (Gy)] [Mass of Selected Liver Target (kg)]  
50[1-F] 
Calculation of estimated lung radiation exposure (Gy): 
Lung Dose (Gy) per infusion = 50 * Calculated Activity in GigaBecquerel (GBq) * F 
Cumulative exposure is the sum of estimated exposure per infusion for all planned 
infusions. 
9.2.14.5 THERASPHERE DOSE VIAL SELECTION 
Selection of the dose vial size to supply the required activity (GBq) for delivery of the 
desired target dose to the selected target liver volume via the selected vascular route is 
dependent on the day and time of the scheduled patient treatment and must account 
for the time zone in which the hospital is located and the decay in radioactivity over 
time. The impact of time for standard dose sizes is illustrated in the decay curve below. 
The TheraSphere Treatment Window Illustrator can be used to select the appropriate 
dose vial or combination of dose vial(s) required to deliver the calculated activity 
required. 
 
 
 

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9.2.14.6  THERASPHERE ORDERING 
Orders must be placed using the study-specific order form provided by the sponsor. 
Most standard dose vials are made to stock and can be ordered at any time per current 
institutional practices.  Shipment will be arranged according to specified treatment time 
as per current practice.  TheraSphere will be delivered to the institution’s designated 
radiopharmacy and handled according to institutional practices.  
Each vial of TheraSphere will be shipped with a packing slip, a copy of which must be 
transferred to the study coordinator for device accountability so that the vials used can 
be tracked to the specific infusion(s) for each patient.  Disposal of used or any unused 
vials will be handled in accordance with hospital standard practices for disposal of 
radioactive materials. 
9.2.14.7 THERASPHERE ADMINISTRATION 
TheraSphere will be administered at a dose of 120 ± 10% Gy to each area being treated, 
administered in one or more selective administrations on the same day.   
Patients in the Study Treatment group who have hepatic progression with hepatic 
lesions that are still amenable to TheraSphere are eligible for re-treatment with 
TheraSphere.  In these cases, TheraSphere may be administered at the investigator’s 
discretion using lobar infusions on separate treatment days. 
TheraSphere should be administered by appropriately trained or designated personnel 
from the departments of Radiology, Nuclear Medicine, and/or Interventional Radiology. 
TheraSphere administration is generally considered to be an outpatient procedure in 
the United States. It is generally considered to be an inpatient procedure in Europe. The 
physical location for after-care and recovery will be determined by individual 
institutional policies and facility configurations.  The location and sequencing of 
treatment procedure may vary depending on the physical location of the angiography 
and nuclear medicine suites, the availability of portable gamma cameras, and the clinical 
judgment of the physician responsible for the treatment plan. 
On the day of treatment, an arterial catheter will be placed percutaneously via the 
femoral or brachial artery under image guidance.  The interventional radiologist 
performs this procedure.  The patency of the catheter is maintained by an infusion of 
normal saline and a coagulation inhibitor (per institutional protocols) administered via a 
continuous infusion pump. Proper catheter positioning in the selected location in the 
hepatic artery will be verified on angiography before TheraSphere administration.  
Standard medication protocol for sedation, pain and infection prophylaxis should be 
implemented per established institutional protocols. Prophylaxis with a gastric inhibitor 
(H2 blocker) is recommended to minimize risk of post-treatment gastrointestinal side 
effects.  Although recommended for all patients undergoing treatment, this prophylaxis 
is especially important for patients undergoing TheraSphere treatment to the left lobe 
of the liver, due to the proximity of the gastrointestinal organs, and for patients with a 
prior history of peptic ulcer disease.  Therapy should begin on the day of TheraSphere 
treatment and continue for 14-21 days following each TheraSphere treatment. 

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The TheraSphere Package (Appendix 1) Instructions for Use describes the specific 
procedure used to administer TheraSphere.   
9.2.14.8 THERASPHERE ADMINISTRATION DOCUMENTATION 
Any technical problems or complications related to the delivery of TheraSphere 
treatment to the patient must be documented in the medical record.  The details of any 
event and its impact on the patient should be documented on an Adverse Event eCRF.  
Using institutional practices, the activity of each vial of TheraSphere will be determined 
prior to administration. This activity will be used to calculate the actual dose delivered 
to the liver and lung which will be recorded on the appropriate eCRF. 
 
Calculation of the liver dose (Gy) delivered: 
Calculation of the delivered dose per infusion takes into account the activity lost to lung 
shunting plus activity associated with residual microspheres in the administration 
system and is provided by the following formula: 
 
Dose (Gy) =  
50[Injected Activity (GBq)][1-F][1-R] 
Mass of Selected Liver Target (kg) 
where  F = lung shunt fraction (determined in Section 9.2.14.1.3) 
R = residual fraction (1-fraction of microspheres delivered) 
Calculation of residual activity fraction for microspheres: 
The fraction of microspheres remaining in the device is calculated using the following 
formula: 
R = (W-b’) 
(I-b) 
Where   R = residual activity fraction 
b = background dose rate prior to source vial measurement 
I = measured dose rate of source vial positioned greater than 30 cm from 
ionization chamber (or other measuring device) 
b’ = background dose rate prior to waste measurement 
W = average dose rate of shielded waste container (containing discarded vial, 
microcatheter, tubing) positioned with center in same location as I 
 
Calculation of Actual Lung Radiation Exposure: 
Calculation of the lung dose (Gy) delivered in each infusion is provided by the following 
formula: 
Lung dose (Gy) = 50* activity delivered (GBq)*F 

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9.2.14.9 THERASPHERE POST-TREATMENT PATIENT MANAGEMENT 
Immediately following treatment, the patient should remain under observation 
consistent with institutional standard of care guidelines for aftercare in procedures 
involving femoral or brachial artery catheterization.  These aftercare guidelines are 
unique and subject to the policies and procedures dictated by the respective radiology 
and radiation safety departments at each institution.  Prophylactic treatment using 
gastric inhibitor (H2 blocker) should continue for 14 – 21 days post treatment. In 
addition, steroids (e.g., Medrol Dose Pack) may be taken (with food) over the first six 
days post-treatment. 
Prior to discharge, patients should be instructed regarding after-care and provided with 
a 24-hour telephone number that they may use to contact the Site Investigator if they 
develop a problem or have questions about their treatment.  
Any concurrent medication or therapy deemed necessary, including gastric prophylaxis, 
to provide adequate supportive care to the patient in the post-treatment period may be 
administered according to institutional standard of clinical care and should be 
documented on the Concurrent Medications eCRF. 
9.2.14.10 RADIATION SAFETY IN THE IMMEDIATE POST-TREATMENT PERIOD 
Special radiation isolation procedures for Study Treatment group patients are not 
necessary following TheraSphere Treatment. The existence of a small amount of long-
lived radioactive byproducts in TheraSphere is a function of the production method19.  
The predominant byproducts are Y-91, Y-88 and Cr-51 with respective half-lives of 59, 
107 and 28 days. The 3 year accumulated dose to the patient’s liver is estimated to be 
1/1000 of the planned treatment dose. 
Should a patient die or require surgery in the period immediately following-TheraSphere 
treatment the hospital radiation safety officer should be consulted. At 60 days after the 
TheraSphere calibration date, a surgeon explanting a treated liver in a procedure lasting 
one hour would be exposed to an estimated dose to the hands of <0.6mrem. This is 
similar to estimated background doses from natural radiation sources which range from 
0.5 to 0.8 mrem/day. Institutional radiation safety guidelines for handling of the body 
and/or body tissues should be followed.   
9.2.14.11 
SECOND-LINE CHEMOTHERAPY 
The chemotherapy for this trial consists of either standard of care second-line 
irinotecan-based chemotherapy, or standard of care oxaliplatin-based chemotherapy.   
If the patient received an oxaliplatin-based chemotherapy during first line 
chemotherapy, they should receive an irinotecan-based chemotherapy as their second 
line chemotherapy regimen under this protocol.  If the patient received an irinotecan-
based chemotherapy regimen during first line chemotherapy, they should receive an 
oxaliplatin-based chemotherapy regimen as their second line regimen under this 
protocol.   

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Generally, second-line chemotherapy is given every two weeks for 6-12 cycles. It can be 
continued at the discretion of the investigator.  The times and doses of the cytotoxic 
agents administered will be recorded on the relevant eCRF. 
The Control group patients will start the second line chemotherapy regimen after 
randomization, after the 14 day washout period from first line chemotherapy has been 
completed. Biological agents can start with the first cycle of second-line chemotherapy 
for patients randomized to the Control group. 
For patients randomized to the Treatment group, one cycle of chemotherapy will be 
administered prior to the TheraSphere treatment. Biological agents may only be added 
to the chemotherapy regimen with the first subsequent cycle following the 
TheraSphere administration. 
9.2.14.2.12 ALLOWABLE TREATMENTS FOLLOWING DISEASE PROGRESSION 
After disease progression is observed and confirmed, patients in either group may 
receive the Best Alternative Therapy or Best Alternative Care that is considered 
appropriate by the investigator for further treatment of their disease. Biological agents 
must be discontinued for at least 28 days prior to any additional TheraSphere 
administration. 
9.2.15 
EFFICACY IMAGING – CT/MRI 
Baseline disease assessment imaging scans will be obtained during screening.  Images taken 
during the course of standard-of-care clinical management may be used as baseline images if 
they are taken within 28 days prior to randomization and conform to the baseline/disease 
assessment imaging requirements of the protocol.  The baseline efficacy images must also 
have been taken after, or at the time of completion of first line chemotherapy.  Baseline 
efficacy images must have measurable target tumors in the liver and be assessable according 
to RECIST 1.1. Efficacy assessment scans will be taken in accordance with standard-of-care 
clinical management guidelines every 8 weeks (+/- 1 week) post randomization until death 
or end of study. Most patients will be evaluated by CT images. CT scans for the assessment 
of liver metastases must include a portal venous phase. MRI images are also permitted. The 
imaging modality used at baseline must continue to be used for all efficacy images 
throughout the study. 
Spiral CT abdomen/pelvis – must be performed with cuts of 5 mm or less in slice thickness 
contiguously in the axial plane.  From these images, hepatic and extra-hepatic lesions will be 
read according to the RECIST criteria v1.1 (Appendix 3).   
Spiral CT Chest – must be performed with cuts of 5 mm or less in slice thickness contiguously 
in the axial plane.  From these images, extra-hepatic lesions will be read according to the 
RECIST criteria v 1.1 (Appendix 3). 
All study visit CTs/MRIs taken for disease assessment (i.e. until demonstration of disease 
progression as determined by the Investigator plus a confirmatory scan from the next 
subsequent visit) must be submitted to the sponsor or designate for Centralized Review. In 
addition to a confirmatory scan, all efforts should be made to collect images until hepatic 

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progression has been confirmed. These images do not have to conform to an 8-week 
schedule. All disease assessment images including the baseline images must be assessable 
according to RECIST 1.1. Baseline images conducted in the course of standard-of-care clinical 
management may be used if the images conform to RECIST 1.1 and are taken after, or at the 
time of completion of first line chemotherapy. Images taken for clinical patient management 
after determination of disease progression in the liver are not submitted for Central Image 
Review. 
A central and independent review will be done by a Central Imaging Review Organization, 
located in the United States (ICON Medical Imaging) designated to review the CT/MRI 
images. The Central Imaging Review Organization will be qualified by training and 
experience.  All Central Image Review readings (independent reads by two radiologists with 
adjudication by a third radiologist) will be performed in a blinded fashion on the full set of 
patient images and captured on appropriate eCRF for database entry.  The results of the 
study endpoints will be based on the Central Image Review findings. 
9.2.16 
STUDY TREATMENT MEDICATION RECORD 
At all relevant study visits, the details of treatment administered during the study will be 
recorded, including the doses and start and stop times.  
The addition of any treatments for colorectal carcinoma after disease progression is 
observed will be documented on the appropriate eCRF.   
9.2.17 
CONCURRENT MEDICATION RECORD 
At every study visit until disease progression or 30 days after discontinuation of the last 
study therapy, new medications or changes in concurrent medications will be documented 
on the appropriate concurrent medication eCRF.  Documentation will include dosage, 
start/stop dates, date of change of dosage and any drug holidays. After disease progression 
or 30 days after discontinuation of the study therapy (second-line chemotherapy alone or 
TheraSphere administration and second–line chemotherapy) whatever comes first, only data 
about anti-cancer treatments (systemic therapy or liver directed treatments) or medications 
given for the treatment of adverse events related to TheraSphere will be collected. 
9.2.18 
REASONS FOR STUDY COMPLETION/ EARLY WITHDRAWAL 
In accordance with the Declaration of Helsinki, and applicable state and federal regulations, 
a trial subject has the right to withdraw from the study at any time and for any reason. Every 
effort should be made to have patients complete the study within the provisions of informed 
consent. However, the participation of the patient may be discontinued at any time during 
the study when, in the judgment of the investigator, sponsor or subject, it is appropriate. For 
example: 
• 
Patient’s desire for any reason to withdraw consent 
• 
Death of the patient 
• 
Administrative reasons 
• 
It is considered necessary by the investigator or sponsor, for any reason 

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Lost to follow-up is not an adequate reason for withdrawal. Patients should be encouraged 
to attend study visits until completion of the study or until a decision is taken to withdraw 
for one of the above-noted reasons. 
If the patient is removed because of intolerance to the study treatment, he/she should be 
under medical supervision as long as deemed appropriate by the treating physician. If the 
patient is discontinued due to an AE, the event will be followed until it resolves to the 
Investigator’s satisfaction or is considered stable. The details and reasons for discontinuation 
must be carefully and completely documented.   
10. STATISTICS 
10.1 SAMPLE SIZE ESTIMATE 
This study is a randomized open label multi-center Phase III adaptive trial using a group 
sequential design with primary endpoints of PFS and HPFS.  The study could be stopped early for 
efficacy at an interim analysis for superiority in PFS but not HPFS. 
The study is designed to detect a 2.5 months increase in median PFS from 6 months in the 
control arm to 8.5 months in the TheraSphere arm (i.e., hazard ratio  = 0.71), and a 3.5 month 
increase in median HPFS time, from 6.5 months in the control arm to 10 months in the 
TheraSphere arm (ie, HR =0.65), using log rank tests.  
The analysis of PFS will be based on a group sequential design with 2 interim analyses (at 50% 
and 70% of PFS events) with a stopping boundary defined by the rho family error spending 
function with rho=1.5 (Jennison and Turnbull, 200020).  It is estimated that a maximum of 420 
patients will need to be recruited over 36 months, with a 1 year additional follow-up period.  This 
includes an adjustment to take account of an assumed 10% of patients who will be lost to follow-
up and for whom a date of progression or death is not recorded.  The Hochberg procedure23 will 
be used to control Type I error for the two primary endpoints at the final analysis. 
A simulation study, assuming that PFS and HPFS have a correlation between 0.3 and 0.8, showed 
that the power to detect the target difference in either median PFS (ie, HR=0.71) or median HPFS 
(ie, HR=0.65) is >90%, and the power to detect the target difference in PFS or HPFS alone is 
>80%.   The simulation study also demonstrated control of Type I error. 
Although the forecasted accrual period has now been increased to 60 months, this does not 
increase the number of patients required, or affect the statistical power of the study since both 
the power and the timing of the interim and final analyses are based on the number of PFS 
events rather than the number of patients. 
 
10.2 STATISTICAL ANALYSIS PLAN 
The statistical analysis plan will be written after the final protocol is issued and will be updated, 
as required, in association with any protocol amendments. The plan will include tables, listings 
and graphs and describe statistical programming considerations. 

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10.2.1 
POPULATIONS AND SUB-GROUPS 
 
Intent To Treat population (ITT) 
All randomized patients will be analyzed according to the treatment group to which they 
were randomized.  
 
Per Protocol Population (PP) 
All randomized patients will be analyzed according to the treatment actually received. 
Patients with major protocol deviations which may affect the efficacy evaluation will be 
excluded from the PP population. 
 
Safety Analysis Population (SA) 
All randomized patients who received study treatments at least once will be included in 
the safety analysis.  
 
Early drop-outs  
According to an intention-to-treat methodology, randomization will be performed upfront, 
before any further invasive tumor assessment (angiogram) or treatment planning. 
10.2.2 
TRIAL ENDPOINTS 
10.2.2.1 PRIMARY EFFICACY ENDPOINTS 
The primary study endpoints are PFS and HPFS.  The study will be considered to have met 
its objective if at least one of the primary endpoints is statistically significant.  PFS is 
defined as the time from randomization until progression, as defined by RECIST v 1.1, or 
death, and HPFS is defined as the time from randomization to the date of disease 
progression in the liver according to RECIST 1.1, or death. For this protocol, the minimum 
time from baseline to establish Stable Disease is 6 to 8 weeks, the time to complete a 
minimum of one set of follow-up disease assessment images from baseline. For patients 
who terminate the study before progression or death, patients will be censored at the date 
the patient is last known alive and not progressed. 
10.2.2.2 SECONDARY STUDY ENDPOINTS 
• 
Overall Survival (OS): OS is defined as the time from randomization until the patient 
dies. 
• 
Time to symptomatic progression (TTSP):  TTSP is defined as the time from 
randomization to assessment of ECOG performance status >2. Deterioration in 
performance status is to be confirmed at one subsequent evaluation 8 weeks later. 
• 
Objective Response Rate and Disease Control Rate:  At Baseline, target tumors are 
identified, read and measured for size.  At all subsequent follow-up visits, the target 
tumor will be assessed and categorized as Complete Response (CR), Partial Response 
(PR), Stable Disease (SD), or Progressive Disease (PD) per RECIST v1.1 at each time 
point.  Objective Response rates at each time point and Best Overall Objective 

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Response Rates will be evaluated.  Also, Disease Control rates at each time point and 
Best Overall Disease Control Rates will be evaluated.  
• 
Quality of Life: will be assessed at all visits for enrolled patients using FACT-c. 
Safety: will be assessed at all visits for enrolled patients using v 4.0 of the National 
Cancer Institute’s Common Terminology for Adverse Events (NCI: CTAE). All adverse 
events, serious adverse events, and unanticipated adverse device effects as defined by 
the study protocol will be collected throughout the duration of the study.  These 
events will be documented and recorded on the Adverse Event ECRF using the NCI-
CTCAE v. 4.0 standards, and will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
10.2.3 
EFFICACY ANALYSIS 
10.2.3.1 
PRIMARY ENDPOINTS STATISTICAL ANALYSIS PLAN 
The efficacy analysis will be performed on the ITT and PP populations. Tumor response 
as assessed by a central imaging laboratory blinded to treatment assignment will be 
used for the primary efficacy analysis. This analysis will be repeated using the 
investigator assessment of tumor response as a supportive analysis of PFS and HPFS. 
PFS and HPFS will be compared between treatment arms using log rank tests at an 
overall one-sided alpha level of 0.025 to test the null hypothesis that the hazard rates 
for the treatment and control arms are equal versus the alternative hypothesis that the 
hazard rate for the TheraSphere arm is less than the hazard rate for the control arm, ie,  
H0: λT = λC   versus H1:  λT < λC,  
where λT and λC represent the PFS or HPFS hazard rates for TheraSphere and control 
arms respectively. The Kaplan-Meier method will be used to estimate the PFS and HPFS 
curves in the two treatment arms. The hazard ratio and two-sided 95% confidence 
limits for the treatment effect will be presented.  Log rank tests converted to z-scores 
will be used to compare the primary endpoints between the treatment arms. 
Interim Analysis of PFS: Two interim analyses of PFS are planned to be performed by the 
Independent Data Monitoring Committee (IDMC) based on group sequential stopping 
rules using an alpha boundary defined by the rho family error spending function with 
rho=1.5. The first interim analysis is planned at 172 PFS events (progressions or deaths). 
PFS will be compared between treatment arms using a log rank test converted to a z-
score and compared to the nominal critical value of 2.372 based on the rho family error 
spending function, corresponding to a one-sided p-value ≤0.0088 allowing the study to 
be stopped early for efficacy, in which case HPFS will be tested at the same boundary as 
PFS  using a log rank test converted to a z-score.   
A second interim analysis is planned at 241 PFS events, where PFS will be compared 
between treatment arms using a log rank test converted to a z-score and compared to 
the nominal critical value of 2.330 based on the rho family error spending function, 
corresponding to a one-sided p-value ≤0.0099 allowing the study to be stopped early for 
efficacy.  If the study is stopped early for PFS at the second interim analysis, HPFS will be 
tested using the boundary derived based on an incremental alpha of 0.0057.  This 

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boundary will account for the correlation between the z-score for HPFS at the first 
interim analysis and the z-score for HPFS at the second interim analysis, which is 
determined by the observed number of HPFS events at the first interim analysis and the 
cumulative number of HPFS events observed at the second interim analysis. 
At each of the interim analyses, if the conditional power for both PFS and HPFS is less 
than 15% the study could be stopped early for futility, using the method described in 
Proschan et al (2006)21 .   
OS will also be analyzed at the interim analyses. However, no formal stopping rules will 
be performed based on this interim OS analysis. 
Final Analysis of PFS and HPFS: The final analysis is planned at 344 PFS events.  The 
Hochberg procedure22 will be used to control Type I error for the two primary 
endpoints.  Whichever of PFS or HPFS that has the larger p-value, will be compared 
between treatment arms using a log rank test converted to a z-score and compared to 
the nominal critical value of 2.312 with a corresponding one-sided p-value ≤0.0104 
required to declare a statistically significant improvement in hazard rate for this 
endpoint.  To ensure that Type I error is controlled for both primary endpoints, this 
boundary is based on the incremental alpha of 0.0104 instead of the p-value scale 
boundary of 0.0168 using the rho family error spending function with rho=1.5. 
According to the Hochberg procedure, if the primary endpoint with the larger p‐value is 
statistically significant then the other primary endpoint is also statistically significant.  
However, if the primary endpoint with the larger p‐value is not statistically significant 
then the other primary endpoint will be compared between treatment arms using a log 
rank test converted to a z‐score and compared to the nominal critical value of 2.562 
based on the rho family error spending function, with a corresponding one‐sided p‐
value ≤0.0104/2 = 0.0052 required to declare a statistically significant improvement in 
hazard rate for this endpoint.   
Further supportive analyses of the data using the Cox regression model may be 
conducted to evaluate the effect of multiple covariates, including the stratification 
factors. 
10.2.3.2 
SECONDARY ENDPOINT STATISTICAL ANALYSIS PLAN 
Secondary study endpoints, with the exception of OS, will be analyzed only at the final 
analysis to determine the statistical significance, if any between, the Study Treatment 
and Control groups.  
A hierarchical approach for analysis of secondary endpoints will be employed as shown 
in the figure below. That is, if both primary comparisons are statistically significant, the 
secondary endpoints will be analyzed in order of the list below and will continue as long 
as the obtained 1-sided probability is equal to or less than 0.025. If a probability of 
greater than 0.025 is obtained, the inferential analysis of secondary endpoints will stop 
and not proceed further down the ordered list. In this manner the overall study alpha is 
protected and no further adjustment for multiplicity of analyses is required.   

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Hierarchical approach to control study-wise Type I error of primary and secondary efficacy endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Type I error is controlled at α = 0.025 (1-sided) over the 2 planned interim analyses and final analysis. 
• 
Overall Survival will be calculated as the time from randomization until death for 
any cause, with censoring at the date of last contact for patients alive. The Kaplan-
Meier method will be used to estimate the OS curves in the two treatment arms. 
Comparison between the treatment arms will be performed using the log-rank test 
converted to a z-score, to test the null hypothesis that the OS hazard rates for the 
treatment and control arms are equal versus the alternative hypothesis that the 
OS hazard rate for the Therasphere arm is less than the OS hazard rate for the 
control arm , ie, 
H0: λT = λC   versus H1:  λT < λC 
where λT and λC represent the OS hazard rates for TheraSphere and Control arms 
respectively. 
Not Significant 
STOP 
Both 
Significant 
SECONDARY 
PRIMARY 
Progression Free Survival (PFS) 
and  
Hepatic progression-free 
survival (HPFS)  
Overalla α = 0.025 (1-sided)  
Overall Survival            
(OS)  
α = 0.025 (1-sided)  
Both Not 
Significant 
STOP 
Significant 
Not Significant 
STOP 
Significant 
Time to symptomatic 
progression (TTSP) 
 α = 0.025 (1-sided)  
Not Significant 
STOP 
Disease Control Rate 
(CR+PR+SD) 
 α = 0.025 (1-sided)  
Time to deterioration in 
QoL (TTDQoL) 
α = 0.025 (1-sided)  
Significant 
Not Significant 
STOP 
Objective Response Rate 
(CR+PR) 
 α = 0.025 (1-sided)  
Significant 

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A sensitivity analysis for OS will be performed displaying control treatment failures 
who go on to receive Yttrium-90 microspheres separately from controls treatment 
failures that do not go on to be treated with Yttrium-90 microspheres. 
• 
Time to symptomatic progression (TTSP) will be calculated as the time of 
randomization to assessment of ECOG performance status>2. Deterioration in 
performance status is to be confirmed at one subsequent evaluation 8 weeks later. 
The Kaplan-Meier method will be used to estimate the TTSP curves in the two 
treatment arms. Comparison between the treatment arms will be performed using 
the log-rank test converted to a z-score, to test the null hypothesis that the TTSP 
hazard rates for the treatment and control arms are equal versus the alternative 
hypothesis that the TTSP hazard rate for the Therasphere arm is less than the TTSP 
hazard rate for the control arm, ie, 
H0: λT = λC   versus H1:  λT < λC 
where λT and λC represent the TTSP hazard rates for TheraSphere and control 
arms respectively. 
• 
Objective response rate. The response probability will be estimated in each of the 
two treatment arms as proportion of CR+PR (as defined by RECIST v 1.1) over the 
total number of ITT or PP patients. Best overall objective response rate will be 
compared using the continuity adjusted Newcombe-Wilson test, to test the null 
hypothesis that the proportions of patients achieving a ORR are equal in the 
treatment and control arms versus the alternative hypothesis that the proportion 
of patients achieving ORR is greater in the TheraSphere arm compared to the 
control arm, ie, 
H0: pT = pC  versus H1: pT > pC 
where  pT and pC  represent the proportion of patients achieving an objective 
response for TheraSphere and control arms respectively. The two-sided 95% 
confidence limits will be calculated. 
• 
Disease control rate. The response probability will be estimated in each of the two 
treatment arms as proportion of CR+PR+SD (as defined by RECIST v 1.1) over the 
total number of ITT or PP patients. Best overall disease control rate will be 
compared using the continuity adjusted Newcombe-Wilson test, to test the null 
hypothesis that the proportions of patients achieving a DCR are equal in the 
treatment and control arms versus the alternative hypothesis that the proportion 
of patients achieving DCR is greater in the TheraSphere arm compared to the 
control arm, ie, 
H0: pT = pC  versus H1: pT > pC 
where  pT and pC  represent the proportion of patients achieving disease control 
for TheraSphere and control arms respectively. The two-sided 95% confidence 
limits will be calculated. 

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• 
Quality of Life. The total score of the FACT-c QoL instrument will be calculated, the 
scores of each domain and each question at each time-point and their differences 
from baseline will be summarized for each treatment arm. The two treatment 
arms will be compared applying a mixed linear model with the treatment as 
factors, the baseline score and the relative time from baseline as covariates. A 
deterioration in QoL is defined as a 7-point decline in the total score or death 
whichever occurs first. The time to deterioration in QoL (TTDQoL) will be 
calculated as the interval between the randomization date and deterioration in 
QoL. The Kaplan-Meier method will be used to estimate the TTDQoL curves in the 
two treatment arms. The treatment arms will be compared using a log-rank test 
converted to a z-score, to test the null hypothesis that the TTDQoL hazard rates for 
the treatment and control arms are equal versus the alternative hypothesis that 
the TTDQoL hazard rate for the TheraSphere arm is less than the TTDQoL hazard 
rate for the control arm, ie, 
H0: λT = λC   versus H1:  λT < λC 
where λT and λC represent the TTDQoL hazard rates for TheraSphere and Control 
arms respectively. 
Further supportive analyses of the secondary efficacy endpoints using the Cox regression 
model may be used to evaluate the effect of multiple covariates, including stratification 
factors. 
10.2.4 
SAFETY ANALYSIS 
The safety analyses will be performed on the SA population. 
All treatment emergent adverse events (TEAEs), defined as events which were not present at 
baseline or worsened in severity following the start of treatment, will be reported according 
to NCI Criteria. The incidence of TEAEs will be summarized according to MedDRA coded 
primary system-organ class (SOC) and preferred term (PT). The summaries will be presented 
overall (severity grades 1-5), for grade ≥3 events and by treatment discontinuation. These 
summaries will present the number and percentage of patients reporting an adverse event 
for each classification level as well as the number of events reported. 
 
Serious adverse events (SAE) will be tabulated by treatment group.  
Laboratory values will be summarized by treatment group over time and overall.  
10.2.4.1 
FEASIBILITY SAFETY ANALYSIS 
After the first 20 patients in the treatment group have received TheraSphere followed 
by at least 2 cycles of chemotherapy, a feasibility safety assessment will be conducted.  
The IDMC will review the safety results of both the control and treatment groups in an 
unblinded fashion.  The IDMC will take into consideration the established safety profiles 
of TheraSphere, oxaliplatin based, and irinotecan based chemotherapy, as described in 
the package inserts for each product as well as the published literature.  The expected 
high rates of adverse events and death that are associated with disease progression in 
patients with advanced colorectal cancer will be considered.     

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A consideration for adjusting the dose of cytotoxic agents, or other safety 
recommendations, or stopping further enrollment to trial may be made by the IDMC if 
there is: 
• 
an unanticipated patient death definitely or probably related to the sequential 
administration of TheraSphere with oxaliplatin based or irinotecan based 
chemotherapy 
• 
there is  a pattern of serious toxicity clearly related to the sequential 
administration of TheraSphere with oxaliplatin based or irinotecan based 
chemotherapy.   
Such a toxicity pattern must be clearly different from, or more severe than, what might 
be expected from independent administration of the chemotherapy regimens and 
TheraSphere. The potential adverse impact of any such pattern of toxicity on the 
survival or well being of the patient should be considered in the context of the safety 
and outcome expectations of patients with advanced colorectal cancer. References to 
consider include a Phase I trial of yttrium-90 microspheres in combination with 
oxaliplatin10 based chemotherapy and a Phase I trial of yttrium-90 microspheres in 
combination with irinotecan11 based chemotherapy, and the experience of TheraSphere 
in the treatment of patients with colorectal cancer and hepatic metastases7.  
10.2.5 
POOLABILITY AND OTHER ANALYSES 
The number of randomized patients, the number of patients treated, the number of patients 
in each analysis population will be summarized. The number of patients discontinuing from 
active treatments and reasons for discontinuation will be summarized. In the same manner 
the number of patients discontinuing follow up and reasons for discontinuations will be 
reported.  
Listings of reasons for discontinuation from active treatments, from follow up, and reasons 
efficacy data cannot be evaluated in the PP population will be also provided.  
Duration of follow up will be described by descriptive statistics such as median and 
interquartile range.  
Demographic, patient and disease characteristics will be listed and summarized using 
appropriate descriptive statistics.  
Multivariate Cox regression analysis of efficacy endpoints will be conducted on stratification 
criteria and other factors such as age, gender, duration of disease prior to randomization to 
determine the impact of these factors on study endpoints. 
As a sensitivity analysis, to address the poolability of data across regions, study sites and 
gender, a Cox regression analysis of the primary efficacy endpoints, PFS and HPFS, will be 
conducted including additional factors of region, study site and gender, and to determine 
the impact of these factors on PFS and HPFS.  (NOTE: region and study site will not be 
included simultaneously in the model due to collinearity.) Should the impact of region, site 
or gender on PFS and HPFS be statistically and clinically relevant, the reasons for the 
observed differential treatment effect, such as patient demographic or clinical 

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characteristics, will be investigated and reported. If the poolability of PFS or HPFS results is in 
direct question as a result of this sensitivity analysis, the primary endpoints (PFS and/or 
HPFS) will also be analyzed separately by region, site or gender.  In addition, the primary 
endpoints (PFS and HPFS) will be analyzed separately by US and non-US region. The specific 
mechanism of merging low enrolling study sites into virtual sites for purposes of analysis will 
be detailed in the Statistical Analysis Plan.    
10.2.6 
INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to oversee the 
conduct of the study, will follow the FDA’s Guidance on IDMCs/DSMBs and comply with ISO 
14155.  The IDMC will meet periodically during the study to review enrollment, protocol 
deviations, and safety events for the study.  In addition the IDMC will evaluate the data at 
interim analyses for consideration of stopping the study for overwhelming efficacy or futility 
and for sample size re-estimation at the second interim analysis. The IDMC will make formal 
recommendations to the study Sponsor at the time of the interim analysis and during the 
conduct of the study based on detailed decision rules specified in the IDMC charter. An IDMC 
member or designate may act as the study independent medical monitor. 
11. ELECTRONIC DATA COLLECTION AND MANAGEMENT 
11.1 ELECTRONIC DATA COLLECTION (EDC) 
Data from this trial will be captured on electronic case reporting forms (eCRFs), and will be entered 
into a validated clinical database.  An audit trail will be maintained to document all data changes in 
the database.  Procedures will be followed to ensure the validity and accuracy of the clinical 
database.  
The investigator will sign and date all indicated places on the eCRFs.  This signature will indicate 
that thorough inspection of the data has been made and will certify that the Site Investigator has 
reviewed and approved the data contained on the forms. 
11.2 DATA MANAGEMENT 
The investigator will ensure that trial data quality is maintained to current standards of Good 
Clinical Practice and that data are submitted in a timely manner as outlined in the protocol and 
supporting documentation, including responses to data queries, until the trial is terminated.  
Errors must be corrected in accordance with EDC data entry guidelines. 
12. ADVERSE EVENTS 
12.1 ADVERSE EVENT DEFINITIONS 
Adverse experience will be considered synonymous with the term adverse event and vice versa. 
12.1.1 
DEFINITIONS OF AE/SAE FOR DRUGS 
Adverse Event (AE) 

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An AE is any untoward medical occurrence or undesirable event(s) experienced in a subject 
or clinical investigation subject that begins or worsens following administration of the study 
drug, whether or not considered related to the treatment by the investigator.  
An undesirable event(s) can be, but is not limited to, symptoms experienced by a subject or 
objective findings, such as significant clinical laboratory abnormalities. 
Serious Adverse Event (SAE)  
Any untoward medical occurrence that at any dose: 
• 
results in death; 
• 
is life-threatening (“life-threatening” refers to an event in which the subject was at 
risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe); 
• 
requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
results in a persistent or significant disability/incapacity; or 
• 
is a congenital anomaly/birth defect. 
 
Medical and scientific judgment should be exercised in deciding whether medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above, should also be considered serious. 
12.1.2 
DEFINITIONS OF ADE/SADE/UADE FOR DEVICES 
Serious Adverse Event (SAE)  
Adverse event that: 
• 
led to a death, 
• 
led to a serious deterioration in health that either: 
o 
resulted in a life-threatening illness or injury, or 
o 
resulted in a permanent impairment of a body structure or a body 
function, or 
o 
required 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization, or 
o 
resulted in medical or surgical intervention to prevent life threatening 
illness or injury or permanent impairment to a body structure or a body 
function. 
• 
led to fetal distress, fetal death or a congenital abnormality or birth defect. 
NOTE 1: This includes device deficiencies that might have led to a serious adverse event if a) 
suitable action had not been taken or b) intervention had not been made or c) if 
circumstances had been less fortunate. These are handled under the SAE reporting system. 
NOTE 2: A planned hospitalization for pre-existing condition, or a procedure required by the 
Clinical Investigation Plan, without a serious deterioration in health, is not considered to be a 
serious adverse event. 
 
 
 

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Adverse Device Effect (ADE) 
An adverse device effect is an adverse event (AE – previously defined) related to a medical 
device including device procedure and includes but not limited to any event resulting from 
device deficiencies such as insufficiencies or inadequacies in the instructions for use or the 
deployment, implantation, installation or malfunction of the device; any event that is the 
result of user error. 
Serious Adverse Device Effect (SADE) 
A Serious Adverse Device Effect is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event (SAE – previously defined).  
Unanticipated Adverse Device Event (UADE) 
An unanticipated adverse device effect is any serious adverse effect which by its nature, 
incidence, severity and outcome has not been identified in the risk assessment, the informed 
consent form as well as the protocol. 
12.2 RECORDING ADVERSE EVENTS 
All adverse events and adverse device effects will be documented from the date of randomization 
until disease progression or 30 days after discontinuation of the study therapy (second-line 
chemotherapy alone or TheraSphere and second-line chemotherapy), whatever comes first. After 
this, only adverse events related to TheraSphere will be collected. 
In this study, patients should be encouraged to report adverse events spontaneously or in 
response to general, non-directed questions.  At any time during the study, the patient may 
volunteer information that resembles an adverse event. Once it is determined that an adverse 
event has occurred, the Investigator should obtain all the information required to complete the 
adverse event form.  Any medical management of an event and the date of resolution of the event 
must be recorded in the source document and on the appropriate case reports form(s) using 
medical terminology according to sponsor instructions. 
For each AE, the following information will be recorded:  
• 
Adverse event 
• 
Serious/non-serious  
• 
Severity 
• 
Action taken 
• 
Relationship to study treatment 
• 
Expected/Unexpected 
• 
Date and time of onset 
• 
Date and time of resolution 
An expected adverse event is any AE, the nature or severity of which is identified in the relevant 
Package Insert or Investigator’s Brochure. 
Any AE experienced by a subject will be followed until the AE has resolved to the investigator's or 
physician sub-investigator's satisfaction or is considered stable.  If a problem still exists, then the 

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investigator or physician sub-investigator at his/her discretion will ask the subject to come back to 
the clinic for further evaluation.  Any serious adverse events should be managed as discussed in 
Section 12.3. 
Once the subject has been discharged from the study, the investigator has no obligation to seek 
further follow-up with the subject in order to identify new AEs. However, if the investigator 
becomes aware of an SAE that has occurred following the subject's discharge from the study and 
the investigator considers the SAE possibly, probably, or definitely related to a study drug or 
device, then the investigator should report the SAE as described in the protocol. 
Disease progression itself is not to be considered as an AE, but signs and symptoms that led to 
disease progression should be recorded.  If disease progression is due to the primary cancer type 
than this should be stated as event term for recorded SAE.  
12.2.1 
CAUSALITY (RELATIONSHIP TO DEVICE) ASSESSMENT 
The investigator or physician sub-investigator must indicate whether he/she believes the AE 
is unrelated, possibly related (reasonable possibility that the investigational device caused 
the AE), probably related, or definitely related to the device.  
The Investigator should pay careful attention to the attribution of relation for all adverse 
events.  Because there are many similar events between the TheraSphere and the second-
line chemotherapy regimen safety profiles, judgment of relation by time of administration 
and patient assignment to treatment or Control group should be considered. 
An adverse event becomes an adverse device effect when the adverse event is considered 
associated with the use of the test device if the attribution is Possibly, Probably or Definitely 
Related.  Relation to TheraSphere (screening, procedure, embolization or radiation) is not 
appropriate for the Control Group.  Only those events with a possible, probable or definitely 
related attribution to TheraSphere will subject to expedited reporting. All other events 
documented in the trial will be addressed through periodic clinical trial reporting in the US.  
In the EU all SAEs are subject to expedited reporting. 
12.3 SUBMITTING EXPEDITED SAFETY REPORTS  
Any SAE, SADE or UADE (defined previously) must be reported by telephone or fax to the sponsor 
or its designate as specified in the study procedures within 24 hours of learning of the event.  In 
the event of an emergency, the Investigator will contact the CRO using the coordinates specified in 
the study procedures manual. 
The SAE form provided by the sponsor should be completed and signed by the investigator or 
physician sub-investigator. The entire SAE form needs to be completed, if possible, to keep 
requests for additional information to a minimum. Patients experiencing SAE, SADE or UADE 
should be followed clinically and with laboratory studies, if appropriate, until medical treatment 
and/or medical monitoring of the event is no longer required because the event resolves or 
stabilizes, returns to baseline if a baseline value is available, can be attributed to agents other 
than the study treatments or a referral for appropriate follow-up care has been made. 

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The Investigator must promptly inform the IRB of all UADE and SAE as needed per IRB 
requirements. These events will be reported by the sponsor as appropriate to the regulatory 
authorities according to relevant jurisdictional medical device regulations. The Investigator will 
receive notification of these events across all study centers from the sponsor.  
Each AE reported on an SAE form must also be reported in the adverse event section of the eCRF. 
12.4 PERIODIC SAFETY REPORTING 
Adverse events will be recorded on the AE form and coded using NCI CTCAE v 4.0.  The investigator 
or physician sub-investigator will judge the severity of each AE and whether or not it is treatment-
related.  All AEs that occur after randomization, including events likely to be related to the 
underlying disease or likely to represent concurrent illness, will be reported, including events 
present at Baseline which worsened during the trial.   
Periodic safety reports prepared by the sponsor will be distributed across all study centers. The 
Investigator will be responsible for informing the IRB. 
12.5 EXPECTED ADVERSE EVENTS  
12.5.1 
THERASPHERE ADVERSE EVENT PROFILE 
TheraSphere has been approved for the treatment of HCC since 1999. Adverse events known 
to be related to the device or the procedure listed in the current package insert (Appendix 
1). Those adverse events identified in clinical trials investigating treatment with TheraSphere 
of liver lesions metastatic to non-HCC primary cancers are listed below in decreasing order 
of frequency. 
 
Frequency 
Description of Adverse Event (per NCI-CTCAE v 3.0) 
Common - 
>10% 
Fatigue, pain, nausea, vomiting, anorexia and laboratory value 
abnormalities including increased alkaline phosphatase, AST, ALT, 
hypoalbuminemia and lymphopenia with no clinical sequelae 
Infrequent - 
<10% 
Constipation, heartburn, weight loss, fever, ascites, muscle weakness, 
variations in creatinine, platelets,  hemoglobin and leukocytes, GI ulcer, 
dyspnea, supraventricular arrhythmia, diarrhea, hypotension, insomnia, 
rigors/chills, sweating, distension, GI obstruction, hematoma, GI 
hemorrhage, pleural effusion, hyponatremia, dehydration, allergic 
reaction, GI other, neurology other 
Rare – < 1% 
Alopecia, bruising, pruritis, rash, hot flashes, dehydration, taste 
alteration, hemorrhage, liver dysfunction, infection, dizziness, mood 
alteration, sensory neuropathy, somnolence, urine color change, 
intraoperative injury, flu-like symptoms, tumor lysis syndrome, 
thrombosis, metabolic/laboratory abnormalities – neutrophils, 
hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, lipase, 
lymphatics other, pulmonary other vascular other, death 
 

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In addition, the following events, which may or may not be related to the use of 
TheraSphere or the administration procedure, have been reported in clinical trials of 
treatment of primary or secondary liver cancer: 
Abdominal pain, dyspnoea, abdominal distention, anxiety, blurred vision, chills, hot flashes, 
bladder infection, lower extremity edema, gastrointestinal stoma complication including 
mild pain, hepatic encephalopathy, hepatorenal failure, edema, malaise, hepatic 
decompensation, hepatitis, duodenal ulcer, hypertension, hypertension, aspiration 
pneumonia, fall, gastrointestinal bleeding, elevated CEA, elevated LDH, elevated 
prothrombin time, elevated BUN, bacterial sepsis, hypoglycemia, abnormal platelets and 
electrolyte 
disturbances 
including 
hypercalcemia, 
hyperkalemia, 
hypomagnesemia, 
hyponatremia, low serum bicarbonate and low serum chloride. 
12.5.2 
SECOND-LINE CHEMOTHERAPY ADVERSE EVENT PROFILE 
The nature and severity of expected adverse events associated with second-line 
chemotherapy will vary depending in part on the drug or combination of drugs used, the 
dosages used and the treatment regimen.  To assist in the assessment of the attribution of 
adverse events to one or more chemotherapy drugs, the Investigator is referred to the 
current package insert for the respective drug(s) administered. The following summary 
presents a compilation of adverse events associated with second-line chemotherapy 
treatment of metastatic colorectal cancer reported in the literature6 and package inserts of 
the relevant drugs.   
FOLFOX CLINICALLY SIGNIFICANT TOXICITY PROFILE: Severe (grade 3 or 4) events include 
neuropathy, diarrhea, neutropenia, thrombocytopenia, nausea/vomiting (although unlikely 
to be grade 3 or 4), fatigue and alopecia (grade 1 or 2). There are two types of peripheral 
neuropathy associated with oxaliplatin - an acute self-limiting, cold-sensitive peripheral 
neuropathy lasting approximately 3 days and a delayed, cumulative dose dependant sensory 
peripheral neuropathy which has a median time to reduction or resolution of approximately 
13 weeks after cessation of oxaliplatin therapy.  Rarely, some patients may experience 
anaphylactic reactions or laryngeal paresthesia at infusion which can be addressed through 
extending the infusion time from 2-6 hours or pre-medication with lorazepam. Oxaliplatin 
has been associated rarely with pulmonary fibrosis which may be fatal. Increases in 
transaminases and alkaline phosphatase have been observed with oxaliplatin. 
FOLFIRI CLINICALLY SIGNIFICANT TOXICITY PROFILE: Severe (grade 3 or 4) events include 
diarrhea, neutropenia and thrombocytopenia and nausea/vomiting. The severity of 
irinotecan-induced diarrhea may be greater than that associated with oxaliplatin. The 
incidence of neutropenia and thrombocytopenia with FOLFIRI may be lower than that 
associated with FOLFOX but may include febrile neutropenia.  Increased numbers of patients 
treated with first-line FOLFIRI, vs FOLFOX, have reported grade 3 or 4 nausea/vomiting. 
Alopecia (grade 1 or 2) occurs more frequently with FOLFIRI than FOLFOX. Some mild 
changes in liver values, including increased bilirubin, transaminases and alkaline 
phosphatase, unlikely to cause symptoms have been observed. 
5-FU/LEUCOVORIN CLINICALLY SIGNIFICANT TOXICITY PROFILE: Diarrhea, neutropenia and 
mucositis are commonly associated with bolus administration of 5-FU/Leucovorin. Infusion 

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administrations significantly reduce the incidence of gastrointestinal and dermatological 
toxicities but increase the incidence of hand-foot syndrome. In some patients receiving 
fluorouracil there may be an increased production of tears or a brown marking on the skin 
following the injection vein. 
OTHER ADVERSE EVENTS ASSOCIATED WITH SECOND-LINE CHEMOTHERAPY DRUGS: include 
decreased platelets clinically manifested as bruising or petechia, anemia, fatigue, pain, sore 
mouth or ulcers, hair thinning or hair loss, sensitivity to sun, loss of appetite, nail changes, 
skin rash (hives, pruritis, urticaria), constipation, flatulence, sweating, insomnia, edema, 
blurred vision, difficulty breathing or swallowing, tinnitus, allergic reaction, angina, heart 
pain, confusion, dizziness or unsteadiness. The impact of chemotherapy drugs on 
reproductive ability is unknown.  Some drugs may be present in breast milk. 
EGFR INHIBITOR ADVERSE EVENTS: Serious adverse events include infusion reactions 
(including anaphylactoid reactions, bronchospasm, hypotension, pyrexia, chills, rigors, 
dyspnea, angioedema, urticaria, hypertension), cardiopulmonary arrests, interstitial lung 
disease, pulmonary fibrosis, dermatologic toxicities (including acneform rash, pruritus, 
erythema, skin exfoliation, paronychia, dry skin, fissures and infectious sequelae); 
photosensitivity, electrolyte abnormalities including hypomagnesemia, infections and renal 
failure. Other adverse events include nail changes, fatigue, fever, rigors, chills, pain, dyspnea, 
cough, constipation, diarrhea, nausea, vomiting, steatites, mucosal inflammation, malaise, 
infection without neutropenia, insomnia, confusion, anxiety, depression. As with all 
therapeutic proteins, there is a potential for immunogenicity. Increased toxicity with 
combination chemotherapy has been noted with pantitumamab which should be 
administered as monotherapy. 
 
13. INVESTIGATOR AND SITE QUALIFICATION AND OBLIGATIONS 
13.1 STUDY SITE AND INVESTIGATOR QUALIFICATION 
This study will be performed by qualified investigators at multiple research centers in the United 
States, Canada, Europe, and Asia. 
All participating study sites will be reviewed by the study Sponsor or designee in order to verify 
that they are able to conduct the trial.  Each participating institution must have an established IRB 
and clinical protocol review process in compliance with the appropriate regulations (21 CFR 56 or 
ISO 14155) so the clinical protocol can be adequately evaluated and approved at the institutional 
level. 
The institution must have appropriately qualified investigators, and clinical and administrative 
support staff in place to adequately conduct the trials according to GCP in general, and must have 
adequate expertise and staff in the treatment of patients with colorectal carcinoma and the ability 
to adequately conduct clinical research under Good Clinical Practice Standards (GCP) consistent 
with the regulations of 21 CFR 812, Investigational Device Exemptions, and ISO 14155. 

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In addition, all participating study sites must be appropriately experienced in the use of Y-90 
microspheres for the treatment of liver tumors, and must have completed adequate training in 
order to use the TheraSphere Y-90 microsphere product.  The required training will be specified by 
the sponsor.  Generally, an adequate level of experience consists of a minimum of 5 TheraSphere 
administrations for sites without radioembolization experience and at least 3 administrations of 
TheraSphere for sites experienced with a different radioactive microsphere product. 
13.2 INSTITUTIONAL APPROVAL AND DOCUMENTATION OF THE PROTOCOL 
Prior to initiating the clinical study, each participating institution must have documentation that 
the Institution Review Board (IRB) has reviewed and approved the protocol and the Informed 
Consent Form (ICF).  
The final IRB approved protocol, consent form, documentation of IRB approval of the consent and 
protocol, Study  Contract, Statement of Investigator, CVs of all investigators and study 
coordinators, records of protocol training, and all  other study-related required regulatory 
documentation as described in the Sections below must also be maintained in the clinical study 
files for this trial. 
The Site Principal Investigator is ultimately responsible for ensuring that required study 
documentation has been obtained, that all study procedures are properly followed, and that all 
enrolled patients meet the eligibility criteria prior to enrollment under this protocol. 
The Investigator is responsible for submission of the protocol, informed consent form, any patient 
education materials, and any recruitment or advertising materials and the institution’s IRB.  
• 
Written approval of the protocol and Informed Consent Form must be obtained prior to 
recruitment of patients into the trial at each site and prior to administration of protocol 
treatment to any randomized patient.   
• 
Written approval of the recruitment and advertising materials must have IRB approval 
before use.   
• 
The Investigator is responsible for obtaining and maintaining IRB approval at his facility 
and providing copies of all IRB correspondence to the Sponsor or designee.   
This protocol is a multi-center protocol and as such must remain consistent with all other sites. 
13.3 REGULATORY DOCUMENTS  
The following documentation must be obtained before study enrollment can begin (with the 
exception of Final Report). 
• 
Institutional Review Board Approval 
A copy of the protocol and any amendments, the proposed informed consent form (ICF), other 
written subject information and any proposed advertising material must be submitted by the 
Investigator to the IRB for written approval.  A copy of the written approval of the protocol and ICF 

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must be received by the sponsor or designee before recruitment of subjects into the study and 
shipment of investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the ICF.  The investigator should notify the IRB 
of deviations from the protocol and SAEs as required by local procedures. 
The investigator will be responsible for updating the IRB about the status of the trial at least 
annually and obtaining any required approvals renewal throughout the duration of the study.  
Copies of any correspondence and other documentation between the investigator and the IRB 
must be retained as part of the site documentation of the study. Copies of all such documents 
must be sent to the sponsor or designee. 
• 
Institutional Review Board Membership Roster 
The investigator must submit a complete and current roster of the IRB to the sponsor 
(Biocompatibles) or designee.  Some institutions, on grounds of confidentiality, may not release 
the IRB roster.  In such instances, the institution’s General Assurance Number, assigned by the 
Department of Health and Human Services, is an acceptable substitute. 
• 
Statement of Investigator 
The investigator will be required to sign and date a Statement of investigator form provided to 
them by the sponsor or designee.  A copy of this form will be given to the investigator for their 
files.  The original form will be maintained by the sponsor or designee. 
• 
Curriculum Vitae 
The investigator will provide the sponsor or designee with his/her up-to-date curriculum vitae and 
those of any sub-investigators or staff personnel with significant trial responsibilities. 
• 
Laboratory Certification and Normal Values 
The Investigator will provide the sponsor or designee with the name and location of the clinical 
laboratory to be utilized for determination of laboratory assays, copy of certification and a list of 
the normal range of values of all laboratory tests.  Any changes in laboratory, certification or 
normal ranges will be communicated promptly to the sponsor or designee or designee. 
• 
Financial Disclosure 
Financial disclosure statements will be completed for the investigator and all sub-investigators to 
disclose potential conflicts of interest (per 21 CFR 54 and ISO 14155).  The investigator is 
responsible for ensuring completed and signed financial disclosure forms, which are provided by 
the sponsor or designee.  A copy of the form(s) will be given to the investigator for their files.  The 
original form(s) will be maintained by the sponsor or designee.  Financial disclosure information 
will be collected by the sponsor before the start of the study and maintained for one year after 
study completion. 
• 
Final Report 

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Upon completion of the clinical trial, a final study report will be provided by the sponsor; The 
Investigator will prepare and submit to the IRB a final report, including final study report.   
13.4 SOURCE RECORDS AND STUDY DOCUMENTATION 
Investigators are required to prepare and maintain adequate source documentation.  Source 
documentation includes: 
• 
documents relative to the patient’s medical history that verify the eligibility criteria  
• 
records covering the patient’ participation in the study which include but are not limited 
to basic identification information, results of physical examinations and diagnostic tests, 
therapy, device administration, concurrent medication information and visit/consult 
notes.) 
The Investigator will initial and date all laboratory reports or initial and date statements at each 
study visit that all clinical laboratory data was reviewed. 
Federal regulations concerning the period during which study records must be maintained by the 
Investigator vary from country to country.  Investigators are required to comply with their local 
regulatory authority for storage of study documentation.  For the purpose of this study the 
minimum retention for Study Documentation is a period of two (2) years after the later of the 
following:  (a) date on which the Study is terminated or completed; or (b) date records are no 
longer required to support a premarket approval application, notice of completion of a product 
development protocol, or other application for research or marketing permit. 
 
Completed eCRFs that are dated and signed by the investigator must be made available for review 
and retrieval by the sponsor or designee at the time the subject completes the study.  The sponsor 
or designee will provide the investigator with a copy of completed eCRFs for their files. 
In order to ensure the accuracy of data collected in the eCRFs, it is mandatory that representatives 
of the sponsor, as well as representatives of a regulatory agency (e.g.  Food and Drug 
Administration) or the institutional review board (IRB), have access to source documents (i.e., 
subject records, subject charts, and laboratory reports).  During the review of these documents, 
the anonymity of the subject will be maintained with strict adherence to professional standards of 
confidentiality.  The sponsor reserves the right to terminate the study for refusal of the 
investigator to supply source documentation of work performed in this clinical trial. 
13.5 ETHICAL CONDUCT OF THE STUDY  
This study will be conducted in compliance with standard operating procedures of the sponsor or 
designee, which are designed to ensure adherence to good clinical practice (GCP) guidelines as 
required by the following:  
1. World Medical Association (WMA), Declaration of Helsinki, Ethical Principles for Medical 
Research Involving Human Subjects, Adopted by the 18th WMA General Assembly, 
Helsinki, Finland, June 1964, and as amended at subsequent WMA General Assembly 
meetings. 

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2. E6 Good Clinical Practice: Consolidated Guidance (International Conference on 
Harmonization of Pharmaceuticals for Human Use [ICH], April 1996 governing drugs and 
ISO 14155 governing devices. 
3. Title 21 of the Code of Federal Regulations (21 CFR) Parts 50, 54, 56, and 812. 
13.6 RESPONSIBLE CONDUCT OF RESEARCH 
The Sponsor will ensure that this trial is conducted in full conformity with the current revision of 
the ‘Declaration of Helsinki”, ISO 14155, the U.S. Code of Federal Regulations 21 CFR 812, and 
applicable state and federal regulations, whichever affords the greatest protection to the patient.  
The Sponsor is responsible for providing monitoring oversight for the study to ensure the 
involvement of the Investigator in the trial, to ensure the rights, safety and well-being of the 
patients, compliance to the protocol and to all applicable laws, and to oversee the completeness, 
accuracy and consistency of the data collected in support of a pre-market approval application in 
the United States.  
The procedures defined in the protocol and the eCRFs will be carefully reviewed by the Sponsor 
with the Investigator and staff prior to time of trial initiation to ensure appropriate interpretation 
and implementation.  No deviations from the protocol may be made without advance approval 
from the sponsor and the IRB as required by the policies of the IRB. 
Monitors from the Sponsor, or their designees, will periodically visit the site to review case report 
forms, the Regulatory Binder, patient medical records including electronic records, imaging files, 
laboratory reports, device accountability, site training and authorization of delegation and any 
other records related to the study conduct.  Investigator will maintain and release the records for 
review, provide access to the records and copies as needed, and will meet with the monitor as 
needed to discuss study progress and needs.  The Investigator should maintain the files suitable for 
inspection at any time by a trial monitor from the sponsor or designee, or the appropriate 
regulatory authority, or designate representing these organizations. 
 
13.7 INFORMED CONSENT 
An IRB approved signed informed consent form (ICF) must be obtained from a patient before that 
patient can enter the trial, and before any study related evaluations can be performed on that 
patient. 
The investigator is responsible for the creation of the ICF and must ensure that the informed 
consent adheres to the U.S Code of Federal Regulations, 21 CFR 50, ISO 14155 or equivalent, as 
appropriate to his/her country.  The Investigator will ensure that the local IRB has approved the 
protocol and the informed consent prior to the initiation of the trial.  The signed informed consent 
from each patient must be kept in the patient’s study file.   
The investigator or designee will review the treatment plan with the patient and the patient will 
have an opportunity to ask questions regarding study procedures, the required visit schedule, 
risks/benefits of the use of the device (TheraSphere), and alternative treatment options prior to 
signing the ICF.  The patient will receive a copy of the signed informed consent to keep for their 

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records.  Periodically during the study, revisions to the informed consent form may be needed.  
Patients will be informed of such revisions and any revisions must be signed and kept in the 
patients study file.   
The acquisition of informed consent should be documented in the subject’s medical record and the 
ICF should be signed and personally dated by the subject and by the person who conducted the 
informed consent discussion (not necessarily by the investigator).   
Patients for whom English is not their first language may need a written translation of the 
document and/or a patient advocate, according to the policies of the IRB.  The Investigator will 
provide the sponsor or designee a copy of the IRB approved translation, if any. 
13.8 PATIENT MEDICAL RECORDS 
The Investigator must maintain adequate medical records regarding their care of the patient, 
including case histories, to support the clinical data in the case report forms.  These records must 
be maintained and made available for monitoring and auditing by the Sponsor, or their designee, 
and the appropriate regulatory agency.  All CT/MRIs will be maintained or archived along with the 
medical chart for review for at least 2 years after pre-market approval of the device. 
13.9 PATIENT PRIVACY AND CONFIDENTIALITY 
All collected patient data will be treated confidentially and identified only by a patient 
identification number.  Medical records relating to this trial, including those that are electronically 
maintained and those that may contain information that would identify an individual patient will 
remain confidential, but may be reviewed by, released, and/or transmitted to representatives of 
the hospital, the appropriate regulatory agency, Biocompatibles (the Sponsor) or its agents, and 
the Independent Data Monitoring Committee when reasonable and appropriate for the conduct of 
the trial. 
As part of the required content of the informed consent, the patient must be informed that his/her 
records will be reviewed by Biocompatibles and/or a representative of the appropriate regulatory 
agency and the Independent Data Monitoring Committee. The informed consent or related 
document will also state that patient privacy will be maintained pursuant to the Health Insurance 
Portability and Accountability Act (HIPAA), 21 CFR 21 or equivalent for countries other than the 
United States.  Should access to the medical record require a separate HIPAA waiver or 
authorization per institutional confidentially policies, it is the Investigator’s responsibility to obtain 
such permission from the patient in writing before the patient is entered into the trial. 
13.10 ADDITIONAL INVESTIGATOR RESPONSIBILITIES 
Additional Investigator responsibilities are noted in ISO 14155 in Section 11 of the US 21 CFR 
812.100, 812.110 and in country-specific guidelines and laws and responsibilities for reporting of 
unanticipated adverse device events and deviations from the investigational plan per 812.150 as 
well as the following: 
• 
Ensure compliance with institutional and appropriate relevant jurisdictional Radiation 
Safety policies and procedures. 

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• 
Assemble and coordinate a team that includes a designated co-investigator in all of the 
medical disciplines necessary for the efficient conduct of the protocol (oncology, 
interventional radiology, nuclear medicine, diagnostic radiology, etc). 
• 
Provide a trial coordinator who will be responsible for assisting the Investigator in 
meeting data collection and reporting requirement and for scheduling, management and 
follow-up of trial patients. 
• 
Provide adequate access to study materials for the sponsor or designee to monitor the 
trial at appropriate and convenient intervals and provide an adequate, secure area, within 
the study site facility for a sponsor or representative to conduct these monitoring 
activities. 
14. PROTOCOL DEVIATIONS 
It is vital to the success of the study that the investigator adheres to the details of the protocol. A protocol 
deviation is any change, divergence or departure from the study protocol in any section related to patient 
regardless the consequences to the patient or study outcomes.  
 
A minor protocol deviation is defined as a divergence from the protocol that is without significant 
consequences to the patient and the study data. An example is  missing a visit window because a patient 
is traveling.  
A major protocol deviation   is defined as a divergence from the protocol that materially (a) reduces the 
quality or completeness of the data, (b) makes the Informed Consent Form inaccurate, or (c) impacts a 
subject's safety, rights, or welfare, example:  
 
• 
Enrollment deviations 
• 
Eligibility criteria deviations 
• 
Inadequate informed consent 
• 
Intentional  repeated deviations from the protocol 
• 
TheraSphere Administration deviations: TheraSphere treatment dose outside the range of  
120 Gy ± 10% (i.e. 108-132  Gy)   
 
15. STUDY MONITORING 
The study will be monitored by qualified personnel from the sponsor or a contract research organization 
(CRO) contracted to provide such monitoring by the sponsor.  Data management and statistical analyses 
will be the responsibility of the sponsor who will contract with one or more organizations to manage 
these functions.  
Before initiation of the trial, representatives from the sponsor will, together with the investigator, review 
the protocol and the facilities.  At trial initiation, the sponsor's representative will thoroughly review the 
protocol and go over the eCRFs and electronic data entry procedures with the investigator(s) and other 
authorized staff.   

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During the course of the trial, a study monitor or other authorized representatives of the sponsor will visit 
the investigator at suitable intervals.  The purpose of these visits will be to verify compliance with 
applicable government regulations and adherence to the protocol, ensure correct completion of the 
eCRFs. 
In order to perform his/her role effectively, the study monitor(s) must be given access to source 
documentation (eg, clinic charts, original laboratory records), which support data on the eCRF, and 
informed consent forms.  The monitor must be able to verify data appearing in the eCRFs against data in 
the subject's clinic chart (eg, chart notes) or in printout forms (eg, laboratory results). 
16. STUDY TERMINATION 
Biocompatibles reserves the right to discontinue this study for administrative reasons at any time.  The 
end of the study is defined as the reaching of the required number of PFS events and all TheraSphere 
treated patients have been followed-up for a minimum of 30 days from the last TheraSphere treatment, 
and all treated patients in the control arm have been followed-up for a minimum of 30 days after the 
second cycle of second line chemotherapy. 
17. APPENDICES 
1. TheraSphere Product Labeling 
a. US Package Insert 
b. CA Package Insert 
c. 
EU Instructions for Use 
 
2. Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art 
brachytherapy treatment for primary and secondary liver malignancies. Part 1: Technical and 
methodologic considerations. J Vasc Interv Radiol. 2006 Aug; 17(8):1251-78. Review. Erratum in: J 
Vasc Interv Radiol. 2006 Oct; 17(10):1594.  
3. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 
Jan;45(2):228-47. 
4. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN guidelines™) 
Colon Cancer  v.2.2011, pages COL-7 and COL-C 1-6. 
 
 

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18. REFERENCES 
                                                                
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