Conditions: Intrahepatic Cholangiocarcinoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 89
Healthy volunteers: no

Brief summary:
The study planned to evaluate the benefit of applying Selective Internal Radiation Therapy (SIRT) using SIR-Spheres Y-90 resin microspheres prior to receiving systemic chemotherapy treatment (cisplatin-gemcitabine, or CIS-GEM) in patients with unresectable intrahepatic cholangiocarcinoma. Half of the patients were randomized to CIS-GEM chemotherapy plus SIRT, and half of the patients were randomized to CIS-GEM alone.

Detailed description:
This clinical study was a prospective, multicenter, randomized, controlled study evaluating SIR-Spheres Y-90 resin microspheres followed by cisplatin-gemcitabine (CIS-GEM) chemotherapy vs. CIS-GEM chemotherapy alone as first-line treatment of patients with unresectable intrahepatic cholangiocarcinoma.

Randomized patients were to be followed until death, withdrawal of consent, or until end of study.

Arms:
arm 1: Cisplatin 25mg/m2 in 1000ml 0.9% saline given over 1 hour followed by 500 ml 0.9% saline over 30 minutes, followed by Gemcitabine 1000 mg/m2 in 250-500 ml 0.9% saline over 30 minutes by intravenous infusions on days 1, and 8 of a 21-day cycle. arm 2: A single treatment of hepatic arterial injection of SIR-Spheres Y-90 resin microspheres (SIRT) followed 14-16 days later by systemic chemotherapy (ABC-02 CIS-GEM protocol) with an intention to treat with 8 cycles of cisplatin + gemcitabine, or until progression, toxicity or patient choice. Treatment may be continued beyond 8 cycles in the absence of significant disease progression, at the treating clinicians' discretion.

Interventions: intervention 1: Cisplatin-gemcitabine intervention 2: Radiation: SIRT + chemotherapy (cisplatin-gemcitabine)
Intervention descriptions: intervention 1: Systemic chemotherapy intervention 2: SIR-Spheres microspheres followed by systemic chemotherapy

Protocol document:
Prot_SAP_000.pdf: 
Study Name: SIRCCA 
Study Number: STX 0115 
NCT Number: NCT02807181 
Study Title  A prospective, multicentre, randomised, controlled study evaluating 
SIR-Spheres Y-90 resin microspheres preceding standard cisplatin-gemcitabine 
(CIS-GEM) chemotherapy versus CIS-GEM chemotherapy alone as first-line treatment of 
patients with unresectable intrahepatic cholangiocarcinoma (SIRCCA) 
Clinical Investigation Plan 
Version 5 
Document Date: 12 April 2019 


CIP STX 0115 - SIRCCA Srudy, Rev 5, 12 Apr2019 
The SIRCCA Study 
A prospective, multicentre, randomised, controlled study evaluating SIR-Spheres® 
Y-90 resin microspheres preceding standard cisplatin-gemcitabine (CIS-GEM) 
chemotherapy versus CIS-GEM chemotherapy alone as first-line treatment of 
patients with unresectable intrahepatic CholangioCArcinoma (SIRCCA) 
Study Sponsor: 
Co-Principal Investigator: 
Co-Principal Investigator: 
Sirtex Technology Pty Ltd 
Level 33, 101 Miller Street 
North Sydney 
NSW 2060 Australia 
Tel: +61 2 9964 8400 
Fax: +61 2 9964 8410 
cgiS1crcd Tradc1narlt of Sincx SIR-Spheres Pty Ltd 
Conftdtntial Sil'l<x T,cl,wolu~· Pty Lid 
12th April 2019 
Date: Apr, I ) /p 2-o I q 
Date: / 0 A f rc ;;v1 1 
~., ol9J 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
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CHANGE HISTORY 
 
CR # 
Reason for change 
1927 
New Document March 2016 
2009 
Section 7.3, Page 23 – change “gemcitabine” to “radiation” and “be cleared from 
the body” to “have decayed” 
2072 
See Changes Document Rev 1 to Rev 2 Sept 06 2016 
2074 
See Changes Document Rev 2 to Rev 3 Sept 20 2016 
2074 
2519 
See Changes Document Rev 3, 28 Sep 2016 to Rev 4, 20 Jun 2018 
See Summary of changes Rev 4 - Rev 5 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
CLINICAL INVESTIGATION PLAN (CIP) APPROVAL & AGREEMENT ................ 6 
2 
STUDY SYNOPSIS .......................................................................................................... 7 
Inclusion Criteria ......................................................................................................... 8 
Exclusion Criteria ........................................................................................................ 9 
3 
STUDY ENDPOINTS ..................................................................................................... 10 
3.1 
Primary endpoint ...................................................................................................... 10 
3.2 
Secondary endpoints ................................................................................................ 10 
4 
SIR-Spheres Y-90 resin microspheres ............................................................................. 11 
4.1 
Product Description ................................................................................................. 11 
4.1.1 
Mode of Action .......................................................................................... 11 
4.1.2 
Form and Stability...................................................................................... 11 
4.2 
Regulatory Status ..................................................................................................... 12 
4.3 
Manufacture ............................................................................................................. 12 
4.4 
Radiation Safety ....................................................................................................... 12 
4.4.1 
Radiation Dose Levels for Staff involved in SIRT .................................... 13 
4  4.4.2 
Radiation Dose Levels for Nursing Staff or Visitors ................................. 13 
5 
CLINICAL EXPERIENCE WITH SIR-SPHERES Y-90 RESIN MICROSPHERES ... 15 
6 
STUDY  JUSTIFICATION ............................................................................................. 16 
6.1 
Biliary Tract Cancer ................................................................................................. 16 
6.2 
Current Treatment Options for Intrahepatic Cholangiocarcinoma .......................... 16 
6.2.1 
Surgery ....................................................................................................... 16 
6.2.2 
Transplantation .......................................................................................... 16 
6.2.3 
External Beam Radiation Therapy ............................................................. 16 
6.2.4 
Chemotherapy ............................................................................................ 17 
6.3 
Justification for this Clinical Study.......................................................................... 17 
7 
CLINICAL RISK SUMMARY ....................................................................................... 19 
7.1 
Complications of SIR-Spheres Y-90 Resin Microspheres....................................... 19 
7.1.1 
Post Embolisation Syndrome ..................................................................... 19 
7.1.2 
Gastrointestinal Complications .................................................................. 19 
7.1.3 
Hepatic Complications ............................................................................... 19 
7.1.4 
Pulmonary Complications .......................................................................... 20 
7.1.5 
Haematological Complications .................................................................. 20 
7.2 
Known Contraindications to SIR-Spheres Y-90 resin microspheres ....................... 20 
7.3 
Identifying risks of combining SIR-Spheres Y-90 resin microspheres with 
chemotherapy ....................................................................................................................... 21 
8 
DEVICE RISK ANALYSIS ............................................................................................ 22 
9 
STUDY DESIGN............................................................................................................. 23 
9.1 
Patient Eligibility ..................................................................................................... 23 
9.2 
Inclusion/Exclusion Criteria .................................................................................... 24 
9.2.1 
Inclusion Criteria ....................................................................................... 24 
9.2.2 
Exclusion Criteria ...................................................................................... 24 
10 SCREENING AND  STUDY ENTRY ............................................................................ 26 
10.1 
Patient Screening ..................................................................................................... 26 
10.2 
Histological / Cytological Investigation .................................................................. 26 
10.3 
Clinical Assessments ............................................................................................... 26 
10.4 
Physical Examination and Performance Status ........................................................ 27 
10.5 
Haematological and Biochemical Investigations ..................................................... 27 
10.6 
Radiological Investigation: CT Scan of the Abdomen, Chest, Pelvis ..................... 27 
10.7 
Quality of Life.......................................................................................................... 28 


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10.8 
Randomisation ......................................................................................................... 28 
11 BASELINE ASSESSMENTS ......................................................................................... 29 
11.1 
Physical Examination and ECOG performance status............................................. 29 
11.2 
Haematological and Biochemical Investigations ..................................................... 29 
11.3 
Radiological Investigation: CT Scan of the Abdomen, Chest, Pelvis ..................... 30 
11.4 
Baseline Measurement of Lesions ........................................................................... 30 
11.5 
Selective internal radiation therapy (SIRT) ............................................................. 30 
11.6 
Commencement of Protocol Treatment ................................................................... 30 
12 TREATMENT ................................................................................................................. 31 
12.1 
Treatment Arm A: Chemotherapy Arm – CIS-GEM (as per ESMO guidelines) .... 31 
12.2 
Treatment Arm B: Sequential Therapy Arm – SIRT followed by CIS-GEM ......... 31 
12.2.1 
Assessing patient suitability for SIRT (Work-Up) .................................... 31 
12.2.2 
Calculation of SIR-Spheres Y-90 resin microspheres activity .................. 32 
12.2.3 
Administration of SIR-Spheres Y-90 resin microspheres ......................... 33 
12.2.4 
Ancillary protocol treatment ...................................................................... 34 
12.2.5 
Treatment Arm B: Post-SIRT Bremsstrahlung scan .................................. 34 
12.2.6 
Treatment Arm B: Administration of CIS-GEM ....................................... 34 
12.3 
Supportive Treatment............................................................................................... 35 
12.3.1 
Recommendation for antibiotic prophylaxis and treatment of patients with 
intrahepatic cholangiocarcinoma (ICC) undergoing radioembolisation followed by 
chemotherapy ............................................................................................................. 35 
12.3.2 
For patients undergoing a biliary intervention during follow up (after RE and 
chemo) the recommended treatment is: ..................................................................... 36 
12.3.3 
For patients with risk profile (see above, e.g. history of ERC) undergoing 
radioembolisation the recommended treatment is: .................................................... 36 
12.4 
Concomitant Medications ........................................................................................ 36 
12.5 
Non-Study Treatments ............................................................................................. 36 
12.6 
Additional non study anti-cancer treatment ............................................................. 36 
12.7 
Use of contraceptives during study treatment .......................................................... 37 
13 FOLLOW-UP STUDY ASSESSMENTS ....................................................................... 38 
13.1 
Study Calendar ......................................................................................................... 38 
14 RESPONSE ASSESSMENT ........................................................................................... 40 
14.1 
Survival at 18 months (Primary Endpoint) .............................................................. 40 
14.2 
Liver resection / ablation rate (Secondary Endpoint) .............................................. 40 
14.3 
Safety and tolerability (Secondary Endpoint) .......................................................... 40 
14.3.1 
Independent Data Safety Monitoring Committee (IDSMC) ...................... 40 
14.4 
Tumour Response Rate (Secondary Endpoint) ........................................................ 40 
14.4.1 
RECIST 1.1 Guidelines ............................................................................. 41 
14.5 
Progression-Free Survival (PFS) and Liver-specific PFS ....................................... 42 
14.6 
Quality of Life.......................................................................................................... 42 
15 STATISTICAL CONSIDERATIONS & METHODOLOGY ........................................ 43 
15.1 
Study Hypothesis ..................................................................................................... 43 
15.2 
Study Design and Sample Size ................................................................................ 43 
15.3 
Statistical Analyses .................................................................................................. 44 
16 Protocol Adherence / Premature Termination of THE STUDY ...................................... 46 
16.1 
Protocol Adherence .................................................................................................. 46 
16.2 
Premature Termination of the Study ........................................................................ 46 
17 ADVERSE EVENTS ....................................................................................................... 47 
17.1 
Definitions................................................................................................................ 47 
17.1.1 
Adverse Event ............................................................................................ 47 
17.1.2 
Serious Adverse Event ............................................................................... 47 


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17.1.3 
Adverse Device Effect (ADE) and Serious Adverse Device Effect (SADE)47 
17.2 
Reporting.................................................................................................................. 48 
17.3 
Pregnancy during the Study ..................................................................................... 48 
18 ETHICAL CONSIDERATIONS ..................................................................................... 49 
18.1 
Informed Consent..................................................................................................... 49 
18.2 
Confidentiality ......................................................................................................... 49 
18.3 
Changes to the Final Study Plan .............................................................................. 49 
19 PUBLICATION POLICY ............................................................................................... 51 
20 ADMINISTRATIVE PROCEDURES ............................................................................ 52 
20.1 
Site Initiation Visit ................................................................................................... 52 
20.2 
Investigator File ....................................................................................................... 52 
20.3 
Monitoring of the Study ........................................................................................... 52 
20.4 
Quality Assurance .................................................................................................... 52 
20.5 
Documentation and Data Management .................................................................... 52 
20.6 
Investigational Device Accountability ..................................................................... 52 
20.7 
Study Funding .......................................................................................................... 53 
20.8 
Completion of the Study .......................................................................................... 53 
21 BIBLIOGRAPHY ............................................................................................................ 54 
22 STANDARD OF CARE GUIDELINES ......................................................................... 60 
Technique for Administration of SIR-Spheres Y-90 resin microspheres .... 61 
Nuclear Medicine Break-Through Scan ...................................................... 64 
Administered Dose Calculation ................................................................... 65 
NCI CTCAE v4.03 Recommendation for Grading of Adverse Events ....... 70 
CIS-GEM Treatment Details according to ABC-02 .................................... 71 
Recommended acquisition guidelines for CT scanning............................... 76 
RECIST Assessments .................................................................................. 77 
EQ-5D Quality of Life Questionnaire ........................................................... 82 
World Medical Association Declaration of Helsinki ................................... 86 
APPENDIX 1 
APPENDIX 2 
APPENDIX 3 
APPENDIX 4 
APPENDIX 5 
APPENDIX 6 
APPENDIX 7 
APPENDIX 8 
APPENDIX 9 
APPENDIX 10 
Abbreviations and Acronyms .................................................................. 90 
APPENDIX 11    Netherlands specific safety reporting procedures ....................................... 93 


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1 
CLINICAL INVESTIGATION PLAN (CIP) APPROVAL & AGREEMENT 
I have read and understand the requirements of this study plan (protocol), entitled ‘A 
prospective, multicentre, randomised, controlled study evaluating SIR-Spheres Y-90 resin 
microspheres preceding standard cisplatin-gemcitabine (CIS-GEM) chemotherapy versus 
CIS-GEM chemotherapy alone as first-line treatment of patients with unresectable 
intrahepatic cholangiocarcinoma (SIRCCA)’.  
I agree to treat all patients entered into the study in accordance with the study plan and to keep 
the appropriate records and documentation required. I will ensure that all staff participating in 
this study are appropriately trained and informed about the study and I will document such 
training appropriately. 
_________________________________ 
___________________ 
Investigator Signature 
Date (dd / mm / yyyy) 
_________________________________ 
Investigator Name 
_________________________________ 
Institution 


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2 
STUDY SYNOPSIS 
This clinical study is a prospective, multicentre, randomised, controlled study evaluating SIR-
Spheres Y-90 resin microspheres preceding standard cisplatin-gemcitabine (CIS-GEM) 
chemotherapy vs. CIS-GEM chemotherapy alone as first-line treatment of patients with 
unresectable intrahepatic cholangiocarcinoma.  
 
The target recruitment is about 180 randomised patients who started treatment. However, it is 
expected that about 160 of the patients in both arms will satisfy the compliance criteria i.e.  (Arm 
A: completed at least one cycle; Arm B completed SIRT treatment and complete at least one 
cycle).  
 
Patients will be randomised 1:1 (about 90 patients in each arm) to receive either: 
 
1. Treatment Arm A: Standard of care systemic chemotherapy with an intention to treat with 8 
cycles of cisplatin + gemcitabine, or until progression, toxicity or patient choice. Treatment 
may be continued beyond 8 cycles in the absence of significant disease progression, at the 
treating clinicians’ discretion. 
 
2. Treatment Arm B: A single treatment of hepatic arterial injection of SIR-Spheres Y-90 resin 
microspheres followed 14-16 days later by standard of care systemic chemotherapy (ABC-
02 CIS-GEM protocol) with an intention to treat with 8 cycles of cisplatin + gemcitabine, or 
until progression, toxicity or patient choice. Treatment may be continued beyond 8 cycles in 
the absence of significant disease progression, at the treating clinicians’ discretion. 
 
Patients will be stratified by: presence of extra-hepatic disease, presence of cirrhosis, intention 
for whole liver versus non-whole liver Y-90 treatment, ECOG status (0 versus 1) and prior 
adjuvant therapy vs no prior adjuvant therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cirrhosis:  
Absence of cirrhosis should be registered when 
- 
The non-tumoural part of the liver is regular and without nodularity on imaging and 
- 
There is no evidence of portal hypertension with no clinically significant ascites, oesophageal 
varices or splenomegaly with dilated portal vein in the absence of portal vein thrombosis.  
 
Recruit: 
 
Eligible patients 
with unresectable 
intrahepatic 
cholangio-
carcinoma (ICC) 
 
 
R 
A 
N 
D 
O 
M 
I 
S 
E 
Treatment Arm A 
Systemic chemotherapy 
CIS-GEM 
Treatment Arm B 
SIR-Spheres Y-90 resin 
microspheres  
followed by systemic 
chemotherapy CIS-GEM 
Stratify: 
• 
Extra-hepatic 
disease 
• 
Cirrhosis 
• 
Whole liver 
vs. non-whole 
liver intended  
Y-90 
treatment 
• 
ECOG 0 vs. 
ECOG 1 
• 
Prior adjuvant 
therapy 
yes/no 
\ 
I 
t 
t 


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Detection of any of the above findings, and/or a positive biopsy diagnosis (F4=cirrhosis 
according to the METAVIR scoring system) and/or an increased elastography value, establishes 
the existence of cirrhosis. 
Randomised patients will be followed until death, withdrawal of consent, or until end of study. 
Non-randomised patients are addressed in Section 10.1. 
The enrolment period for the study is estimated to be 40 months. The study will be conducted in 
approximately 45 selected investigational sites worldwide. The sponsor will maintain a list of 
principal investigators, investigational sites, and institutions. The definitive list will be provided 
with the final clinical study report. 
A comparison between treatment arms will be made by assessment of the following criteria: 
Primary endpoint: 
Survival at 18 months 
Secondary endpoints: 
Liver-specific PFS  
PFS at any site 
Objective response rate by RECIST 1.1 and refined RECIST* - liver  
Objective response rate by RECIST 1.1 and refined RECIST* - at any site 
Overall Survival 
Liver surgical resection  
Liver ablation rate 
Safety (CTCAE v4.03) and tolerability 
Quality of Life  
*Refer to APPENDIX 7 for RECIST1.1 and refined RECIST assessments
Inclusion Criteria 
a) Willing, able and mentally competent to provide written informed consent
b) Aged 18 years or older
c) Histologically or cytologically confirmed unresectable and non ablatable intrahepatic
cholangiocarcinoma
d) Liver-only or liver predominant intrahepatic cholangiocarcinoma. Patients are permitted
to have loco-regional lymph node involvement defined as: portal LN ≤ 2 cm and/or para
aortic LN ≤ 1.5 cm in longest diameter, and/or up to 2 indeterminate lung lesions < 1 cm
if these lung lesions are PET negative.
e) Chemotherapy for advanced disease naïve. Capecitabine only based adjuvant
chemotherapy is permitted (last administered dose of capecitabine ≥ 6 months prior
randomization in the study).
f)
ECOG performance status 0 or 1
g) Adequate haematological function defined as:
Haemoglobin  10g/dL
WBC ≥ 3.0 x 109/L
Absolute neutrophil count (ANC)  1.5 x 109/L
Platelet count  100,000/mm3,
h) Adequate liver function defined as:


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Total bilirubin ≤ 30 µmol/L (1.75 mg/dL) 
Albumin ≥ 30 g/L 
i) Adequate renal function defined as:  
Serum urea and serum creatinine < 1.5 times upper limit of normal (ULN)  
Creatinine clearance ≥ 45 ml/min (calculated with Cockcroft-Gault Equation) 
 
All blood test results must be within 14 days prior to randomisation.  
 
j) Life expectancy of at least 3 months without any active treatment 
k) Female patients must either be postmenopausal, sterile (surgically or radiation- or 
chemically-induced), or if sexually active use an acceptable method of contraception 
during the study.  
l) Male patients must be surgically sterile or if sexually active must use an acceptable 
method of contraception during the study.  
m) Considered suitable to receive either treatment regimen in the clinical judgement of the 
treating investigator. 
 
Exclusion Criteria 
a) Patients with only non-measurable lesions in the liver according to RECIST criteria  
b) Incomplete recovery from previous liver surgery, e.g. unresolved biliary tree obstruction 
or biliary sepsis or inadequate liver function 
c) Biliary stent in situ 
d) Main trunk Portal Vein Thrombosis (PVT) 
e) Ascites, even if controlled with diuretics (a minor peri-hepatic rim of ascites detected at 
imaging is acceptable). 
f) Mixed HCC-ICC disease. 
g) History of prior malignancy. Exceptions include in-situ carcinoma of the cervix treated 
by cone-biopsy/resection, non-metastatic basal and/or squamous cell carcinomas of the 
skin, recurrent intra-hepatic cholangiocarcinoma post local treatment or any early stage 
(stage I) malignancy adequately resected with curative intent at least 5 years prior to study 
entry 
h) Suspicion 
of 
any 
bone 
metastasis/metastases 
or 
central 
nervous 
system 
metastasis/metastases on clinical or imaging examination.  
i) Prior internal or external radiation delivered to the liver. 
j) Pregnancy; breast feeding, 
k) Participation within 28 days prior to randomisation, in an active part of another clinical 
study that would compromise any of the endpoints of this study.  
l) Evidence of ongoing active infection that may affect treatment feasibility or outcome. 
m) Prior Whipple’s procedure 
 
 
The study will be performed in accordance ISO 14155 Clinical investigation of medical devices 
for human subjects – Good clinical practice (current version), ICH-GCP (current version) and 
World Medical Association Declaration of Helsinki (APPENDIX 9). All participating 
institutions must obtain approval from their Institution’s Ethics Committee (EC) or Institutional 
Review Board (IRB) and forward a copy of this to Sirtex Technology Pty Ltd prior to enrolling 
patients.  
 


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3 
STUDY ENDPOINTS 
The study will evaluate the benefit of applying Selective Internal Radiation Therapy (SIRT) 
using SIR-Spheres Y-90 resin microspheres prior to receiving a standard of care (See 
APPENDIX 5) systemic chemotherapy treatment regimen (CIS-GEM) in the experimental arm 
(Arm B) against the standard of care systemic chemotherapy treatment regimen (CIS-GEM) 
alone in the control arm (Arm A) in patients with unresectable intrahepatic cholangiocarcinoma.  
 
Randomised patients will be followed until death, withdrawal of consent, or until end of study. 
 
A comparison between treatment arms will be made by assessment of the following criteria: 
 
3.1 
Primary endpoint  
Survival at 18 months  
 
3.2 
Secondary endpoints 
 
Liver-specific PFS 
PFS at any site 
Objective response rate by RECIST 1.1 and refined RECIST* - liver  
Objective response rate by RECIST 1.1 and refined RECIST* - at any site 
Overall Survival 
Liver surgical resection rate 
Liver ablation rate 
Safety (CTCAE v4.03) and tolerability 
Quality of Life 
 
 
Toxicity will be assessed using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events version 4.03 (CTCAE v4.03). 
 
 
 
 
 
 
*: refer to APPENDIX 7 for RECIST 1.1 and refined RECIST assessments 
 


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4 
SIR-SPHERES Y-90 RESIN MICROSPHERES 
4.1 
Product Description 
SIR-Spheres Y-90 resin microspheres consist of biocompatible resin microspheres containing 
yttrium-90, with a size between 20 and 60 microns in diameter. Yttrium-90 is a high-energy pure 
beta-emitting isotope with no primary gamma emission. The maximum energy of the beta 
particles is 2.27MeV, with a mean of 0.93MeV. The maximum range of emissions in tissue is 
11mm, with a mean of 2.5mm. The half-life of yttrium-90 is 64.1 hours and it decays to stable 
zirconium-90. In clinical use requiring the isotope to decay to infinity, 94% of the radiation is 
delivered in 11 days, leaving only background radiation with no therapeutic value. SIR-Spheres 
Y-90 resin microspheres themselves are a permanent implant and each device is for single patient 
use.  
 
Each device consists of sufficient microspheres to provide 3.0GBq (±10%) at a predetermined 
time on the day of calibration (as shown on the product label). The SIR-Spheres Y-90 resin 
microspheres are suspended in sterile water for injection. Each vial of 3.0GBq is dispatched in a 
volume of ~5ml (microspheres and water together).  
 
4.1.1 Mode of Action 
 
Intrinsic to the concept of selective internal radiation therapy is the preferential placement of the 
radioactive microspheres selectively into the distal microvascular supply of tumours (Mackie 
2011 (44)), Kennedy 2004 (36)); Campbell 2000 (11)).  
 
A study in a porcine kidney model established unequivocally that the direct irradiation of tissue 
and microvascular bed destruction, rather than embolization, is responsible for the tissue 
destructive effects of SIRT (Mackie 2011 (44)). 
 
SIRT, which may also be known as radioembolisation (RE) involves two procedural 
components:  
 
1. Embolisation: injection into the distal arterial tumour feeding vessels of permanently 
embolic microspheres (SIR-Spheres Y-90 resin microspheres) which act as the delivery 
vehicle for the therapeutic moiety yttrium-90, and 
 
2. Irradiation: once located in the distal microvasculature of the tumour, SIR-Spheres Y-90 
resin microspheres deliver high dose beta irradiation to the tumour microvascular plexus 
and to tumour cells directly. 
 
 
4.1.2 Form and Stability 
SIR-Spheres Y-90 resin microspheres do not exhibit pharmacodynamics in the classic sense, but 
induce cell damage by emitting beta radiation. Once implanted, the microspheres remain within 
the vasculature of hepatic tumours, with small amounts within the vasculature of normal 
parenchyma. The device is not phagocytised nor does it dissolve or degrade after implantation. 
High dose radiation emitted from the device is cytocidal within the range of the beta radiation. 
After the yttrium-90 has decayed, the non-radioactive microspheres remain intact and are not 
removed from the body.  
 


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SIR-Spheres Y-90 resin microspheres have the potential to interact with other cytotoxic agents 
and are typically administered concomitantly with systemic chemotherapeutic agents. This 
interaction may be exploited to the benefit of the patient, as there may be an additive toxicity on 
tumour cells, which can enhance the cell kill rate. This interaction may also lead to additive 
toxicity on non-tumorous cells. 
 
4.2 
Regulatory Status 
SIR-Spheres Y-90 resin microspheres are regulated as a medical device product based on 
international definitions of devices, as they have no primary therapeutic pharmaceutical, 
chemical or metabolic activity. SIR-Spheres Y-90 resin microspheres are classified as a sealed 
source brachytherapy device and have the following regulatory approval status in major markets: 
 
European Union 
SIR-Spheres Y-90 resin microspheres were approved in October 2002 as an active implantable 
medical device under the Active Implantable Medical Device (AIMD) Directive (90/385/EEC), 
indicated for: 
 
‘the treatment of primary and secondary (metastatic) liver cancer’. 
 
USA 
SIR-Spheres Y-90 resin microspheres were approved as a Class III medical device product via 
PMA P990065 in March 2002 in the United States for: 
 
‘the treatment of unresectable metastatic liver tumours from primary colorectal cancer 
together with adjuvant intra-hepatic artery chemotherapy (IHAC) of FUDR (Floxuridine)’. 
 
Australia 
SIR-Spheres Y-90 resin microspheres were listed on the TGA Australian Register of Therapeutic 
Goods (ARTG) in February 1998 as a medical device in accordance with the Therapeutic Goods 
Act 1989, under AUSTL No. 63369 and subsequently as an included active implantable medical 
device (AIMD) in January 2008 under ARTG 149332 with the following purpose:  
 
 
‘for the treatment of inoperable liver cancer’. 
 
4.3 
Manufacture 
The SIR-Spheres Y-90 resin microspheres being supplied for this clinical study will be from 
batches of product approved for supply commercially for the treatment of hepatic tumours, 
manufactured under the approved Sirtex Quality Management System processes and at the 
approved locations. The SIR-Spheres Y-90 resin microspheres will be manufactured by Sirtex 
from a production facility located in Boston (USA), Singapore, or Frankfurt (Germany). 
 
4.4 
Radiation Safety 
The following information on radiation exposure to the treating clinicians and to nursing staff or 
visitors following the implantation of SIR-Spheres Y-90 resin microspheres is presented here in 
a summary form. These data are presented in detail in the Sirtex Training Manual, which is 
provided by Sirtex to all institutions that use SIR-Spheres Y-90 resin microspheres. By way of 
comparison with the figures listed herein, the radiation dose from normal background radiation 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
is approximately 2mSv per year. 
4.4.1 Radiation Dose Levels for Staff involved in SIRT 
The following exposure levels are representative for the nuclear medicine technician preparing 
a typical patient dose of SIR-Spheres Y-90 resin microspheres and for the inte1ventional 
radiologist implanting that dose. 
Trunk 
Lens of 
Hands 
Eye 
(mSv) 
(mSv) 
(mSv) 
Nuclear Medicine 
Shallow dose (0.07 mm) 
0.027 
0.026 
0.35 
Technician 
Deep dose 
(10mm) 
0.003 
0.004 
Interventional 
Shallow dose (0.07 mm) 
0.038 
0.12 
0.32 
Radiologist 
Deep dose 
(10 mm) 
0.004 
0.054 
Radiation Safety 
Shallow dose (0.07 mm) 
< 0.02 
0.04 
0.2 
Officer 
Deep dose 
(10mm) 
0.01 
0.017 
The International Commission on Radiological Protection (IRCP) Occupational Radiation Dose 
Limits are as follows: 
Whole body effective dose limit: 
20mSv per year (averaged over 5 years) 
and no more than 50mSv in anv 1 vear 
Lens equivalent dose limit: 
150mSv per year 
Extremity ( e.g. finger) equivalent dose limit: 
500 mSv per year over any 1 cm2 
These representative exposure levels are additive to other sources of exposure for workers. 
4.4.2 Radiation Dose Levels for Nursing Staff or Visitors 
The following dose rates may be expected at various distances from a patient with an implanted 
activity of approximately 2.0GBq when taken approximately 5 - 6 hours after implantation. 
Distance from Patient 
Radiation Dose (µSv/hr) 
(m) 
0.25 
18.8 
0.5 
9.2 
1 
1.5 
2 
0.4 
4 
< 0.1 
In the adjoining room at the wall immediately behind a patient's bed head, the measurement was 
< 0.1 µSv/hr. Typical measurements within limits are 20µSv in any hour and 250~LSv in any seven 
days. 
While the median implanted activity of SIR-Spheres Y-90 resin microspheres for this cmTent 
study is presently unknown - as this will be dete1mined by: 1) the volume of the tumour in 
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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 14 of 93 
patients recruited to the study; and 2) the dose cohort that the patient is recruited to – the median 
implanted activity for hepatic tumours is 1.8GBq (range, 0.75GBq to 2.44 GBq) (van Hazel 2009 
(66)).  
 


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 15 of 93 
5 
CLINICAL EXPERIENCE WITH SIR-SPHERES Y-90 RESIN MICROSPHERES 
SIR-Spheres Y-90 resin microspheres have been in use since the late 1990s and approved for the 
treatment of inoperable hepatic tumours since 2002 in the EU (see Section 4.2 for US and 
Australian approvals).  
 
Over the past two decades, many theoretical and clinical aspects of the use of SIR-Spheres Y-90 
resin microspheres for the treatment of primary and metastatic liver cancer have been published, 
including: 
 
• microsphere characteristics (Meade 1987 (47)),  
 
• the relationship between the amount of yttrium-90 administered and radiation dose 
received by the tumour and normal liver compartments (Burton 1990 (8); Burton 1989 
(9); Gray 1989 (22); Klemp 1989 (41)),  
 
• the tolerance of the liver to yttrium-90 radiation (Gray 1990 (21)),  
 
• enhancement with vasoactive drugs (Burton 1985 (10)),  
 
• dosimetry (Fox 1991 (16); Klemp 1989 (41)),  
 
• and clinical responses to treatment in both metastatic colorectal cancer (Seidensticker 
2012 (60); Cosimelli 2010 (14); Hendlisz 2010 (25); van Hazel  2009 (67); Sharma 2007 
(61); van Hazel 2004 (66); Gray 2001 (20); Gibbs 2015 (18)); 
 
• metastatic neuroendocrine cancer (Cao 2010 (12); Kalinowski 2009 (30); Kennedy 2006 
(33); Kennedy 2008 (32); King 2008 (40); Meranze 2007(48); Murthy 2008(49); 
 
• hepatocellular carcinoma (Gulec 2007 (23); Jakobs 2007 (28); Sangro 2011 (57)), 
  
• and intrahepatic cholangiocarcinoma (Coldwell 2006 (13)); Hoffman 2011 (27); Saxena 
2010 (58)); Khanna 2009 (38); Rafi 2011 (0); Gaba 2009 (17). 
 
 
 


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 16 of 93 
6 
STUDY  JUSTIFICATION  
The following discusses the justification for this clinical study in intrahepatic cholangiocarcinoma: 
 
6.1 
Biliary Tract Cancer 
Malignant tumours of the biliary tract and gallbladder (biliary tract system) are rare diseases with 
an incidence of estimated 5 new cases per 100,000. Biliary tract cancer (BTC) is a rare cancer 
with a large worldwide variation. According to Randi (Randi 2009 (52)) and collaborators the 
incidence is relatively low in several European countries and in the United States, while it is 
relatively high in selected central and eastern European countries, and very high in some 
countries of Latin America and Asia. However the incidence is rapidly rising even in western 
countries. While biliary tract cancer is diagnosed more often in male patients the incidence of 
malignant tumours in the gallbladder is found more often in females: the male/female ratio is 
2:1. Intrahepatic cholangiocarcinoma is the second most prevalent intrahepatic primary cancer. 
It occurs in the middle-aged and elderly with no obvious sex differences.  
 
6.2 
Current Treatment Options for Intrahepatic Cholangiocarcinoma 
Intrahepatic cholangiocarcinoma is defined as a cholangiocarcinoma originating within the liver 
and located proximally to the second degree bile ducts.  
 
6.2.1 Surgery 
 
Although surgery of the tumour represents the only curative treatment modality the 5-years 
survival rates for cholangiocarcinoma are low (< 30%) and the patients are often diagnosed too 
late for surgical treatment.  
 
6.2.2 Transplantation 
 
Liver transplantation is reported as a potentially curative option for selected patients with 
perihilar but not with intrahepatic or distal cholangiocarcinoma (Razumilava 2014 (53)). This 
option is not available in most countries and often requires neo-adjuvant multi-modal treatment.  
 
6.2.3 External Beam Radiation Therapy 
Radiation therapy (RT) may be employed as a local modality as the technologies are improving 
both for efficacy and safety.  There is no current standard of care of radiotherapy as a routine 
modality. The optimal radiation dose in the definitive treatment of biliary malignancies is 
unknown, however higher dose radiotherapy (RT) approaches that use either a combination of 
transcatheter brachytherapy plus external beam radiation therapy (EBRT), three-dimensional 
conformal radiation therapy (3D-CRT), or intensity modulated radiation therapy (IMRT) with or 
without chemotherapy may be associated with better local control (LC) and possibly prolonged 
survival. Advances in imaging and radiation technology delivery such as image guided 
radiotherapy (IGRT) and stereotactic body radiotherapy (SBRT) ((Maithel 2013 (45), Kim, 2013 
(39), Aitken 2014 (3) now permit tumouricidal doses of radiation to be delivered safely. 
 
The evidence regarding the use of radiotherapy in cholangiocarcinoma is scarce. Systematic 
Reviews and Meta-Analyses (PRISMA) review of the role of radiotherapy in primary liver 
malignancies. (Aitken 2014(3)) 
 


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 17 of 93 
6.2.4 Chemotherapy  
After the publication of ABC-01 (Valle 2009 (63)) and ABC-02 (Valle 2010 (64)) studies, the 
combination of gemcitabine plus cisplatin as per the ABC-02 protocol, became the standard of 
care or reference treatment in most countries. Between 2005 and 2009, the National Cancer 
Research Institute (NCRI) Upper Gastrointestinal Clinical Studies Group (CSG) conducted the 
ABC-02 trial, a randomised phase III design evaluating the benefit of gemcitabine with or 
without cisplatin in advanced or metastatic BTC. The ABC-02 (Valle 2010 (64)) data was 
combined with data from a previous randomised phase II study with an identical design [ABC-
01 (Valle 2009 (63)]. This pre-planned analysis of the combined data demonstrated an 
improvement in overall survival (OS; from 8.3 to 11.7 months hazard ratio 0.64 [95% CI 0.52 – 
0.80, p<0.001]), progression-free survival (PFS; from 5.0 to 8.0 months, p<0.001) and tumour 
control rate (radiological stable disease, partial or complete response, 71.8% to 81.4%, p=0.049). 
This improvement was achieved with no significant increase in toxicity and improved quality of 
life.  
 
The ABC-02 (Valle 2010 (64)) study has established cisplatin and gemcitabine (CIS-GEM) as 
the standard of care for advanced BTC as well as providing a backbone for subsequent studies. 
A meta-analysis (Valle 2014 (65)) including data from the BT22 Japanese study (Okusaka 2010 
(50)) using the same treatment arms as the ABC-02 study (Valle 2010 (64)) has confirmed that 
CIS-GEM combination is the 1st line standard of care in good performance status (PS) patients 
regardless of ethnicity, in both intra and extrahepatic tumour locations. 
 
The CIS-GEM regimen as developed in the ABC studies is confirmed as reference treatment in 
the current ESMO and EASL guidelines. 
According to the ESMO guideline (Valle JW et al. Ann Oncol. (2016)), “Cisplatin/gemcitabine 
is the reference chemotherapy regimen for good PS (0-1) patients”. 
According to the EASL guideline (Bridgewater J et al, J Hepatol. 2014 Jun (7)), “Cisplatin and 
Gemcitabine is a systemic therapy practice standard for iCCA in patients with ECOG 
performance status 0 or 1, but the data are too limited to make this an established standard of 
care” 
 
Because the curative options are still limited and the outcome is poor, enrolment in clinical trials 
is recommended when possible. 
 
6.3 
Justification for this Clinical Study 
Despite the advances in different modalities for cholangiocarcinoma the 3 and 5 year survival in 
non-surgically resected selected patients remains below 50% and 10% respectively.  
 
This approach to integrating potentially curative tumouricidal therapies (ablation, locoregional 
SIRT and external beam radiotherapy) in patients with unresectable intrahepatic 
cholangiocarcinoma has to be compared to the current standard of care therapy – cisplatin and 
gemcitabine (CIS-GEM) systemic chemotherapy (Valle 2009 (63), Valle 2010 (64)) – in order 
to judge potential benefits. 
SIR-Spheres Y-90 resin microspheres have been studied for the treatment of patients with 
inoperable intrahepatic cholangiocarcinoma. Although no randomised controlled study has been 
performed to date, the results of SIRT in patients with ICC, in either prospective or retrospective 
cohort studies, look very promising and provide preliminary evidence that SIRT is a safe and 
effective treatment option for unresectable ICC. The studies are summarised in table 1 below.  
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
Table1. Summary of prospective and retrospective Clinical Study Results of SIR-Spheres 
Y-90 resin microspheres in unresectable intrahepatic cholangiocarcinoma 
Study Autho1· & 
Treatment 
ORR(%) 
SD 
Median Sm-vival 
Median Sm-viva] 
Desi2n 
n 
Post SIRT 
Post Dia2nosis 
Saxena 
25 
SIRT alone 
24% 
48% 
9.3 months 
20.4 months 
2010 (59) 
Coldwell 
23t 
SIRT alone 
45% 
NR 
74% alive at 14 
NR 
2006 (13) 
months 
Khanna 
9t 
SIRT 
66% 
13.5 months 
20.0 months 
2009 (38) 
Rafi 
19t 
SIRT 
79% 
11.3 months 
24.7 months 
2011 (0) 
Hoffmann 
33t 
SIRT alone 
36.4% 
51.5% 
22 months 
43.7 months 
2011 (27) 
Gaba 
It 
SIRT alone 
1 CR 
Na 
Alive at 1 7 months 
NR 
2009 (17) 
(Simde al'm) 
NR: 
not reported 
ORR: 
objective response rate (complete response+ partial response) by RECIST 
SD: 
stable disease 
na 
not applicable 
t 
Retrospective study 
Accordingly, this study will assess the benefit of applying SIRT prior to the initiation of the 
standard regimen of cisplatin and gemcitabine (CIS-GEM) systemic chemotherapy m 
unresectable liver-only or liver predominant intrahepatic cholangiocarcinoma. 
Patients will be offered the accepted treatment in conventional practice and in the active aim of 
the trial, the standard of care will be preceded with radioembolisation. Such a trial design 
guarantees that patients do not lose the benefits of conventional therapy and allows the 
dete1mination of smvival benefits of the SIR T treatment. As a consequence, the trial design does 
not pose any ethical concern that would exist if standard of care would not be incorporated. The 
investigator must at the outset, before consent, have the intention to provide the standard of care 
chemotherapy regimen irrespective of which treatment ann the patient is randomised. 
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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 19 of 93 
7 
CLINICAL RISK SUMMARY 
7.1 
Complications of SIR-Spheres Y-90 Resin Microspheres 
As at July 2015, approximately 50,000 doses of SIR-Spheres microspheres have been supplied 
globally for the management of patients with inoperable liver cancers at more than 800 medical 
centres in over 40 countries. Overall, the incidence of complications after SIR-Spheres Y-90 
resin microspheres therapy in broader clinical use is low. This is enhanced if patients are selected 
appropriately and target delivery (i.e. liver) is performed meticulously.  
 
7.1.1 Post Embolisation Syndrome 
Mild symptoms attributable to the radiotherapeutic and embolic effect of microsphere deposition 
into the hepatic vasculature have been reported (Sirtex Package Insert and Ahmadzadehfar 2010 
(2)). These may include fever, mild to moderate abnormality of liver function tests, nausea, 
vomiting, constipation, dehydration and associated symptoms/sequelae including acute renal 
failure, confusion, fatigue, and weakness. Symptoms are typically mild to moderate, transitory 
and manageable with the administration of oral corticosteroids, IV steroids and analgesics, as 
necessary.  
 
7.1.2 Gastrointestinal Complications 
Gastrointestinal complications occur in less than 10% of those treated (Kennedy 2006 (33); 
Stubbs 2004 (62) and are largely preventable. In the SIRFLOX study (Gibbs 2015 (18)), the 
gastric and duodenal ulceration rate have been reported after SIRT in 3.7% (per ITT), they are 
related to the inadvertent intestinal deposition of microspheres via extra-hepatic visceral arterial 
branches. Even in the absence of extra-hepatic activity on 99mTc labelled MAA and 
bremsstrahlung emission images, gastrointestinal symptoms have been reported to develop. The 
risk of gastrointestinal ulceration can be minimised via the routine coil embolisation of the extra-
hepatic visceral arteries (e.g. gastroduodenal, right gastric, supraduodenal arteries) before 
infusion of SIR-Spheres Y-90 resin microspheres (Liu 2005(43)). 
 
The gallbladder may also receive SIR-Spheres Y-90 resin microspheres through a patent cystic 
artery, leading to radiation cholecystitis. In order to avoid this potential complication, infusion 
of the SIR-Spheres Y-90 resin microspheres distal to the origin of the cystic artery may be 
possible. However, even with infusion of SIR-Spheres Y-90 resin microspheres proximal to the 
cystic artery, the risk of radiation cholecystitis requiring cholecystectomy is low (Liu 2005(43)). 
This issue is addressed at the time of administration by the treating interventional radiologist via 
catheter placement and/or selective embolisation/optimization of the hepatic arterial vasculature. 
 
7.1.3 Hepatic Complications 
Radioembolisation induced liver disease (REILD) is a rare complication following SIRT (Sangro 
2008 (56)) and is characterized by a well-defined constellation of temporal, clinical, biochemical 
and histopathologic findings. REILD typically manifests approximately 4 – 8 weeks post-SIRT 
and is characterized clinically by jaundice and ascites in the absence of tumour progression or 
bile duct obstruction. The typical biochemical picture of REILD is an elevated bilirubin 
(>3mg/dL) in almost all cases, elevated alkaline phosphatase (ALP) and gamma-glutamyl 
transpeptidase (GGT) in most cases, accompanied by virtually no change in the transaminases 
(AST and ALT). In the event that a liver biopsy is performed, the typical histological appearance 
is of sinusoidal obstruction. 
 


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 20 of 93 
REILD may occur in both non-cirrhotic and cirrhotic patients. In non-cirrhotic patients, the main 
risk factors for the development of REILD include prior exposure to systemic chemotherapy and 
whole-liver SIRT. In cirrhotic patients, the main risk factors are small liver volume (< 1.5L) and 
elevated bilirubin (> 1.2mg/dL) at baseline. The treatment of REILD is absolutely empiric and 
may comprise a tapering schedule of initially high dose corticosteroids, and standard dose 
ursodeoxycholic acid. If liver decompensation develops, imaging, diuretics, defibrotide or early 
TIPS placement should be considered on an individual basis.  Low molecular weight heparin 
may also be considered but both corticosteroids and heparin may only be useful if commenced 
very early in the course of the disease. 
 
7.1.4 Pulmonary Complications 
Progressive pulmonary insufficiency secondary to radiation pneumonitis and radiation-induced 
lung fibrosis can be avoided by excluding from SIRT any patient with significant liver-to-lung 
shunting (Leung 1995 (42)). The shunting of microspheres through the liver and thence into the 
lungs occurs via abnormal arterio-venous malformations (AVMs), which are characteristic 
within primary hepatocellular carcinomas but are rare in metastatic liver tumours. It is relevant 
to note that there have not been any cases of radiation induced lung disease reported in HCC 
patients undergoing SIRT since routine pre-treatment liver-to-lung shunt quantification has been 
standard practice. 
 
7.1.5 Haematological Complications 
Pancytopenia as a result of bone marrow suppression from the leaching of yttrium-90 was 
reported after the use of the earliest microsphere device (Mantravadi 1982 (46)). The 
development of SIR-Spheres Y-90 resin microspheres – which are classified as a sealed-source 
device – solved the problem of leaching of yttrium-90 from the microsphere carrier. 
Consequently, this complication has very rarely been reported since that time. Transient and 
reversible lymphopenia or neutropenia (including febrile neutropenia) are possible, particularly 
if concomitant immunosuppressive agents are used with SIR-Spheres Y-90 resin microspheres. 
In the SIRFLOX study which compared the addition of SIR-Spheres Y-90 resin microspheres 
with oxaliplatin based chemotherapy vs oxaliplatin based chemotherapy, (N = 530 patients) 
grade 3/4 neutropenia was reported in 40.7% of the patients in the SIRT arm compared to 28.5% 
in the control group, thrombocytopenia in 9.8% versus 2.6%. The toxicities were as expected 
and manageable (Gibbs 2015 (18)).  
 
7.2 
Known Contraindications to SIR-Spheres Y-90 resin microspheres 
In the treatment of liver cancer, it is established that SIR-Spheres Y-90 resin microspheres are 
contraindicated (Sirtex Package Insert) in patients who have: 
 
• 
Received previous external beam radiation therapy to the liver 
• 
Ascites or other clinical signs of liver failure 
• 
Abnormal synthetic and excretory liver function tests as determined by serum albumin 
(must be > 3.0 g/dL) and total bilirubin (must be < 2.0 mg/dL), respectively 
• 
Disseminated extra-hepatic disease 
• 
Tumours amenable to surgical resection or ablation with intent to cure 
• 
Greater than 20% liver-to-lung shunting, as determined by pre-treatment nuclear medicine 
shunt quantification study 
• 
Pre-assessment angiogram and MAA nuclear medicine scan demonstrating significant and 


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 21 of 93 
uncorrectable activity in the stomach, duodenum or pancreas 
• 
Been treated with capecitabine within the previous 8 weeks, or who will be treated with 
capecitabine within 8 weeks of treatment with SIR-Spheres Y-90 resin microspheres 
 
7.3 
Identifying risks of combining SIR-Spheres Y-90 resin microspheres with 
chemotherapy 
Previous studies documenting the combined use of SIR-Spheres Y-90 resin microspheres and 
contemporary systemic chemotherapy have indicated that when used in combination with either 
5-FU/LV, or with irinotecan that there has been no detectable increase in adverse events in 
comparison with SIR-Spheres microspheres alone (van Hazel 2004 (67), van Hazel 2009 (66)). 
 
Concomitant use of SIR-Spheres Y-90 resin microspheres and oxaliplatin (as part of a FOLFOX 
regimen), as demonstrated in a 20 patient dose-escalation study, has resulted in a slight increase 
in neutropenia in the immediate cycles following treatment. This decrease was transient, being 
resolved by a 1-week delay in the administration of chemotherapy. Besides the early neutropenia 
the rate of adverse events reported in this study was similar to those normally reported for 
FOLFOX chemotherapy alone (Sharma 2007 (61)).  
 
More recently, the SIRFLOX randomised controlled study reported on the efficacy and safety of 
SIR-Spheres Y-90 resin microspheres when administered concurrently with mFOLFOX6 
chemotherapy (Gibbs 2015 (18)). Recently reported early safety data from this study showed a 
statistically significant increase in the rate of grade 3 or higher neutropenia, febrile neutropenia 
and thrombocytopenia in patients receiving mFOLFOX6 chemotherapy + SIR-Spheres Y-90 
resin microspheres compared to patients receiving mFOLFOX6 chemotherapy alone. The study 
also reported a statistically significant increase in the rate of grade 3 or higher gastric or duodenal 
ulcers and ascites in patients receiving the combination therapy. However, the addition of SIR-
Spheres Y-90 resin microspheres to mFOLFOX6 chemotherapy was shown to have no negative 
impact on the duration of systemic chemotherapy and the study investigators concluded that 
these toxicities were acceptable and as predicted. 
 
To date, there are no formal prospectively collected clinical data reporting the efficacy, 
tolerability or safety of SIR-Spheres Y-90 resin microspheres given concurrently with either 
cisplatin, gemcitabine, or a combination of these two agents. In the present study however, the 
systemic agents, cisplatin and gemcitabine, will not be administered concurrently with SIR-
Spheres Y-90 resin microspheres but instead will be withheld until 14-16 days following the 
administration of SIR-Spheres Y-90 resin microspheres. 
 
The half-life of yttrium-90 is approximately 64.1 hours so that in therapeutic use, requiring the 
isotope to decay to infinity, 94% of the radiation is delivered in 11 days. Given these decay 
characteristics for the yttrium-90 isotope approximately 3% of the radiation will be expected to 
be remaining at the time of initiation of cisplatin-gemcitabine chemotherapy 14 -16 days post-
SIRT. In addition, gemcitabine is a potent radiosensitizer, and has a half-life of up to 94 minutes 
when administered in a short infusion over < 70 minutes. Given the time between administration 
of SIR-Spheres Y-90 resin microspheres and commencement of gemcitabine, the vast majority 
of the radiation will have decayed, thereby minimising any additive toxicities between the 
radiation emitted from SIR-Spheres Y-90 resin microspheres and gemcitabine. Given this 
therapeutic sequencing, the risk of toxicity due to an unknown or unforeseen interaction between 
the therapeutic agents is considered acceptable, within this study setting.  


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 22 of 93 
8 
DEVICE RISK ANALYSIS 
As CIS-GEM is the reference chemotherapy regimen for cholangiocarcinoma, a risk analysis 
performed in accordance with ISO 14971 addressing the use of SIR-Spheres Y-90 resin 
microspheres followed by cisplatin-gemcitabine chemotherapy is maintained on file at Sirtex as 
part of the Design File for this study. This is a Quality Record and is recorded and maintained 
under the Sirtex Quality Management System, which includes additional Risk Management 
relating to production processes. All risk analysis documents are updated as required or reviewed 
at least every two years.  
 
For the use outlined in this Clinical Investigational Plan (CIP), all identified unacceptable 
hazards have been addressed and control strategies are in place to render the hazards acceptable. 
It is concluded that there are no unacceptable hazards remaining and based on supporting 
published literature the potential patient benefits of SIRT (using SIR-Spheres Y-90 resin 
microspheres plus Delivery Set and V-Vial) outweigh the risks with an anticipated 15% 
improvement in survival at 18 months. 
 
 
 


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 23 of 93 
9 
STUDY DESIGN 
The study is a prospective, multicentre, randomised, controlled study evaluating SIR-Spheres Y-
90 resin microspheres preceding standard cisplatin-gemcitabine (CIS-GEM) chemotherapy vs. 
CIS-GEM chemotherapy alone as first-line treatment of patients with unresectable intrahepatic 
cholangiocarcinoma.  
 
Patients will be randomised 1:1 (about 90 patients in each arm) and will be stratified by: presence 
of extra-hepatic disease, presence of cirrhosis, intention for whole liver versus non-whole liver 
Y-90 treatment, ECOG (0 versus 1) and prior adjuvant therapy vs no prior adjuvant therapy.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cirrhosis:  
Absence of cirrhosis should be registered when 
• The non-tumoural part of the liver is regular and without nodularity on imaging and 
• There is no evidence of portal hypertension with no clinically significant ascites, oesophageal 
varices or splenomegaly with dilated portal vein in the absence of portal vein thrombosis.  
 
Detection of any of the above findings, and/or a positive biopsy diagnosis (F4=cirrhosis 
according to the METAVIR scoring system) and/or an increased elastography value, establishes 
the existence of cirrhosis. 
 
Randomised patients will be followed until death, withdrawal of consent, or until end of study. 
A comparison between treatment arms will be made. 
 
The enrolment period for the study is estimated to be 40 months. The study will be conducted in 
approximately 45 selected investigational sites worldwide. The sponsor will maintain a list of 
principal investigators, investigational sites, and institutions. The definitive list will be provided 
with the final clinical study report.  
 
9.1 
Patient Eligibility 
Patients must have histologically or cytologically confirmed intrahepatic cholangiocarcinoma. 
 
In order to be considered eligible for this study, patients must fulfil the inclusion and exclusion 
Patients: 
 
Patients with 
unresectable 
intrahepatic 
cholangio-
carcinoma (ICC) 
 
Stratify: 
• 
Extra-hepatic 
disease 
• 
Cirrhosis 
• 
Whole liver 
vs. non-
whole liver 
intended  Y-
90 treatment 
• 
ECOG 0 vs. 
ECOG 1 
• 
Prior 
adjuvant 
therapy 
yes/no 
 
R 
A 
N 
D 
O 
M 
I 
S 
E 
Treatment Arm A 
Systemic chemotherapy 
CIS-GEM 
Treatment Arm B 
SIR-Spheres Y-90 resin 
microspheres 
followed by systemic 
chemotherapy CIS-GEM 
\ 
I 
t 
t 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 24 of 93 
criteria specified in 9.2 below. 
9.2 
Inclusion/Exclusion Criteria 
9.2.1 Inclusion Criteria 
a) Willing, able and mentally competent to provide written informed consent 
b) Aged 18 years or older 
c) Histologically or cytologically confirmed unresectable and non ablatable intrahepatic 
cholangiocarcinoma 
d) Liver-only or liver predominant intrahepatic cholangiocarcinoma. Patients are permitted 
to have loco-regional lymph node involvement defined as: portal LN ≤ 2 cm and/or para 
aortic LN ≤ 1.5 cm in longest diameter, and/or up to 2 indeterminate lung lesions < 1 cm 
if these lung lesions are PET negative.  
e) Chemotherapy for advanced disease naïve. Capecitabine only based adjuvant 
chemotherapy is permitted (last administered dose of capecitabine ≥ 6 months prior 
randomization in the study). 
f) ECOG performance status 0 or 1 
g) Adequate haematological function defined as:  
Haemoglobin  10g/dL 
WBC ≥ 3.0 x 109/L 
Absolute neutrophil count (ANC)  1.5 x 109/L  
Platelet count  100,000/mm3, 
h) Adequate liver function defined as:  
Total bilirubin ≤ 30 µmol/L (1.75 mg/dL) 
Albumin ≥ 30 g/L 
i) Adequate renal function defined as:  
Serum urea and serum creatinine < 1.5 times upper limit of normal (ULN)  
Creatinine clearance ≥ 45 ml/min (calculated with Cockcroft-Gault Equation) 
 
All blood test results must be within 14 days prior to randomisation.  
 
j) Life expectancy of at least 3 months without any active treatment 
k) Female patients must either be postmenopausal, sterile (surgically or radiation- or 
chemically-induced), or if sexually active use an acceptable method of contraception 
during the study.  
l) Male patients must be surgically sterile or if sexually active must use an acceptable 
method of contraception during the study.  
m) Considered suitable to receive either treatment regimen in the clinical judgement of the 
treating investigator. 
 
9.2.2 Exclusion Criteria 
a) Patients with only non-measurable lesions in the liver according to RECIST criteria  
b) Incomplete recovery from previous liver surgery, e.g. unresolved biliary tree obstruction 
or biliary sepsis or inadequate liver function 
c) Biliary stent in situ 
d) Main trunk Portal Vein Thrombosis (PVT) 
e) Ascites, even if controlled with diuretics (a minor peri-hepatic rim of ascites detected at 
imaging is acceptable). 
f) Mixed HCC-ICC disease. 


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 25 of 93 
g) History of prior malignancy. Exceptions include in-situ carcinoma of the cervix treated 
by cone-biopsy/resection, non-metastatic basal and/or squamous cell carcinomas of the 
skin, recurrent intra-hepatic cholangiocarcinoma post local treatment or any early stage 
(stage I) malignancy adequately resected with curative intent at least 5 years prior to study 
entry 
h) Suspicion 
of 
any 
bone 
metastasis/metastases 
or 
central 
nervous 
system 
metastasis/metastases on clinical or imaging examination.  
i) Prior internal or external radiation delivered to the liver. 
j) Pregnancy; breast feeding, 
k) Participation within 28 days prior to randomisation, in an active part of another clinical 
study that would compromise any of the endpoints of this study.  
l) Evidence of ongoing active infection that may affect treatment feasibility or outcome. 
m) Prior Whipple’s procedure 
 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 26 of 93 
10 SCREENING AND  STUDY ENTRY 
No patient may undergo any screening procedures that are not considered standard of care to 
assess his/her eligibility to receive protocol treatment, or commence protocol treatment, prior to 
signing the informed consent form.  
 
The study Sponsor should be contacted in the event of any query or uncertainty relating to a 
patient’s eligibility:  
 
Sirtex Technology Pty Ltd 
Clinical Operations 
 
Europe 
Tel: +49 228 18407 30 
Fax: +49 228 18407 35 
United States 
Tel: +1 781 721 3840 
Fax: +1  877 221 0256 
Australia 
Tel: +61 2 9964 8400 
Fax: +61 2 9964 8410 
 
10.1 
Patient Screening 
All patients referred for possible participation in this study must be assessed at screening to 
confirm the patient’s eligibility to be randomised into the study. Screening assessments must be 
performed within 28 days prior to randomisation, in the exception of haematology/biochemistry 
assessments, which must be performed within 14 days prior to randomisation.  
 
All documentation in support of the inclusion and exclusion criteria and screening investigation 
results are to be retained by the Investigator and made available for monitoring by the study 
Sponsor. 
 
Study entry is defined as the date that the Informed Consent has been signed by the patient. 
After signing the informed consent, the patient will be allocated with a screening number. 
 
All patients assessed as ineligible after study entry (date of informed consent) are considered 
screening failures. The reasons for screen failures will be collected and capture in the eCRF as 
well as on the screening log. The Patient Screening Log will include the reason(s) for the patient 
not meeting the eligibility criteria and will be maintained by the site and copies retained by the 
study Sponsor. These patients will be treated with best available care at the discretion of the 
treating physician and local guidelines. No further information will be captured. 
 
10.2 
Histological / Cytological Investigation 
Histological or cytological evidence of intrahepatic cholangiocarcinoma must be available prior 
to randomisation and is commonly available as routine clinical practice.  
 
10.3 
Clinical Assessments 
All patients must be assessed clinically by the Investigator to determine the patient’s eligibility 
to receive protocol treatment prior to the study entry. Clinical assessment includes a 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 27 of 93 
comprehensive medical history with concurrent illnesses and concomitant medication.   
 
10.4 
Physical Examination and Performance Status 
Physical examination and patient’s height, weight, blood pressure and temperature must be 
performed within 28 days prior to randomisation. 
All patients must have an ECOG performance status 0 or 1. 
 
10.5 
Haematological and Biochemical Investigations 
All patients are required to undergo the following haematological and biochemical assessments 
in order to confirm their eligibility to be randomised into the study.  
All blood test results must be within 14 days prior to randomisation 
 
Haematological 
Haemoglobin 
WBC 
Absolute neutrophils 
Platelets 
Liver 
Total bilirubin 
Albumin 
Renal 
Serum urea 
Serum creatinine  
Creatinine Clearance 
Pregnancy test 
Serum or urine pregnancy test in premenopausal 
female patients 
 
Local practice guidelines such as NICE guidance, EASL guidelines or AASLD-IDSA 
Recommendations should be followed for Testing, Managing, and Treating Adults Infected with 
HCV or HBV which may interfere with systemic treatment of the protocol. 
 
10.6 
Radiological Investigation: CT Scan of the Abdomen, Chest, Pelvis 
All patients are required to have the following radiological investigation in order to confirm their 
eligibility to be randomised in the study, and to demonstrate the extent of the disease, and the 
intention for whole liver or non-whole liver treatment. This scan must be performed within 28 
days prior to randomisation. 
 
A contrast enhanced CT scan of the chest, abdomen and pelvis must be available for assessment 
of local-regional, or distant spread, staging, and resectability.   
 
Refer to APPENDIX 6 for recommended acquisition guidelines for CT scanning 
 
If the CT scan which was performed prior to study entry was also obtained within 28 days prior 
to commencement of protocol treatment, it can be used for baseline RECIST assessment too. 
The same acquisition parameters should be maintained and also need to be consistent with the 
follow up scans.  
 
If the CT scan performed prior to study entry was obtained > 28 days before start of protocol 
treatment or the acquisition parameters will not be consistent with the follow up parameters, then 
the baseline CT scan must be repeated.  


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 28 of 93 
 
10.7 
Quality of Life 
Quality of life (QoL) will be measured by using the EQ-5D questionnaire. The EQ-5D will be 
completed at screening. 
 
10.8 
Randomisation 
Upon documentation of confirmed eligibility, the patient will be randomised and allocated with 
a patient enrolment number. The patient enrolment number will be multi-digit, to represent the 
investigational site and will be unique to each subject. This will be the patient’s ID number to be 
used throughout the entire study. 
 
The subject’s ID number will be used in the electronic CRF. A total of about 180 patients will 
be randomised 1:1 between the two treatment groups (about 90 patients in each group). 
 
Any patients who are not able to receive the treatment according to the assigned study arm, 
irrespective of the reason, will continue to be followed and assessed according to the CIP and 
their data will be captured in the eCRF. They will be analysed per the assigned study arm 
according to the intention to treat principle (see 15.3) 
 
 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
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11 BASELINE ASSESSMENTS 
The following baseline assessments are required within 7 days prior to start of protocol 
treatment: 
11.1 
Physical Examination and ECOG performance status 
All patients are required to undergo a full physical examination including weight, blood pressure 
and body temperature. Also, the ECOG performance status has to be assessed by the 
Investigators. 
Full Physical examination includes assessment of the following body systems:  
Dermatological 
HEENT / Neck 
Respiratory 
Cardiovascular 
Gastrointestinal / Digestive 
Genitourinary 
Neurological 
Musculoskeletal 
Endocrine 
Hematologic / Lymphatic 
Metabolic / Nutritional 
General Appearance 
 
11.2 
Haematological and Biochemical Investigations 
All patients are required to undergo the following haematological and biochemical assessments 
within 7 days of treatment commencement in order to confirm their eligibility to receive protocol 
treatment.  
 
Haematological 
Haemoglobin 
WBC 
absolute neutrophils 
platelets 
Liver 
Total bilirubin 
Albumin 
ALT, AST, AP, GGT 
Renal 
Serum urea 
serum creatinine 
sodium, potassium, calcium, phosphate, glucose 
creatinine clearance 
Tumour markers 
CEA 
CA 19-9 
CA125 
AFP 
 
 
Additionally, for patients randomised to Arm B, tumour markers are also to be done within 7 
days prior to SIRT eligibility workup, and do not need to be repeated prior to SIRT treatment. 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 30 of 93 
 
11.3 
Radiological Investigation: CT Scan of the Abdomen, Chest, Pelvis 
A contrast enhanced CT scan of the chest, abdomen and pelvis must be available for assessment 
of local-regional, or distant spread, staging, and resectability.   
Refer to APPENDIX 6 for acquisition guidelines for CT scanning 
 
Imaging must be performed within 28 days prior to the start of protocol treatment. In case a CT 
scan of chest, abdomen, pelvis was obtained for eligibility confirmation more than 28 days prior 
to commencement of protocol treatment, a new baseline CT scan must be obtained during the 
Baseline period, i.e. within 28 days prior to start of protocol treatment. 
 
11.4 
Baseline Measurement of Lesions 
The extent of disease will be recorded and measured according to the RECIST 1.1 Guidelines 
(RECIST: Response Evaluation Response Criteria In Solid Tumours) and refined RECIST (Reig 
2014 (54)) (See APPENDIX 7). 
 
11.5 
Selective internal radiation therapy (SIRT)  
The SIRT procedure comprises of a baseline mapping angiogram to determine the vascular 
anatomy of the liver and potential coil embolisation of afferent vessels that may arise from the 
hepatic arteries and supply other organs, followed by the actual implantation of the SIR-Spheres 
Y-90 resin microspheres which occurs 3 – 8 days after the baseline mapping angiogram. The full 
process is described in detail in the Sirtex Training Manual, which is provided by Sirtex to all 
users.  
 
11.6 
Commencement of Protocol Treatment 
Protocol treatment may commence once patients have been randomised into the study. Suitability 
to receive SIRT (patients in Arm B) must be reconfirmed prior to the implantation of SIR-
Spheres Y-90 resin microspheres. The study Sponsor should be contacted in the event of any 
query or uncertainty relating to patient’s suitability to receive SIRT. 
 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
12 TREAT;\IE:.\"T 
Consenting patients satisfying the study eligibility criteria, will be randomised to receive either 
a) Treatment Alm A: 
Standard of care systemic chemotherapy (as per ESMO guidelines) consisting of 8 
cycles of cisplatin + gemcitabine (CIS-GEM) or until progression 
or 
b) Treatment Alm B: 
A single treatment of hepatic aiterial injection of SIR-Spheres Y-90 resin 
microspheres followed by standard of cai·e systemic chemotherapy (as per ESMO 
guidelines) consisting of 8 cycles of cisplatin + gemcitabine or until progression. 
Treatment may be continued beyond 8 cycles, in the absence of disease progression, at the 
treating clinicians' discretion. 
12.1 
Treatment Arm A: Chemotherapy Arm- CIS-GEM (as per ESMO guidelines) 
Systemic chemotherapy (CIS-GEM) to stait within 14 days(+ 2 days) ofrai1domisation: 
The reference regimen as per ESMO guidelines and ABC 02 protocol consists of: 
2 
Cisplatin 25 mg/m in 1000ml 0.9% saline given over 1 hom followed by 500 ml 0.9% saline 
over 30 minutes followed by 
2 
Gemcitabine 1000 mg/m in 250 - 500ml 0.9% saline over 30 minutes by intravenous infusions 
on days 1, and 8 of a 21-day cycle. 
8 treatment cycles will be given; in the absence of progression treatment may be continued at 
discretion of the clinician. 
Cycle l 
Cycle 2 
Cycle 3 
Cycle 4 onwards 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Day 
1 
8 
1 
8 
1 
8 
1 
8 
Cisplatin 
X 
X 
X 
X 
X 
X 
X 
X 
Gemcitabine 
X 
X 
X 
X 
X 
X 
X 
X 
See APPENDIX 5 for recommended guidelines for CIS-GEM chemotherapy administration as 
per the ABC-02 regimen. 
12.2 
Treatment Arm B: Sequential Therapy Arm - SIRT followed by CIS-GEM 
SIR-Spheres Y-90 resin microspheres to be administered at the calculated dose within 14 days 
of randomisation followed by standard of care systemic chemotherapy (CIS-GEM), to stait 14-
16 days after SIRT treatment (or at the earliest point thereafter on recovery of any 
haematological, bilirnbin or albumin derangements if they occm). 
12.2.1 Assessing patient suitability for SIRT (Work-Up) 
Patients randomised to receive the SIR-Spheres Y-90 resin microspheres plus systemic 
chemotherapy (Alm B) need to be assessed in order to determine their suitability for SIRT. 
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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 32 of 93 
 Hepatic angiogram 
Patients must undergo a preliminary mapping angiogram of the liver, between 3 and 8 days prior 
to the implantation of SIR-Spheres Y-90 resin microspheres to determine the vascular anatomy 
of the liver and to perform a nuclear medicine ‘break-through’ scan performed with 99mTc-MAA. 
The hepatic angiogram will provide a road map of the arterial supply of the liver in order to plan 
delivery of the SIR-Spheres microspheres. (See the Training Manual provided by Sirtex). It is 
important to note that the MAA have to be delivered at the same anatomical place where the 
SIR-Spheres Y-90 resin microspheres are intended to be administered. The hepatic angiogram 
should be performed together with the nuclear medicine ‘break-through’ scan and results must 
be available prior to the implantation of SIR-Spheres Y-90 resin microspheres. Anonymised 
copies of the 99mTc-MAA imaging, i.e. planar images, SPECT/CT, and/or SPECT/MRI, will be 
collected for potential central review. 
 
Patients showing abnormal vascular anatomy on the angiogram which would result in a 
significant reflux of blood from the hepatic artery to the stomach, the pancreas or the intestines 
that cannot be prevented by coil embolisation of the appropriate arteries are not suitable for SIRT 
treatment. 
 
Liver-to-lung nuclear medicine break-through scan 
In some patients there will be significant arterio-venous shunts in the liver which will allow more 
than 10% of the SIR-Spheres Y-90 resin microspheres injected into the liver to pass through the 
liver and lodge in the lungs. As excessive liver-to-lung shunting may cause radiation damage to 
the lungs, a nuclear medicine ‘break-through’ scan must be performed in all patients to exclude 
this level of arterio-venous flow.  
 
The percentage of technetium-99m labelled macro-aggregated albumin (MAA) that has escaped 
through the liver and lodged in the lungs can then be expressed as a ‘per cent lung shunting’. 
Normally this is less than 10% in patients with liver metastases from colorectal cancer. The total 
lung radiation dose delivered by SIR-Spheres Y-90 resin microspheres must be kept at 25 Gy or 
lower. It is assumed that the mass of both lungs plus blood is 1000gm and allows estimation of 
lung parenchymal radiation doses for any given amount of shunting. The administered dose of 
SIR-Spheres Y-90 resin microspheres must be reduced to ensure that the lung dose does not 
exceed 25 Gray. 
 
Patients unable to receive SIRT will receive treatment as in the control arm but will be followed 
– and their safety and efficacy data recorded – and analysed as in the SIRT arm (intention to treat 
analysis). See APPENDIX 2 
 
12.2.2 Calculation of SIR-Spheres Y-90 resin microspheres activity 
The activity of SIR-Spheres Y-90 resin microspheres to be administered is detailed in 
APPENDIX 3. The method of calculation will depend on the presentation of disease in the liver 
[e.g. bi-lobar vs. lobar, focal vs. diffuse, cirrhotic vs. non-cirrhotic, extent of tumour 
involvement, extent of radiation exposure to normal parenchyma] (Gil-Alzugaray, 2013 (19)). 
In the case of bi-lobar disease, whole liver targeted or selective administrations are possible at 
the discretion of the investigator to be determined on a case by case basis. SIR-Spheres Y-90 
resin microsphere administration is to be conducted in one session even when a whole-liver 
approach is used. 
 
SIRT cannot be performed in patients with only non-measurable liver disease according to 
RECIST criteria, since activity calculation requires the tumour volume to be measured. 
12.2.1. 1 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
If the whole liver will receive SIR-Spheres Y-90 resin microspheres, the BSA method will 
be used for activity calculation. The % tumour volume involvement, targeted and total liver 
volumes are calculated from the baseline CT scan of the liver (Kennedy2007(35), Kennedy2012 
(34)). The following fo1mula will be applied: 
V 
Dose activity[GBq] = (BSA - 0.2) + V tumour 
TotalLivec 
V tumour = volume of tumour 
VTotaLivec = volume of total liver, including tumour 
If at least 2 adjacent segments of the liver are spared from SIRT, the paitition model may be 
used to define the activity to be injected. On the basis of tumour and liver volumes measured on 
CT or MRI images and MAA imaging, representative regions of interest of tumour and non-
tumour liver ai·e drawn. MAA imaging such as SPECT CT /MRI or MAA planar images may be 
used and MAA SPECT CT/MRI are prefeITed (Hamami 2009 (24); Kao 2012(30); Roshan 2015 
(54)). The Paitition Model estimates the dose of radiation that will be absorbed by tumour and 
non-tumoural liver compaii ments. 
When the spai·ed liver volume is equal to or less than 40% of the total liver volume and the 
patient is ciIThotic, the Model is used to dete1mine the activity that would result in the non-
tumoural liver absorbing not more than 40 Gy. Conversely, when the spai·ed liver volume is more 
than 40% of the total liver volume or the patient is not ciIThotic, the Model is used to calculate 
an activity that would result in the tumour absorbing 120 Gy. 
Spared Volume 
CiIThosis 
No CiIThosis 
< 40% 
< 40 Gv (Non Tumour) 
120 Gv (Tumour) 
> 40% 
120 Gv (Tumour) 
120 Gv (Tumour) 
If there is a contraindication to the use of the Pa1t ition Model (tumours cannot be delineated on 
MAA SPECT CT/MRI or planar MAA to calculate the T: N ratio), then the activity will be 
calculated using the BSA method. 
12.2.3 Administration of SIR-Spheres Y-90 resin microspheres 
Sequential treatment is not pe1mitted in this study. 
For patients randomised to Alm B, in case of progression in the liver after more than 6 months 
from stait of protocol treatment (i.e. staii date is SIR-Spheres Y-90 resin microspheres implant 
date), retreatment with SIRT is allowed if the patients remain within the safety criteria for SIRT 
treatment. 
However, the whole liver, selective or super-selective administration of the SIRT is left to the 
discretion of the physicians. 
The technique for delivering SIR-Spheres Y-90 resin microspheres is provided iI1 the SIR-
Spheres Y-90 resin microspheres Training Manual and in APPENDIX 1. 
The administration of the SIR-Spheres Y-90 resin microspheres should be delivered exactly in 
the same vascular anatomical place where 99mT c-MAA was administered. 
Confidential Sirtex Technology Pty Ltd 
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CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
Patients will receive the calculated dose of SIR-Spheres Y-90 resin microspheres as 
described in APPENDIX 3. 
The batch number of the used vials of SIR-Spheres Y-90 resin microspheres will be captured for 
accountability purposes. 
12.2.4 Ancillary protocol treatment 
A prophylactic H2 blocking agent or proton pump inhibitor ( e.g. ranitidine, omeprazole) is to be 
administered to patients receiving SIR T for a minimum period of four weeks, commencing either 
just prior to or at the time of administration of SIR-Spheres Y-90 resin microspheres and must 
be recorded as concomitant medication. 
Prophylactic narcotic analgesia is to be administered in conjunction with SIRT as per standard 
hospital policy. Although minor opiates analgesia (e.g. codeine, dihydrocodeine) is usually 
sufficient, major opiates (e.g. pethidine) may be required within the first 24 hours after SIRT. 
All suppo1tive treatment should be recorded, including any supportive treatment provided for the 
implantation of SIR-Spheres Y-90 resin microspheres. 
12.2.5 Treatment Arm B: Post-SIRT Bremsstrahlung scan 
Following the administration of SIR-Spheres Y-90 resin microspheres, Bremsstrahlung scan 
(SPECT/CT), Y-90 PET/CT or Y-90 PET/MRI must be perf01med on the same day or day 1 
post-SIRT. These studies detect the Bremsstrahlung radiation or positron emission from the 
yttrium-90 and are perfonned in order to confnm the placement of SIR-Spheres Y-90 resin 
microspheres in the targeted lesions and to exclude non-targeted delivery of SIR-Spheres Y-90 
resin microspheres. Anonymised copies of the Bremsstrahlung scan (SPECT/CT) or a Y-90 
PET /CT or Y-90 PET /MRI will be collected for potential central review. 
12.2.6 Treatment Arm B: Administration of CIS-GEM 
Patients randomised to receive the SIR-Spheres Y-90 resin microspheres followed by systemic 
chemotherapy will commence administration of CIS-GEM (European guidelines on bilia1y tract 
cancer; Valle et al. New England Journal of Medicine 2010), 14 -16 days after SIRT treatment, 
( or at the earliest point thereafter on recove1y of any haematological, bilirnbin or albumin 
derangements if they occur). 
The reference regimen as per ESMO guidelines and ABC 02 protocol consists of: 
2 
Cisplatin 25 mg/m in 1000ml 0.9% saline given over I hour followed by 500 ml 0.9% saline 
over 30 minutes followed by 
2 
Gemcitabine l000 mg/m in 250 - 500ml 0.9% saline over 30 minutes by intravenous infusions 
on days 1, and 8 of a 21-day cycle. 
14-16 days 
Cycle 1 
Cycle2 
Cycle3 
Cycle 4 onwards 
after SIRT 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Dav 
1 
8 
1 
8 
1 
8 
1 
8 
Cisplatin 
X 
X 
X 
X 
X 
X 
X 
X 
Gemcitabine 
X 
X 
X 
X 
X 
X 
X 
X 
Confidential Sirtex Technology Pty Ltd 
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CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 35 of 93 
 
See APPENDIX 5 for recommended guidelines for CIS-GEM chemotherapy administration as 
per the ABC-02 regimen. 
 
In the absence of disease progression or unacceptable toxicity 8 treatment cycles will be given. 
Beyond 8 cycles, treatment may be continued in the absence of disease progression at the treating 
clinicians’ discretion. 
 
Note: Patients randomised to receive SIRT (Arm B) but for whom SIRT implantation is not 
safely feasible (e.g. following initial angiographic work-up) will be treated according to arm A 
(but retained in Arm B for intention-to-treat analysis within the study).  
 
12.3 
Supportive Treatment 
Supportive treatment should be administered when required according to the patient’s condition. 
Such supportive treatment may include, but is not limited to antiemetics, analgesia, 
corticosteroids, antibiotics etc. All supportive treatment should be recorded on the eCRF, 
including any supportive treatment provided for the implantation of SIR-Spheres Y-90 resin 
microspheres. 
 
Ursodeoxycholic acid (300 mg bid for the first 3 cycles) may provide benefit in terms of adequate 
bile flow and is routinely recommended for SIRT treated patients. 
 
In the event of the development of obstructive jaundice due to biliary tract obstruction, 
appropriate measures will be undertaken to diagnose (e.g. by ultrasound and/or CT scan) and 
relieve the obstruction (e.g. by ERCP/PTC +/- stent insertion/drainage). Chemotherapy will be 
deferred until the Liver Function Tests have improved to adequate levels (i.e. total bilirubin ≤ 
1.5 X ULN; ALT, AST & alkaline phosphatase ≤ 5 x ULN. Chemotherapy may then resume at 
the start of the next treatment cycle. 
 
12.3.1 Recommendation for antibiotic prophylaxis and treatment of patients with 
intrahepatic cholangiocarcinoma (ICC) undergoing radioembolisation followed by 
chemotherapy 
Recommend diligent antibiotic prophylaxis in the following situations: 
 
a) 
Treatment naïve patients with a history of suspected cholangitis (even mild events) 
b) 
Treatment naïve patients with a history of ERC (endoscopic retrograde cholangiography) 
or PTCD (Percutaneous Transhepatic Cholangio-Drainage) with or without 
papillotomy.  This is even more important in patients who present with segmental dilation 
of bile ducts, e.g. through tumour compression, since there may exist cholangitis without 
any clinical evidence (e.g. normal CRP value and normal leucocyte count). 
c) 
Treatment naïve patients with biliodigestive surgical anastomosis 
d) 
Patients who have undergone radioembolisation and chemotherapy who undergo 
endoscopy or any other biliary intervention during follow up. In ICC, abscess formation 
in irradiated ICC may occur even months or more than a year after irradiation when the 
biliary tree is exposed to bacteria colonization. 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 36 of 93 
12.3.2 For patients undergoing a biliary intervention during follow up (after RE and 
chemo) the recommended treatment is: 
Endoscopy/any other biliary intervention under antibiotic prophylaxis 
Antibiotics that cover biliary flora, such as enteric gram-negative organisms and enterococci, 
should be used, e.g. ciprofloxacin 2 x 400 mg, metronidazole 3 x 500 mg i.v.  
• first Infusion terminated ½  hour before the intervention.  
• i.v. Antibiotics during the hospital stay  
• after discharge: ciprofloxacin monotherapy 2 x 500 mg for 10 days p. o.  
• followed by: once a month ciprofloxacin 2 x 500 mg for 1 week for a duration of at least 
6 months 
 
12.3.3 For patients with risk profile (see above, e.g. history of ERC) undergoing 
radioembolisation the recommended treatment is: 
Radioembolisation under antibiotic prophylaxis, e.g. ciprofloxacin 2 x 400 mg, metronidazole 3 
x 500 mg i.v.  
• first Infusion terminated ½ hour before the intervention.  
• i.v. Antibiotics during the hospital stay  
• after discharge: ciprofloxacin mono 2 x 500 mg for 10 days p. o.  
• followed by : once a month ciprofloxacin 2 x 500 mg for 1 week for a duration of at least 
6 months 
 
12.4 
Concomitant Medications 
All medications taken by the patient including medications that are unrelated to their cancer 
management should be recorded in the eCRF. These include long-term as well as short-term or 
acute medications ongoing at the time of signing of the informed consent form or started any 
time after signature of the informed consent form, until 28 days after the last dose of study 
protocol chemotherapy was administered.  
 
Any concomitant medications administered at the time of any study treatment related SAEs or 
any SADE which occurred after 28 days post last dose of protocol chemotherapy, will be reported 
on the SAE Report Form to the study sponsor. 
 
Routine medications should be listed in the appropriate section and need only be recorded in the 
eCRF for cycle one unless they are changed. Additional routine medications should be recorded 
on the CRF for the cycle of chemotherapy closest to the commencement of the new medication. 
Commencement and cessation dates, dosage and route of administration are required. 
 
12.5 
Non-Study Treatments 
Patients may receive all concomitant therapy deemed to provide adequate supportive care at the 
investigator’s discretion. All such medications or other treatments taken by the patient during 
the study (including those initiated prior to the start of the study) will be recorded in the patient’s 
clinical notes. However, the use of experimental drugs is not permitted within 28 days of 
completion of the active part of the study. 
 
12.6 
Additional non study anti-cancer treatment  
Details of any additional non study anti-cancer treatment from end of study treatment until the 


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 37 of 93 
end of study will be collected, i.e. regimen and modality of treatment, including start and stop 
date.  
 
12.7 
Use of contraceptives during study treatment  
Female patients with childbearing potential and sexually active men with a premenopausal 
partner should use an adequate method of contraception during the study treatment and for at 
least 6 months after stopping study treatment. 
 
 


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Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 38 of 93 
13 FOLLOW-UP STUDY ASSESSMENTS 
All consenting patients will be assessed at screening, baseline and at appropriate intervals after 
the commencement of protocol treatment in order to assess their disease status according to the 
following schedule: 
13.1 
Study Calendar 
 Scheduled event 
Screening 
Assessments 
Baseline 
Assessments 
SIRT 
treatment 
Chemo 
treatment 
Follow-up Assessments 
 
≤ 28 days prior 
to 
randomisation 
within 7 days 
prior to start of 
chemo in arm 
A and work up 
in Arm B 
SIRT (Arm 
B only)  
 
 
Arm A and 
Arm B 
Every 12 weeks 
(+/- 2 weeks) 
from start of 
treatment until 
progression in 
the liver – 
regardless patient 
is on chemo 
FU visit after 
progression 
in the liver 
every 12 
weeks (+/- 2 
weeks) 
Informed Consent 
X 
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
Medical history and concurrent 
illness 
X 
  
  
  
  
  
Concomitant medication a 
From informed consent until 28 days post last dose of 
protocol chemotherapy at each patient visit 
 
 
Physical examination, height, 
weight, 
blood 
pressure, 
temperature b 
X 
X 
Xf 
Xm 
 
 
ECOG performance status 
X 
X 
Xf 
Xm 
X 
 
Haematology, 
biochemistry, 
creatinine clearance 
Xi 
X 
Xf, j 
Xg, j 
Xj,n 
 
Tumour markers CEA, CA 19-
9, CA125, and AFP 
 
X 
 
Xh  
Xn 
X 
EQ-5D 
Quality 
of 
Life 
Questionnaire 
X 
 
 
 
Xk 
Xl 
Pregnancy test for females 
X  
 
 
 
  
  
CT-scan chest, abdomen, pelvis 
(until progression) and RECIST 
1.1 
& 
refined 
RECIST 
assessments c 
X 
repeated if  
> 28 days 
prior start of 
chemo or 
SIRT 
implantation 
 
 
X 
 
Adverse events d 
From informed consent until 28 days post last dose of protocol chemotherapy at each patient 
visit (Unless new study treatment related AEs/SAEs or new ADE/SADE)  
Randomisation (IWRS) 
 
X 
 
 
 
 
Work up-Hepatic angiogram/ 
99mTc-MAA (must be 3-8 days 
prior to SIRT) (arm B only) 
  
 
X 
  
  
  
SIRT (Arm B only) e 
  
 
X 
  
  
  
Post SIRT Bremsstrahlung scan 
(SPECT/CT), Y-90 PET/CT or 
y 90 PET/MRI (Arm B only) 
  
  
X 
  
  
  
CIS-GEM treatment 
 
  
  
X  
 
 
Assessment 
for 
resection/ablation 
 
 
 
 
X 
X 
Additional 
non-study 
anti-
cancer treatment 
 
 
 
 
X 
X 
Ongoing review of survival 
 
 
 
 
 
X 
 
 
 


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a. Concomitant medications administered at the time of onset of any new treatment related 
SAE or any SADE which occurred after 28 days post last protocol chemotherapy, must 
be reported on the SAE Report Form to the study sponsor. 
b. At baseline a full physical examination is required. The post-baseline physical 
examinations may include only the body systems clinically indicated by symptom or 
anticipated treatment side effect. Height is only required to be collected during Screening 
Assessments. 
c. In case MRI is the standard radiological assessment for ICC, MRI is permitted on the 
condition that the same method of assessment and the same technique is used for the 
entire course of the study for a particular patient.  However, CT scans (chest-abdomen-
pelvis) are mandatory in any case for extra-hepatic assessments. 12 weekly CT scans 
must be performed until progression in liver detected by both RECIST 1.1 and refined 
RECIST. 
d. All treatment related AEs and all SAEs should be followed until resolution or death or 
end of study. Any new SAE/AEs related to treatment or any new ADE/SADE occurring 
after 28 days post last dose of study chemotherapy will be recorded as well until 
resolution or death, or the end of study. 
e. Suitability to receive SIRT to be re-confirmed prior to implantation  
f. To be performed within 3 days before SIRT implantation  
g. Within 3 days prior to chemotherapy treatment. In the event of an extended delay due to 
total bilirubin > 30 µmol/L (1.75 mg/dL) greater than 3 weeks, total bilirubin should be 
assessed at least once every TWO weeks until recovery, or disease progression, patient 
choice 
or 
intolerance or 
permanent 
discontinuation 
at 
investigator’s 
discretion. Prophylactic treatment with steroids, ursodeoxycholic acid and ciprofloxacin 
should be considered if there is 2 weeks or greater delay due to total bilirubin > 30 µmol/L 
(1.75 mg/dL). Refer to Section 7.1.3 Hepatic Complications for further consideration 
h. Before every chemotherapy cycle (+/- 1 week); if chemo cycle is delayed due to abnormal 
lab tests, tumour markers do not need to be repeated. 
i. Screening haematology/biochemistry assessments to be performed within 14 days prior 
to randomisation. 
j. Same assessments to be performed as baseline. 
k. To be performed every 12 weeks after start of treatment (+/- 2 weeks) until progression 
in the liver. 
l. To be performed once, 12 weeks (+/- 2 weeks window) after the first CT scan with 
detection of liver progression. 
m. Within 3 days prior to chemotherapy treatment. 
n. Laboratory assessments that are required to be performed during the pre-progression 12 
weekly follow up visit do not need to be repeated if already performed while the patient 
is on chemotherapy. The pre-progression 12 weekly laboratory assessment must be 
within +/- 2 weeks from the date of follow up.  
 
 
 


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14 RESPONSE ASSESSMENT 
The following criteria will be used to assess response to treatment and for the evaluation of study 
end points. 
 
14.1 
Survival at 18 months (Primary Endpoint) 
Survival at 18 months is defined as the proportion of patients alive 18 months from the date of 
randomisation. 
 
14.2 
Liver resection / ablation rate (Secondary Endpoint) 
A proportion of patients radiologically down-staged by protocol therapy (Arm A or B) will 
proceed to partial hepatic resection, ablation or other forms of surgical management during or 
after protocol therapy.  The date and type and details of such procedures will be recorded, as well 
as the duration of in-patient admission, surgical complications, drug therapy required during and 
after in-patient admission, surgical notes from the procedure (Brisbane Terminology (4)), post-
operative imaging and the histopathological results (presence of viable tumour/fibrosis, nearest 
resection margin, classification of resection as R0, R1 or R2). 
 
14.3 
Safety and tolerability (Secondary Endpoint) 
Safety and tolerability will be assessed using the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (see APPENDIX 4). Patients are to be followed for safety and 
tolerability from the time of providing informed consent until 28 days after last dose of protocol 
chemotherapy or until resolution of treatments related adverse events. Definitions and the 
requirements for reporting adverse events (AE) and serious adverse events (SAE) are detailed in 
Section 17 Adverse Events. 
 
14.3.1 Independent Data Safety Monitoring Committee (IDSMC) 
The safety profile of Treatment Arm B will be assessed by the IDSMC after 10, 20 and 30 
patients have been treated with SIRT and have had a minimum of 8 weeks safety evaluation post 
SIRT treatment. The results will be compared to patients treated in the control group for 
increased risk related to either the SIRT therapy or the time interval between SIRT and standard 
of care chemotherapy.  The IDSMC will notify the Sponsor of recommendations to revise the 
treatment regimen or discontinue enrolment after which, the Investigators will be notified.    
 
After the review of 30 SIRT patients is complete, the IDSMC will determine the subsequent 
IDSMC meeting intervals based on the SIRT patient safety profile established; additionally, the 
IDSMC will receive SAE listings during the scheduled meeting interims and may convene ad 
hoc meetings for safety review if a single event or aggregate events raise concern by any of the 
IDSMC members. 
 
14.4 
Tumour Response Rate (Secondary Endpoint) 
Response will be calculated using response evaluation criteria in solid tumours version 1.1 
(RECIST 1.1) (Eisenhauer 2009 (15)). There will also be a lesion based assessment if at all 
applicable and refined RECIST (Reig (54)) (See APPENDIX 7).  
 


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14.4.1 RECIST 1.1 Guidelines  
All baseline evaluations should be performed as closely as possible to the beginning of treatment 
start and never more than 28 days before beginning of the treatment. 
 
All measurable lesions (lesions that can be accurately measured in at least one dimension with 
longest diameter ≥ 20 mm with conventional techniques and ≥ 10 mm with spiral CT scan) up 
to a maximum of 2 lesions per organ with a maximum of 5 lesions in total, representative of all 
involved organs, should be identified as target lesions and will be recorded and measured at 
baseline. To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis. 
 
A sum of the diameter (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameter which will be used as 
reference to further characterise any objective tumour regression in the measurable dimension of 
the disease. If lymph nodes are to be included in the sum, only the short axis will contribute. 
 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with 10 to < 15 mm short axis), should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions are not required, 
but the presence or absence of each should be noted throughout follow-up. 
 
 RECIST: Response Criteria 
Complete Response (CR): Disappearance of all target lesions associated with the disappearance 
of all non-target lesions and normalisation of tumour marker levels. All lymph nodes must be 
non-pathological in size (< 10 mm short axis). 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of the target lesions, 
taking as a reference the baseline sum of diameters of target lesions, or a CR associated with 
persistence of non-target lesion(s) and/or maintenance of tumour marker levels above normal 
limits. 
 
Progressive Disease (PD): At least 20% increase in the sum of diameters of target lesions, taking 
as a reference the smallest sum recorded since on study (this may include baseline sum) or the 
appearance of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD with or without persistence of non-target lesion(s) and or maintenance of tumour 
marker levels above normal limits. 
 
Note: Elevated serum tumour markers on their own are not sufficient evidence of progression 
and only imaging examinations can assess and confirm disease progression. 
 Refined RECIST: Response Criteria 
The conventional RECIST was amended for the SHARP trial in order to prevent over-staging 
and non-accurate assessment of progression in the following instances: 
• Detection of lymph nodes in the hepatic hilum, as this may be seen in cirrhotic patients 
and does not reflect cancer involvement. 
• Detection of ascites or pleural fluid at baseline or during follow-up, as this may reflect 
hydrosaline retention because of impaired liver function and not malignant spread. 
14.4. 1.1 
14.4.1.2 


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• Detection of macro regenerative nodules. This may be observed in cirrhotic livers and 
does not reflect progression, even if the nodules are larger than 1 cm. 
 
To prevent the above, the amendments state: 
• Lymph nodes are classified as malignant if their size exceeds 20 mm or if arterial 
vascularization is present. 
• For ascites or pleural effusion, in order to declare malignant, it should be proven by 
positive cytology. 
• New lesions outside the liver follow the same definitions as for RECIST1.1. New 
intrahepatic lesions have specific consideration: 
• ≤ 10 mm should be considered as equivocal and not progression. 
• > 10 mm should be considered malignant if arterial hypervascularisation is present. 
 
Note: As patients in both treatment arms may be considered ‘resectable’ after treatment, it is 
possible that undiagnosed disease may be found at the time of attempted resection of the liver 
disease. For the purpose of defining Progressive Disease, any disease that is found solely as a 
result of the patient undergoing laparotomy for resection will not be considered as Progressive 
Disease. i.e. Only radiological assessments can define and confirm progression 
 
14.5 
Progression-Free Survival (PFS) and Liver-specific PFS 
Progression-free survival (PFS) is defined as the time interval between randomisation and the 
date of tumour progression.  
 
Liver-specific PFS (LPFS) is defined as the time interval between randomisation and the date of 
tumour progression in the liver. 
 
Tumour progression is determined from serial CT scans. 
 
Recommended acquisition guidelines for CT scanning are provided in APPENDIX 6.  
 
Diagnosis of tumour progression should be made by using RECIST Criteria (version 1.1) and 
refined RECIST (see APPENDIX 7). 
 
The documented date of progression will be the date of confirmation of the progression strictly 
by RECIST 1.1 only. At the time of progression, the investigator should clearly indicate the site 
of tumour progression (intra-hepatic or extra-hepatic or indicate both simultaneously). 
 
14.6 
Quality of Life 
Quality of life (QoL) will be measured by using the EQ-5D questionnaire. The EQ-5D will be 
completed at screening, then at follow up assessments every 12 weeks after start of treatment until 
progression in the liver (according to both RECIST 1.1 and refined RECIST), and then completed 
once more 12 weeks after the first CT scan with detection of liver progression according to both 
RECIST 1.1 and refined RECIST. 
 
 


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15 STATISTICAL CONSIDERATIONS & METHODOLOGY 
15.1 
Study Hypothesis 
18-month survival proportion in SIRT arm (Arm B) is no better than in the chemo only arm  (Arm 
A) by at most 15% versus 18-month survival proportion in SIRT arm (Arm B) is better than in 
the chemo only arm (Arm A) by at least 15%. 
 
15.2 
Study Design and Sample Size 
This randomised study is a preliminary efficacy and safety assessment of standard regimen of 
CIS-GEM versus SIRT preceding the standard regimen of CIS-GEM. In this single stage design, 
the standard 18-month overall survival proportion in the CIS-GEM arm is assumed to be 55% 
(under the null hypothesis). The SIRT preceding CIS-GEM regimen is considered worthy of 
further research if the null hypothesis can be rejected in favour of the alternative hypothesis 
where the proportion surviving at 18 months is assumed to be at least 70%.  Therefore, if the 
proportion surviving after 18 months was less than 55%, the assumption is made that there would 
be no interest in pursuing the SIRT preceding standard CIS-GEM regimen. The assumption is 
also made for the probabilities of making the wrong conclusions. First, the probability of 
concluding that the survival proportion is at least 70% when in fact it is no more than 55% (i.e. 
false positive) should be low, say 5% or less. Second, the probability of concluding that the true 
survival proportion is no more than 55% when in fact it is at least 70% (i.e. false negative) should 
also be low, say 20% or less. 
 
Consequently, based on exact (binomial) statistic with actual error rates (Khan 2012 (37)), the 
decision rule provides that a sample size of 80 patients and a minimum of 50 patients surviving 
at 18 months in the SIRT followed by chemotherapy arm are required to warrant further 
investigation of SIRT preceding CIS-GEM, such that statistical significance is achieved. This 
sample size corresponds to an 88% power to detect a significant difference of at least 15% in 
survival proportion at 18 months as per the study assumption. If the number of patients surviving 
at 18 months is at most 50, then this number is the maximum number of survivors for which 
statistical significance is not achieved. 
 
In order to study the true effect, the population of interest is defined as those patients having 
completed at least one cycle of chemotherapy in the control arm and those having completed 
SIRT followed by at least 1 cycle of chemotherapy in the experimental arm. 
 
The primary analysis will be based on only the SIRT arm. However, in order to have a 
comparative arm for secondary endpoint analyses, the sample size has been calculated based on 
a randomization between the SIRT arm and a chemotherapy arm. This resulted in a total sample 
size of 160 patients in the randomized study as per 1:1 randomisation. 
 
Assuming a noncompliance rate of at most 10% patients who would not complete at least one 
cycle of chemo in Arm A and those who would not complete SIRT treatment followed by at least 
one cycle of chemo in Arm B. The number of patients to be recruited will potentially increase 
from 160 patients to 180 patients. 
 
Stratification and Randomisation:  
Randomising patients equally between the two (2) arms, the Fleming’s single stage design with 
exact binomial test (which minimises the total number of patients needed) will be applied to the 
data from the study. 
 


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Prior to randomisation, patients will be stratified according to (a) the presence or absence of 
extra-hepatic metastases and (b) the presence or absence of cirrhosis, (c) intention to treat by 
whole liver versus non-whole liver Y-90 treatment; (d) ECOG 0 vs. ECOG 1 and (e) prior 
adjuvant therapy vs no prior adjuvant therapy. Treatment will be allocated randomly and 
balanced for the above strata using a computer generated allocation. 
 
Cirrhosis: 
 
Absence of cirrhosis should be registered when 
• The non-tumoural part of the liver is regular and without nodularity on imaging and 
• There is no evidence of portal hypertension with no clinically significant ascites, oesophageal 
varices or splenomegaly with dilated portal vein in the absence of portal vein thrombosis.  
 
Detection of any of the above findings, and/or a positive biopsy diagnosis (F4=cirrhosis 
according to The METAVIR scoring system) and/or an increased elastography values, 
establishes the existence of cirrhosis. 
  
15.3 
Statistical Analyses 
 
Efficacy Analyses 
 
The primary endpoint will be analysed in those patients that received at least 1 cycle of 
chemotherapy (arm A) and in those patients who received SIRT and at least 1 cycle of 
chemotherapy (Arm B). Secondary endpoints will be analysed according to the intention-to-treat 
principle with patients being analysed in the treatment group to which they were randomised 
irrespective of what treatment they end up receiving, as well as per efficacy evaluable population 
who received at least 1 cycle of chemotherapy or SIRT followed by at least 1 cycle of 
chemotherapy respectively.  
 
Primary efficacy measure for the study is survival at 18 months from time of randomisation with 
no formal comparison between treatment arms. Secondary efficacy analyses will compare 
efficacy between both treatment groups using the log rank test (Mantel-Haenszel version), and 
time to event secondary endpoints will be compared using the logrank test. The secondary 
efficacy measure liver specific PFS for all ITT patients will be analysed. In addition, separate 
analyses will be conducted for difference in 18 month survival by subgroups of stratification 
factors. Note that, actual proportion in the trial however will be based on the Kaplan-Meier 
estimate which takes into account both lost to follow-up and censored data (i.e. at the end of the 
study, not all patients would necessarily be followed up for 18 months). A 55% survival rate at 
18 months corresponds to a median survival of 21 months and a 70% 18 month rate corresponds 
to a 34 month median survival.  
 
 
For purposes of this study, progression free survival (PFS) is defined as the time, in month, from 
randomisation in the study until such time as progressive disease at any site (RECIST response 
criteria) is confirmed or upon patient death if disease progression has not been evident at that 
time. 
 
Liver-specific time to progression or PFS in the liver is defined, in months, as the time interval 
from randomisation until progression in the liver (RECIST response criteria). 
 


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Exploratory analyses will be performed adjusting for prognostic factors in a multivariate analysis 
framework. This includes the impact of explanatory variables on various outcomes measures of 
interest. Proportional hazards regression will be used to model time to event outcomes, and 
multiple linear regression will be used to model continuous outcomes with appropriate 
transformations if necessary. Logistic regression will be used to model binary response, and 
proportional odds models will be used for categorical outcomes (such as toxicity grades). 
 
Pre-planned sub-group and post-hoc analyses 
Primary and secondary endpoints will be explored based on subgroup analyses by stratification 
factors. Where p-values are reported they will be corrected for multiple comparisons using 
Bonferroni method. 
 
AFP as a biomarker will be analysed by treatment groups and in a responder exploratory analysis.  
Analysis of responders versus non-responders by complete tumour treatment or partial tumour 
treatment will be performed. 
 
Lobar versus bi-lobar disease will be analysed by treatment groups.  
 
Handling Missing Data 
All analyses and descriptive summaries will be based on the captured data. Unless otherwise 
specified, missing data will not be imputed or ‘carried forward’. Details of data handling 
assumptions, including missing and censored data, will be described in the statistical analysis 
plan. 
 
Protocol Deviations and Violations 
Patient data will be monitored to identify protocol deviations, and these deviations will be 
discussed with investigators and preventive actions will be undertaken. 
 
During the study, the patient data will be interrogated to identify protocol deviations, and any 
inconsistency will be queried to the sites for confirmation or correction. 
 
Prior to study closure, observed protocol deviations will be reviewed by a medical reviewer(s) 
and statistician to determine whether these deviations are considered as major.   
 
Patients who are ineligible due to factors unrelated to treatment allocation and outcome whose 
reason for ineligibility were due to pre-randomisation factors may be excluded from the intention 
to treat population.   
 
 
 


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16 PROTOCOL ADHERENCE / PREMATURE TERMINATION OF THE STUDY  
16.1 
Protocol Adherence 
Strict adherence to all specifications laid down in this protocol is required for all aspects of the 
study conduct; the investigator may not modify or alter the procedures described in this protocol. 
If protocol modifications are necessary, all alterations that are not solely of an administrative 
nature require a formal protocol amendment (see section 18.3). 
 
If an investigator has deviated from the protocol in order to eliminate an immediate hazard to 
patients or for other inevitable medical reasons, the investigator shall document all such 
deviations, including the reasons thereof, and submit the document to the sponsor and the EC as 
applicable and according to local regulations. 
 
Lack of adherence to the CIP at an investigational site risks compromising the utility of the 
collected data and power of the study. Ongoing, unauthorised deviation from the Clinical 
Investigation Plan will be a matter addressed by the study monitor to the Principal Investigator 
at the site and may result in plans to correct systemic problems leading to lack of compliance or 
ultimately, closing the site to recruitment or ongoing participation in the study. 
 
16.2 
Premature Termination of the Study 
Notwithstanding the potential benefit of treatment, if excess toxicity is observed, then this would 
provide grounds for treatment modification, dose reduction or stopping the study earlier than 
planned.  
 
At the discretion of the Sponsor and/or the Co-Principal Investigators, the entire study may be 
discontinued for medical, feasibility or futility reasons. In case of premature termination, the 
investigators, IRB/IECs and regulatory authorities will be informed by the study Sponsor. 
 
If the study terminates prematurely, the treating physician of the patient’s choice will then 
provide patient with best available treatment options according to standard of care and in 
consultation with the patient. 
 
 


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17 ADVERSE EVENTS 
17.1 
Definitions 
17.1.1 Adverse Event 
An adverse event (AE) is defined by ISO 14155 as any untoward medical occurrence experienced 
by a patient and which does not necessarily have a causal relationship with any component of 
the study treatment. 
 
An AE can be any sign, abnormal laboratory value, symptom or diagnosis/disease that is 
unfavourable or unintended, that is new, or if pre-existing, worsens in a patient, and that may or 
may not be related to the study treatment. 
 
AEs will be recorded from the date of signature of the informed consent form up to 28 days after 
the last dose of chemotherapy was given. Any new AE related to treatment (protocol 
chemotherapy or SIRT) occurring after this time period will be recorded as well. All 
chemotherapy and/or SIRT -related Adverse Events will be followed up until resolution, death 
or the end of the study.  
 
For this study, adverse events that are clearly related to progression of intrahepatic 
cholangiocarcinoma will not be recorded as Adverse Events and will be considered as lack of 
efficacy. 
 
17.1.2 Serious Adverse Event 
A serious adverse event (SAE) is defined by ISO 14155 as an adverse event that: 
a) Lead to a death, or 
b) Lead to a serious deterioration in the health of the patient that 
1) Resulted in a life-threatening illness or injury, 
2) Resulted in a permanent impairment of a body structure or a body function,  
3) Required in-patient hospitalisation or prolongation of existing hospitalisation,  
4) Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, or 
c) Lead to foetal distress, foetal death or a congenital abnormality or birth defect. 
 
All SAEs will be followed until resolution or the end of the study. 
 
17.1.3 Adverse Device Effect (ADE) and Serious Adverse Device Effect (SADE) 
An adverse device effect is an adverse event related to the use of an investigational medical 
device. 
A serious adverse device effect (SADE) is an adverse device effect that has resulted in any of 
the consequences characteristic of a serious adverse event. 
 
All SADEs will be followed until resolution, death or the end of the study. 
 


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17.2 
Reporting 
In order to adhere to all applicable laws and regulations for safety reporting, the Investigator 
must formally notify the study Sponsor, using the supplied SAE form, of any SAE or SADE 
within 24 hours of becoming aware to: 
 
Email:
 
or 
  
 
 
The causality of all (S)AE/(S)ADEs with study treatments must be assessed by the investigator.  
Safety information shall be reported to IRBs/IECs and/or regulatory authorities and/or 
Competent Authorities as per local law and requirements. 
 
For specific safety reporting procedures in the Netherlands, please refer to APPENDIX 11. 
 
17.3 
Pregnancy during the Study 
Protocol therapy must be discontinued immediately in the event of pregnancy in a female patient 
enrolled in this study. The Investigator must report the pregnancy to the study Sponsor within 24 
hours of becoming aware of the pregnancy. The study Sponsor will monitor the outcome of the 
pregnancy and the health status of the infant until 1 year of age. The same pregnancy outcome 
and health status monitoring will also be performed in the event that a female partner of a male 
patient on study becomes pregnant while the male patient is receiving protocol therapy. 
 
 


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18 ETHICAL CONSIDERATIONS 
The study will be performed in accordance with ISO 14155 which includes a requirement to 
operate in accordance with the World Medical Association Declaration of Helsinki (see 
APPENDIX 9). The study Sponsor and the Investigator must comply with all instructions, 
regulations and agreements in this study protocol, using applicable GCP guidelines as specified in 
ISO 14155, and must also conduct the study according to local regulations. 
 
All patients being treated within this study are covered by a clinical study insurance that the sponsor 
has set out for this research study. The sponsor has insurance to cover research-related injuries.  
 
All participating institutions must obtain approval from their responsible EC/IRB. A copy of this 
approval must be forwarded to the study Sponsor before the study may open for patient 
recruitment. 
 
18.1 
Informed Consent 
Patients will be provided with a full explanation, in lay terms, of the aims of the study and the 
potential benefits as well as the possible side effects and risks involved. It will be explained that 
they may refuse to take part in, or withdraw from the study without prejudice to their future care 
and treatment. 
 
Written informed consent must be obtained from all patients prior to study entry. The informed 
consent form must be filed in the patient record. Consent to participate in this study will be 
obtained from the patient both verbally and in writing. In the case where the patient is not fluent 
in the local national language, the investigator should ensure that the study information is 
presented to the subject in their own language in accordance with local ethical and regulatory 
guidelines. Patients will be issued with a copy of the information provided and their consent to 
participate in the study. All informed consent forms used in this study must be approved by the 
relevant EC/IRB. 
 
At any point of the study, the patient may decide to withdraw consent from the study without 
any particular reason. In this case, the patient will be provided by the treating physician with the 
best standard of care treatment options available. From the time of withdrawal of consent, no 
further data will be collected from the patient. 
 
18.2 
Confidentiality 
All patient data collected as a part of this study will be treated according to ISO 14155 and local 
regulation. All data generated from this study will remain confidential and no published report 
will contain any reference to patient names. The patient identification required by the study 
Sponsor is used to ensure accurate storage and follow-up of individual patients. This information 
will be stored securely by the study Sponsor and will only be available to data management, audit 
or monitoring personnel directly involved with the study. 
 
18.3 
Changes to the Final Study Plan 
All study amendments must be submitted to the relevant EC/IRB. Study modifications that impact 
patient safety, the scope of the study, or affect the scientific quality of the study must be approved 
by EC/IRB and submitted to the appropriate regulatory authorities and/or Competent Authorities 
in accordance with local regulations before implementation of such modifications to the conduct 


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of the study. This applies also to any additional requirements imposed by the EC/IRB or regulatory 
authority. However, the study Sponsor may, at any time, amend this study plan to eliminate an 
apparent immediate hazard to a patient. In this case, the necessary regulatory authorities and/or 
Competent Authorities will be notified. In the event of a study plan modification, the informed 
consent form may require similar modifications. 
 
 


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19 PUBLICATION POLICY 
Sirtex, the study Sponsor is committed to the responsible publishing of data from its clinical 
research program. Sirtex aims to promote the timely presentation of results at an appropriate 
academic meeting and/or the publication of results in an appropriate scientific journal.  
 
Sirtex will assess authorship eligibility according to Good Publication Practice for company 
sponsored research. (GPP3 2015 (5)). 
 
In accordance with these recommendations, authorship credit will be based on: 1) substantial 
contribution to concept and design, or acquisition of data, or analysis and interpretation of data; 
2) drafting the manuscript or revising it critically for important intellectual content; and 3) final 
approval of the version of the manuscript to be published. All three items above should be met 
to qualify for authorship.   
 
The lead author for any publication must be the Principal Investigator or a major contributor to 
the study and must have participated sufficiently in the work to take public responsibility for 
appropriate portions of the content. 
 
These criteria apply both to the Investigators who have participated on the study and any Sirtex 
employee who has contributed to the study. 
 
 
 


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20 ADMINISTRATIVE PROCEDURES 
20.1 
Site Initiation Visit 
The Investigator must not enrol any patients prior to completion of a site initiation visit 
conducted by the study Sponsor or its designee. This initiation visit will include a detailed review 
of the study protocol and procedures with study-associated site personnel. 
 
20.2 
Investigator File 
The Investigator will be provided with an Investigator File. This file should be used for filing all 
study-related documents. The Investigator will be responsible for keeping the Investigator File 
updated and for ensuring that all required documents are filed during and after the study. The 
Investigator File will be inspected during monitoring visits and will remain with the Investigator 
for 15 years after closure of the study. 
 
20.3 
Monitoring of the Study 
During the conduct of the study, the Sponsor’s clinical research associate (CRA) or designee will 
visit the site at regular intervals by prior arrangement. The monitoring visits must be conducted 
according to ISO 14155 and GCP guidelines to ensure adherence to the study protocol, quality of 
data, compliance with regulatory requirements, and continued adequacy of the site and its facilities. 
During these visits, CRFs and other data related to the study will be reviewed and any 
discrepancies or omissions will be resolved. The CRA performs monitoring according to the 
monitoring plan and will be given direct access to relevant source documents (including medical 
records) to enable source data verification. 
 
20.4 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by the study 
Sponsor or regulatory authorities may wish to perform on-site audits and inspections 
respectively. The Investigator and site personnel will be expected to cooperate with any 
audit/inspection and to provide assistance and documentation (including source data) as 
requested. The Investigator and site personnel will immediately inform the study Sponsor of any 
inspection to be performed by a regulatory authority. 
 
20.5 
Documentation and Data Management 
Data management will be performed by 
. Study 
data will be captured in an electronic Case Report Form (eCRF) complying with national and 
international data protection guidelines. The web-based eCRF is a linked to a database system 
 all systems are validated.  
 
Data will be accessed and processed by a restricted number of users with role-based access 
restrictions respecting confidentiality.  
 
20.6 
Investigational Device Accountability 
Access to the investigational devices is controlled and the investigational devices will be used 
only for clinical investigation and according to the clinical investigation plan. 
 


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The investigator will keep records documenting the receipt, use and disposal of the 
investigational devices; these records include dose orders and lot number of doses should be 
recorded and maintained at the site to be verified by the study monitors. 
 
20.7 
Study Funding 
The study Sponsor (Sirtex) will financially support the work of the Investigator related to the 
conduct of the study. All financial details are provided in the separate Clinical Study Agreement 
(contract) between the Investigator and/or the Institution and Sirtex Technology Pty Ltd. 
 
20.8 
Completion of the Study 
The EC/IRB must be notified of completion or termination of this study in a timely manner. The 
Investigator must provide a final clinical study report to the EC/IRB and maintain in the Investigator 
File an accurate and complete record of all submissions made to the EC/IRB.  
 
The Competent Authorities and/or regulatory authorities have to be notified of completion or 
termination of the study according to local law. A final clinical study report will also be provided 
to the Competent Authorities and/or regulatory authorities. 
 
 


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21 BIBLIOGRAPHY 
The following references were used during the preparation of this document. A full literature 
search and review is maintained in the Sirtex Design Dossier file. 
 
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13. Coldwell DD: Treatment of unresectable nodular cholangiocarcinoma with yttrium-90 
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29. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-
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90 microspheres for hepatic metastatic neuroendocrine tumours: A prospective single 
center study. Digestion 2009; 79: 137-142. 
 
31. Kao YH, Hock Tan AE, Burgmans MC et al: Image-guided personalized predictive 
dosimetry by artery-specific SPECT/CT partition modeling for safe and effective 90Y 
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neuroendocrine hepatic metastases using 90y-microspheres: Early results in 148 patients. 
American Journal of Clin Oncol 2008; 31: 271-279. 
 
33. Kennedy AS, Coldwell D, Nutting C et al: Resin 90Y-microsphere brachytherapy for 
unresectable colorectal liver metastases: Modern USA experience. Int J Radiat Oncol, 
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34. Kennedy AS, Coldwell D, Sangro B, Wasan H, Salem R. Radioembolization for the 
treatment of liver tumors: General principles.  Am J of Clin Onc 2012; 35: 91-99. 
 
35. Kennedy AS, Nag S, Salem R, Murthy R, et al. Recommendations for radioembolization  
of hepatic malignancies using yttrium-90 microsphere brachytherapy: A consensus panel 
report from the radioembolization brachytherapy oncology consortium. Int. J. Radiation 
Oncology Biol. Phys 2007; 68:13–23.  
36. Kennedy A, Nutting C, Coldwell D et al: Pathologic response and microdosimetry of 90Y 
microspheres in man: review of four explanted whole livers. International Journal of 
Radiation Oncology, Biology and Physics 2004; 60: 1552-1563. 
 
37. Khan I, Sarker SJ, Hackshaw A: Smaller sample sizes for phase II trials based on exact 
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British Journal of Cancer 2012; 107: 1801-1809. 
 


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38. Khanna V, Dhanasekaran R, Barron BJ et al. Yttrium-90 radioembolization (SIR-
Spheres) for cholangiocarcinoma: Preliminary study. Society of interventional Radiology 
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39. Kim, Y.I., et al., Outcomes of concurrent chemoradiotherapy versus chemotherapy alone 
for advanced- stage unresectable intrahepatic cholangiocarcinoma. Radiation Oncology 
2013. 8: p. 292. 
 
40. King J, Quinn R, Glenn D et al: Radioembolization with selective internal radiation 
microspheres for neuroendocrine liver metastases. Cancer 2008; 113: 921–929. 
 
41. Klemp P, Perry A, Fox R, et al: Aspects of radiation protection during the treatment of 
liver cancer using yttrium-90 labeled microspheres. Radiation Protection in Australia 
1989; 7:70-73.  
 
42. Leung TW, Lau WY, Ho SK et al: Radiation pneumonitis after selective internal radiation 
treatment with intraarterial yttrium-90 microspheres for inoperable hepatic tumours. 
International Journal of Radiation Oncology, Biology and Physics 1995; 33: 919. 
 
43. Liu DM, Salem R, Bui JT et al: Angiographic considerations in patients undergoing liver-
directed therapy. J Vasc Inter Radiol. 2005; 16:911-935. 
 
44. Mackie S, de Silva S, Aslan P et al: Super Selective Radioembolization of the Porcine 
Kidney With 90Yttrium Resin Microspheres: A Feasibility, Safety and Dose Ranging 
Study. The Journal of Urology 2011; 185: 285. 
 
45. Maithel, S.K., et al., Multidisciplinary Approaches to Intrahepatic Cholangiocarcinoma. 
Cancer 2013. 119(22): p. 3929-3942. 
 
46. Mantravadi RV, Spigos DG, Tan WS et al: Intraaterial yttrium 90 in the treatment of 
hepatic malignancy. Radiology; 1982; 142(3):783-786. 
 
47. Meade V, Burton M, Gray B et al: Distribution of different sized microspheres in 
experimental hepatic tumours. Eur J Clin Oncol. 1987; 23(1):37-41.  
 
48. Meranze SG, Bream PR, Grzeszczak E et al: Phase II clinical trial of yttrium-90 resin 
microspheres for the treatment of metastatic neuroendocrine tumor. Society of 
Interventional Radiology meeting 2007; Abs. 422. 
 
49. Murthy R, Kamat P, Nunez R et al: Yttrium-90 microsphere radioembolotherapy of 
hepatic metastatic neuroendocrine carcinomas after hepatic arterial embolization. J Vasc 
Interv Radiol 2008; 19: 145-151. 
 
50. Okusaka T, Nakachi K, Fukutomi A et al; Gemcitabine alone or in combination with 
cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan. 
Br J Cancer. 2010 Aug 10; 103(4): 469–474. 
 
 
 


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51. Rafi S, Piduru SM, El-Rayes B et al. Yttrium-90 radioembolization for unresectable 
standard-chemorefractory intrahepatic cholangiocarcinoma: Survival, efficacy and safety 
study. Society of Interventional Radiology (SIR) 36th Annual Scientific Meeting , J Vasc 
Intervent Radiol 2011; 22 (Suppl): S88 Abs 207.  
 
52. Randi G, Malvezzi M., Levi F. et al: Epidemiology of biliary tract cancers : an update. 
Annals of Oncology, 2008; 20: 146-159.  
 
53. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014; 383(9935): 2168-2179.  
 
54. Reig et al. HCC Treatment Stage Migration and Registration of Progression Using the 
BCLC Refined RECIST. Seminars in Liver Disease Vol. 34 No. 4/2014  
 
55. Roshan RH, Azarm A, Mahmoudian B, Islamian JP. Advances in SPECT for optimizing 
the liver tumors radioembolization using yttrium-90 microspheres. World J Nucl Med 
2015; 14:75-80. 
 
56. Sangro B, Gil-Alzugaray B, Rodriguez J et al: Liver disease induced by 
radioembolization of liver tumours. Cancer 2008; 112: 1538. 
 
57. Sangro B, Carpanese L, Cianni R et al. on behalf of European Network on 
Radioembolization with yttrium-90 resin microspheres (ENRY). Survival after 90Y resin 
microsphere radioembolization of hepatocellular carcinoma across BCLC stages: A 
European evaluation. Hepatology 2011; 54: 868–878. 
 
58. Saxena A, Bester L, Chua TC et al. Yttrium-90 radiotherapy for unresectable intrahepatic 
cholangiocarcinoma: A preliminary assessment of this novel option. Ann Surg Oncol 
2010; 17: 484-491. 
 
59. Saxena A, Chua TC, Bester L et al : Factors predicting response and survival after 
yttrium-90 radioembolization of unresectable neuroendocrine tumor liver metastases : a 
critical appraisal of 48 cases. Annals of Surgery 2010; 251: 910-916. 
 
60. Seidensticker R, Denecke T, Kraus P et al: Matched-pair comparison of 
radioembolization plus best supportive care versus best supportive care alone for 
chemotherapy refractory liver-dominant colorectal metastases. Cardiovascular and 
Interventional Radiology 2012 Oct; 35(5):1066. 
 
61. Sharma RA, van Hazel GA, Morgan B et al: Radioembolization of liver metastases from 
colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, 
fluorouracil, and leucovorin chemotherapy. Journal of Clinicat Oncology 2007; 25: 1099. 
  
62. Stubbs RS, Wickremesekera SK: Selective internal radiation therapy (SIRT): A new 
modality for treating patients with colorectal liver metastases. HPB (Oxford) 2004; 
6:133-139. 
 
63. Valle JW, Wasan H, Johnson P, et al.: Gemcitabine alone or in combination with cisplatin 
in patients with advanced or metastatic cholangiocarcinomas or other biliary tract 
tumours: a multicentre randomised phase II study – The UK ABC01 study. British 
Journal of Cancer 2009;101:621 – 627. 
 


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64. Valle J, Wasan H, Palmer D, et al.: Cisplatin plus Gemcitabine versus Gemcitabine for 
Biliary Tract Cancer. New England Journal of Medicine 2010;362; 1273-1281. 
 
65. Valle JW, Furuse J, Jitlal M, et al.: Cisplatin and gemcitabine for advanced biliary tract 
cancer: a meta-analysis of two randomised trials. Ann Oncol. 2014 Feb; 25(2):391-398. 
 
66. van Hazel GA, Pavlakis N, Goldstein D et al: Treatment of fluorouracil-refractory 
patients with liver metastases from colorectal cancer by using Yttrium-90 resin 
microspheres plus concomitant systemic irinotecan chemotherapy. Journal of Clinical 
Oncology 2009; 27: 4089-4095. 
 
67. van Hazel GA, Blackwell A, Anderson J et al: Randomised phase 2 trial of SIR-Spheres 
plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy 
alone in advanced colorectal cancer. Journal of Surgical Oncology 2004; 88: 78-85.  
 
 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
22 STANDARD OF CARE GUIDEL~ES 
COUNTRY/ 
REFERENCE 
REGION 
futemational 
futemational Liver Cancer Association (ILCA) & European Association of the 
and EU 
study of the Liver (EASL) guidelines: 
Bridgewater J, Galle PR, Khan SA et al: Guidelines for the diagnosis and 
management of intrahepatic cholangiocarcinoma. Journal of Hepatology 2014; 
60: 1268-1289 
Europe 
Biliary Cancer: ESMO Clinical Practice Guidelines 
J. W. Valle, I. Borbath, S. A. Khan, F. Huguet, T. Grnenberger and D. Arnold 
Biliary 
Cancer:. 
Ann 
Oncol 
(2016) 
27 
(suppl 
5): 
v28-
v37htt12://www.esmo.om/Guidelines/Gastrointestinal-Cancers/Biliaa-Cancer 
Netherlands 
Oncoline h!!Q://www.oncoline.nl/galweg-en-galblaascarcinoom 
UK 
Khan SA, Davidson BR, Goldin RD, et al. Guidelines for the diagnosis and 
treatment of cholangiocarcinoma: an update. Gut. 2012;61:1657-1669 
Italy 
Associazione Italiana di Oncologia Medica (AIOM). Linee Guida Tu.mori Delle 
Vie Biliari. 2015. 
httQ ://www .aiom.it/Qrofessionisti/ documenti-scientifici/linee-guida/ l i 413 i l 
France 
Societe Nationale Fran9aise de Gastroenterologie. 8. Cancer des voies biliaires 
(Derniere mise a }our le 24/01/2014). 2014. htw://www.snfge.org/content/8-
cancer-des-voies-biliaires. 
Australia 
eviQ Cancer Treatments online 
htt12s:/ /www.evig.org.au/Protocol/tabid/ 66/ categoi:yid/3 72/id/1200/Biliary+and 
+Gallbladder+Metastatic+cIS12latin+and+Gemcitabine.as12x 
USA 
NCCN Guidelines Version 1.2016 Hepatobiliary Cancers 
Confidential Sirtex Technology Pty Ltd 
Page60of93 


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APPENDIX 1 
Technique for Administration of SIR-Spheres Y-90 resin microspheres 
 
SIR-Spheres Y-90 resin microspheres are administered by injection through a trans-femoral 
catheter into the hepatic artery. As there are frequent arterial anomalies in the blood supply to 
the liver, the radiologist must be familiar with those anomalies. Only radiologists who have 
received formal training and have been approved by Sirtex may participate in this study and 
administer SIRT. All areas of tumour within the liver are to be targeted with SIR-Spheres Y-90 
resin microspheres and this usually involves treating both lobes of the liver. However, it is 
essential that the SIR-Spheres Y-90 resin microspheres are not delivered to other organs such as 
the duodenum, stomach, pancreas etc. 
 
If the tumour is limited to only one lobe, the radiologist can insert the microcatheter selectively 
into the lobar/segmental artery supplying only that lobe. The SIR-Spheres Y-90 resin 
microspheres will then be delivered only to the lobe containing the tumour with sparing of the 
other normal lobe. This is an excellent way of delivering high doses of radiation to the tumour 
without any chance of damaging the normal liver.  
 
It is most important to inject the SIR-Spheres Y-90 resin microspheres slowly into the hepatic 
artery. In order to achieve a slow delivery rate to maintain SIR-Spheres microspheres in 
suspension, the flow from the delivery syringe may be given in pulses of 0.25ml to 0.5ml, 
separated by a pause. The specialist should periodically stop the delivery of SIR-Spheres 
microspheres and inject IV contrast through flushing tube ‘B’ and perform fluoroscopy. This 
ensures that the catheter remains in the correct position at all times and allows the specialist to 
detect imminent stasis or reflux back down the hepatic artery. The speed of the injection must be 
adapted to the flow of contrast seen while performing the fluoroscopy. If they are injected too 
quickly they may reflux back down the hepatic artery and lodge in the pancreas, stomach and 
other organs. 
 
The following principles dictate where the microcatheter is placed when delivering SIRT:  
▪ treat only those parts of the liver that contain tumour e.g. lobar treatment if tumour 
present only in one lobe, rather than whole liver SIRT 
▪ if possible then try and not treat some normal liver parenchyma from SIRT. Even a 
small amount of normal liver that remains untreated provides extra protection against 
the possibility of liver damage e.g. super-selective SIRT is preferred if possible 
▪ use of automated pump injection to identify not only the right and left hepatic arteries, 
but also the gastric arteries and any other accessory vessels which may need to be 
embolised in order to ensure safe administration of SIR-Spheres microspheres 
▪ review with extreme vigilance the pre-treatment angiogram to look for anatomical 
abnormalities  
▪ never allow SIR-Spheres Y-90 resin microspheres to enter any vessel supplying the 
gut i.e. embolise non-target arteries supplying the gut which cannot be avoided by 
distal placement of catheter during administration of SIR-Spheres microspheres 
▪ always inject SIR-Spheres Y-90 resin microspheres at the recommended rates with 
repeated fluoroscopy to check the position of the catheter and to look for any slowing 
of blood flow and possible reflux blood back down the hepatic artery.  
 
Dealing with Anatomical Anomalies  


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Note: 
Inadvertent injection of SIR-Spheres Y-90 resin microspheres into small arteries 
passing from major arteries vessels in the hilum of the liver to the stomach and 
duodenum is the commonest cause of serious adverse events. These small aberrant 
vessels, not described in the standard anatomy texts may be the cause of these SAEs 
if the radiologists do not recognise these small vessels and allow SIR-Spheres Y-90 
resin microspheres to flow to the gut.  
 
Radiologists are referred to the review article of Liu et al, 2005 (43) for an additional 
comprehensive description of how to administer SIRT. 
 
If there is a dual blood supply to the liver, then the radiologist will have to catheterise each artery 
separately to inject the SIR-Spheres Y-90 resin microspheres if there is tumour in both lobes. If 
there is only tumour in one lobe, then the radiologist only needs to inject the SIR-Spheres Y-90 
resin microspheres into that side of the liver. 
 
For instance, if all the tumour was in the right lobe of the liver and there was an accessory right 
hepatic artery arising from the superior mesenteric artery, then injecting all the SIR-Spheres Y-
90 resin microspheres into this accessory right hepatic artery would deliver all the radiation to 
tumour in the right lobe where it is wanted.  
 
If there are separate right and left arteries and there tumour in both right and left lobes, then it is 
necessary to inject some of the SIR-Spheres Y-90 resin microspheres separately into both arteries 
in order to deliver radiation to the tumour in both lobes.  
 
The following anomalies in vascular supply must be noted:  
1. In 20% of patients there will be a replaced right hepatic artery arising from the superior 
mesenteric artery (see diagram b below). This replaced right hepatic artery will supply most 
of the right lobe of liver and is easily demonstrated on an angiogram. If present, it must be 
accessed to deliver SIR-Spheres Y-90 resin microspheres to the right lobe of the liver as well 
as the main hepatic artery; otherwise the radiation will not be delivered to the tumour in the 
right lobe of the liver.  
2. In 17% of patients an accessory left hepatic artery will arise from the left gastric artery (see 
diagram c below). This accessory left artery is usually difficult to demonstrate on an 
angiogram, and is often not recognised at the time of angiography. It is usually possible to 
get a co-axial catheter into this artery if it is necessary to deliver SIR-Spheres Y-90 resin 
microspheres to the left lobe of the liver. If there is no tumour in the left lobe then it can be 
ignored. An alternative, for some cases, could be to occlude proximally (coiling) any 
aberrant/accessory vessel by allowing “vascular redistribution” (Bilbao et al (6)) of the 
arterial intrahepatic flow allowing to perform, both the 99mTc-MAA evaluation as well as the 
Y-90 treatment, by the contralateral artery. 
3. In a minority of patients the gastro-duodenal artery arises from the main hepatic artery distal 
to the origin of the left hepatic artery. It is imperative that the SIR-Spheres Y-90 resin 
microspheres not be delivered into the gastro-duodenal artery, as this will result in the SIR-
Spheres Y-90 resin microspheres lodging in the duodenum and pancreas with severe side 
effects. In this situation the gastro-duodenal artery should be embolised to occlude it before 
administering the SIR-Spheres Y-90 resin microspheres into the hepatic artery. The 
systematic occlusion of the gastroduodenal and the right gastric arteries should not be 
recommended, only when technically needed.  
  
MAJOR VARIATIONS IN ARTERIAL BLOOD SUPPLY TO THE LIVER  


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1. (50%) In the normal setting the gastro-duodenal (GD) artery comes off the common 
hepatic artery proximal to the bifurcation into the right hepatic (RH) and left hepatic (LH) 
arteries. The left gastric (LG) and splenic (SPL) arteries come off the coeliac axis 
separately.  
2. (20%) When the right hepatic artery is replaced the whole blood supply to the right lobe 
comes off the superior mesenteric artery (SMA). In the case of an accessory right hepatic 
artery, the vasculature off the coeliac axis is normal but there is an additional right hepatic 
artery off the superior mesenteric artery.  
3. (17%) When the left hepatic (LH) artery is replaced, the whole blood supply to the left 
lobe comes off the left gastric (LG) artery. In the case of an accessory left hepatic artery 
the vasculature of the common hepatic artery is normal but there is an additional left 
hepatic artery off the left gastric artery.  
4. (3%) In this situation the entire common hepatic artery arises from the superior 
mesenteric artery  
5. (9%) A trituration occurs when the bifurcation of the left hepatic and right hepatic 
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APPENDIX 2 
Nuclear Medicine Break-Through Scan 
 
Purpose:  
To assess arterial perfusion of the liver and the fraction of 
radiopharmaceutical tracer that will pass through the liver and 
lodge in the lungs. 
 
Agent:  
Technetium-99 labelled MAA (Macro-aggregated Albumin)  
  
Dose:  
150MBq 
 
Equipment:  
Any large FOV gamma camera  
 
Administration:  The patient needs to have a trans-femoral catheter placed in the 
hepatic artery. The Technetium 99 labelled MAA is injected 
through the catheter into the hepatic artery by a qualified 
physician. 
 
Imaging:  
The patient is positioned supine under the gamma camera and the 
images recorded. 
  
Analogue:  
Anterior and posterior images of planar abdomen and thorax. 
Measure 700K – 1000K counts for abdomen and equivalent time 
for thorax.  
Right lateral abdomen - same time acquisition as for Anterior. 
 
Digital:  
4 frames; 300”/ frame. 64 x 64 matrix Word mode.  
Image anterior and posterior abdomen. 
Image anterior and posterior thorax. 
 
 
Analysis:  
Draw ROI around whole of liver and whole of lung fields. 
Calculate G mean for liver region and lung region.  
Calculate Lung/liver ratio. 
 
 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 65 of 93 
APPENDIX 3 
Administered Dose Calculation 
The following document provides patient dosing information and is intended for the use of 
Interventional Radiologists and Nuclear Medicine specialists performing the Y-90 
administration as well as Medical Oncologists, Gastroenterologists or Hepatologists designing 
the treatment plan.  
 
If the tumour burden involves both lobes of the liver, either whole-liver or more selective 
administration of SIR-Spheres Y-90 resin microspheres are possible at the discretion of the team; 
the decision should be made by the multidisciplinary team on a case by case basis. However, a 
lobar approach is recommended if tumour burden is unequally distributed between both lobes, 
with the lobe containing most of the tumour load treated first. SIR-Spheres Y-90 resin 
microspheres should be administered in a single session (with one or more sites of injection) 
even when a whole-liver approach is used. Consecutive injections into the right and left hepatic 
artery should be preferred to a single injection from the common hepatic artery. 
 
To determine the amount of SIR-Spheres Y-90 resin microspheres to be implanted the 
Interventional Radiologist and/or Nuclear Medicine specialist will need to know the following 
information about the patient to be treated:  
 
1) Lung shunt (%)  
2) Body Surface Area (BSA)  
3) Tumour Volume (ml), target liver volume (ml), total liver volume (ml) 
Tumour and total liver volumes are calculated from the baseline CT scan of the liver.  
 
If the lung shunt is higher than 20% then the patient is ineligible for SIR-SpheresY-90 resin 
microspheres treatment. 
 
Method of Activity Calculation 
 
The method of activity calculation is based on the presentation of hepatic lesions. If a patient 
only has non-measurable tumours that will typically present in a too-numerous-to-count (TNC) 
“salt and pepper” pattern for which tumour volume cannot be measured the patient is not eligible 
for 90-Y resin microsphere treatment. For patients with measurable disease and additional small 
satellite tumours, activity calculation should be based on the measurable disease. 
 
Prescribed activity for whole liver treatment using the BSA Method 
For whole liver treatment, the BSA method is used to calculate the prescribed activity of SIR-
Spheres Y-90 resin microspheres. The BSA method is dependent on the patient’s estimated BSA 
by Du Bois formula and percentage tumour involvement of the patient’s liver.  
Dose activity[GBq] = (BSA −0.2) + Vtumour
VTotalLiver 
 
Vtumour = volume of tumour 
VTotaLiver = volume of total liver, including tumour 
 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 66 of 93 
SIR-Spheres Y-90 resin microspheres are contraindicated in patients with lung shunt of >20%. 
For patients undergoing SIRT, lung radiation dose should not exceed 25 Gy and appropriate 
reductions in dose activity should be performed to ensure this safety limit is adhered to. 
 
Selective catheterisation of individual branches is recommended for whole-liver treatment 
instead of a single injection via the common or proper hepatic artery. In this case, the activity to 
be injected into each artery should be proportional to the volume of the segments involved. For 
instance, if the treatment includes one administration each into the right and left hepatic arteries 
respectively, then the activity injected into each respective hepatic artery will be: 
 
 
 
 
Vtumour = volume of tumour 
Vlobe = volume of treated lobe, including tumour 
VTotaLiver = volume of total liver, including tumour 
 
Where the sum of activity administered in both right and left hepatic arteries will be the same as 
the BSA formula:  
Dose activity[GBq] = (BSA −0.2) + Vtumour
VTotalLiver 
 
Vtumour = volume of tumour 
VTotaLiver = volume of total liver, including tumour 
 
Prescribed activity for lobar treatment using BSA method 
 
If disease presentation is confined to a single lobe, it is possible to minimise radiation exposure 
to the contralateral lobe with non-tumourous parenchyma and administer SIR-Spheres Y-90 resin 
microspheres to a single lobe only. For example, if all liver tumours are confined to the right 
lobe, then only the right lobe is treated to spare the left lobe from unnecessary radiation exposure. 
In this instance, an adjustment factor is introduced to the BSA calculation to reduce the activity 
which accounts for the untreated lobe. The activity to be injected into the treated lobe is given 
by the following formula: 
 
 
 
Vtumour = volume of tumour 
Vlobe = volume of treated lobe, including tumour 
VTotaLiver = volume of total liver, including tumour 
 
Attention should be paid to individual vascular anatomy. When the liver volume infused from 
the artery where the tip of the catheter is placed is smaller or larger than the corresponding lobe 
(for instance, in the case of aberrant infusion of the right lobe through an accessory right hepatic 
artery arising from the superior mesenteric artery, or infusion of segment IV from a branch of 
the right hepatic artery), the activity to be injected should match the corresponding target volume.  
 
 
Dose activity[GBq] = ((𝐵𝑆𝐴−0.2) +  Vtumour
Vlobe
) .
Vlobe
VTotalLiver
 
Dose activity[GBq] = ((𝐵𝑆𝐴−0.2) +  V
tumou
V
lobe
) .
V
lobe
V
TotalLiver
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
Prescribed activity when at least 2 liver segments are spared from treatment (Partition 
Model) 
Besides the BSA model, the Paitition Model may also be used to detennine the patient-specific 
prescribed activities of SIR-Spheres Y-90 resin microspheres when at least 2 liver segments are 
spai·ed from treatment (typically, in a lobar approach), provided the patient has discrete and 
measurable tumours that can be delimited on the CT/MRI scan. 
The partition model is based on Medical Internal Radiation Dose (MIRD) principles. It relies on 
the fact that three discrete vascular compaiiments - the lungs, tumour and uninvolved liver 
parenchyma - can effectively be partitioned from each other. This model thus only applies to 
patients with a discrete tumour burden that can be localised from uninvolved parenchyma. Such 
regions of interest should be defined in MAA SPECT CT/MRI imaging or planar MAA scan 
(preferably MAA SPECT CT/MRI) in order to calculate the tumour to non-tumour ratio. 
For non-cinhotic patients and provided a significant propo1tion of the liver volun1e is spared 
from radiation - with the likelihood of hype1irophy and functional compensation in the non-
targeted volume - the paitition model is used to calculate an activity with the highest likelihood 
of resulting in an objective tumour remission. 
For cirrhotic patients or when the amount of volume spared from radiation is low - with the 
likelihood of increased risk of complications derived from radiation-induced damage in the non-
tumoural tissue - the paiiition model is used to calculate an activity with the highest chance to 
preserve liver function in the targeted lobe. 
On the basis of tumour and liver volumes measured on CT or MRI images and MAA imaging, 
representative regions of interest of tumour and non-tumour liver are drawn. MAA imaging such 
as SPECT CT/MRI or MAA planar images may be used and MAA SPECT CT/MRI are 
prefened. The Paitition Model estimates the dose of radiation that will be absorbed by tumour 
and non-tumoural liver compaitments (Kao 2012 (31)). 
When the patient is not ciiThotic or the amount targeted volume is less than 60% of the total liver 
volume, the Model is used to calculate an activity that would result in the tumour absorbing 120 
Gy iITespective of the dose delivered to the non-tumoural liver. 
A (GBq) = [120 x ((M!iver / T:N) + Mtumour)] / [49670 (1-Lll00)] 
Conversely, when the patient is cin-l1otic and the amount of targeted volume (tun1our plus non-
tumoural liver) is equal to or more than 60% of the total liver volume, the Model is used to 
detennine the activity that would result in the non-tumoural liver absorbing not more than 40 
Gy. 
A (GBq) = [40 x ((T:N x Mtumour) + M!iver)] / [49670 (1-U l 00)] 
Spai·ed Volume 
CiiThosis 
No Cinhosis 
< 40% 
< 40 Gv (Non Tumour) 
120 Gv (Tumour) 
> 40% 
120 Gy (Tumour) 
120 Gy (Tumour) 
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CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 68 of 93 
 
The prescribed activity should always be lower than the one that would be harmful for the lung 
tissue as per the following formula: 
 
ATotal = (30000 x 100/ Lung Shunt) / 49670 
 
If there is a contraindication to the use of the Partition Model e.g. tumours cannot be delineated 
on MAA SPECT CT/MRI or planar MAA to calculate the T: N ratio, then the activity will be 
calculated using the BSA method using the formula below: 
 
 
 
Vtumour = volume of tumour 
VTotaLiver = volume of total liver, including tumour 
Vlobe = volume of treated lobe, including tumour” 
 
Note: SIR-Spheres Y-90 resin microspheres are contraindicated in patients with lung shunt of 
>20%. The same principles of prescribed dose activity reduction should be applied to ensure that 
lung radiation dose does not exceed 25 Gy. 
 
 
Calculation of Lung Shunt Activity and Estimated Absorbed Pulmonary Dose When the 
BSA Method is Employed 
 
For patients exhibiting lung-shunt when the BSA method for calculating activity is employed, 
estimated activity shunted to the lungs and the associated absorbed dose are to be determined. 
The calculation of estimated radiation exposure to the lungs is given by the following formulae: 
 
Activity that may potentially reach the lung: 
 
Alung [GBq] = Atotal * L/100 
 
Where: 
Alung = lung activity (GBq) 
Atotal = total prescribed activity (GBq) 
L = lung shunt (%) 
 
The resulting lung dose, given that a given amount of activity shunts from the liver to the lung: 
 
 
 
 
 
Dlung (Gy) =   
 
 
Where: 
 
 
 
Dlung = lung dose (Gy) 
 
 
 
Alung = lung activity (GBq) 
 
 
 
Mlung = mass of the lung (g) 
 
The mass of both lungs plus blood is assumed to be 1000gm and allows estimation of lung 
Dose activity[GBq] = ((𝐵𝑆𝐴−0.2) +  V
tumou
V
lobe
) .
V
lobe
V
TotalLiver
 
49670*Alung 
     Mlung 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 69 of 93 
parenchymal radiation doses for any given amount of shunting. The administered dose of SIR-
Spheres Y-90 resin microspheres must be reduced to ensure that the lung dose does not exceed 25 
Gray. 
 
If, based on: 1) the prescribed activity determined by the BSA method and 2) the lung-shunt 
percentage as determined by the 99mTC-MAA scan conducted during the baseline angiographic 
mapping, the lung dose is < 25 Gy, the full prescribed activity will be administered. If it is 
determined that the estimated lung dose exceeds 25 Gy, the prescribed activity will be reduced 
(taking into account the lung shunt percentage) to ensure that ≤ 25 Gy is administered to the 
lungs.  In order to provide an additional measure of safety for patients who exhibit lung shunt, 
any patient whose lung shunt exceeds 20% based on the 99mTc-MAA scan will be considered 
ineligible for SIR-Spheres microsphere treatment.  
 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
APPENDLX 4 
NCI CTCAE v4.03 Recommendation for Grading of Adverse Events 
The full Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 
Published 14 June 2010 can be obtained at the following website: 
http://evs.nci.nih.gov/ftpl/CTCAE/CTCAE_ 4.03_2010-06-14_QuickR.eference_5x7.pdf 
A brief summary of the key metabolic/laboratory values is listed for easy reference in the table 
below. 
Adverse 
Grade 1 
Grade2 
Grade3 
Grade 4 
Event 
Albumin 
30 - LLN g/L 
20 - 30 g/L 
< 20 g/L 
-
ALP 
> ULN - 2.5 x ULN 
2.5 - 5.0 x ULN 
5.0 - 20.0 x ULN 
> 20xULN 
ALT 
> ULN - 2.5 x ULN 
2.5 - 5.0 x ULN 
5.0 - 20.0 x ULN 
> 20xULN 
AST 
> ULN - 2.5 x ULN 
2.5 - 5.0 x ULN 
5.0 - 20.0 x ULN 
> 20xULN 
Bilirnbin 
> ULN - 1.5 x ULN 
1.5 - 3.0 x ULN 
3.0 - 10.0 x ULN 
> 10.0xULN 
Creatinine 
> ULN - 1.5 x ULN 
1.5 - 3.0 x ULN 
3.0 - 6.0 x ULN 
> 6.0x ULN 
Haemoglobin 
100 - LLN g/L 
80 - 100 g/L 
65 - 80 g/L 
< 65 g/L 
Leucocytes 
3.0 - LLN x 109/L 
2.0 - 3.0 X 109/L 
1.0 - 2.0 x 109/L 
< 1.0 X 109/L 
Neut:rophils 
1.5 - LLN x 109/L 
1.0 - 1.5 X 109/L 
0.5 - 1.0 x 109/L 
< 0.5 X 109/L 
Platelets 
75 -LLN x 109/L 
50 - 75 X 109/L 
25 - 50 X 109/L 
< 25 X 109/L 
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CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
APPENDLX 5 
CIS-GE:\I Treatment Details according to ABC-02 
In Treatment Arm A: Chemotherapy Alm - CIS-GEM 
Systemic chemotherapy (CIS-GEM) to staii within 14 days(+ 2 days) of randomisation: 
2 
Cisplatin 25 mg/m in 1000ml 0.9% saline given over 1 hour followed by 500 ml 0.9% saline 
over 30 minutes followed by 
2 
Gemcitabine 1000 mg/m in 250 - 500ml 0.9% saline over 30 minutes by intravenous infusions 
on days 1, and 8 of a 21-day cycle. 
Variations in fluid administration and cisplatin or gemcitabine dilutions are accepted. Cisplatin 
has to be administered prior to gemcitabine. Dose banding is allowed. 
8 treatment cycles will be given; in the absence of progression treatment may be continued at 
discretion of the clinician. 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 onwards 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Day 
1 
8 
1 
8 
1 
8 
1 
8 
Cisplatin 
X 
X 
X 
X 
X 
X 
X 
X 
Gemcitabine X 
X 
X 
X 
X 
X 
X 
X 
In Treatment Alm B: Sequential Therapy Alm - SIRT followed by CIS-GEM 
Patients randomised to receive SIR-Spheres Y-90 resin microspheres followed by systemic 
chemotherapy, will commence administration of CIS-GEM 14-16 days after SIRT treatment. 
2 
Cisplatin 25 mg/m in 1000ml 0.9% saline given over 1 hour followed by 500 ml 0.9% saline 
over 30 minutes followed by 
2 
Gemcitabine 1000 mg/m in 250 - 500ml 0.9% saline over 30 minutes by intravenous infusions 
on days 1, and 8 of a 21-day cycle. 
V ai·iations in fluid administration and cisplatin or gemcitabine dilutions are accepted. Cisplatin 
has to be administered prior to gemcitabine. Dose banding is allowed. 
14-16 
days Cycle 1 
Cycle 2 
Cycle3 
Cycle 4 onwards 
after SIRT 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Day 
1 
8 
1 
8 
1 
8 
1 
8 
Cisplatin 
X 
X 
X 
X 
X 
X 
X 
X 
Gemcitabine X 
X 
X 
X 
X 
X 
X 
X 
In the absence of disease progression or unacceptable toxicity 8 treatment cycles will be given. 
Beyond 8 cycles, treatment may be continued in the absence of disease progression at the treating 
clinicians' discretion. 
Note: Patients randomised to receive SIRT (Alm B) but for whom SIRT implantation is not 
safely feasible ( e.g. following initial angiographic work-up) will be treated according to aim A 
(but retained in Alm B for intention-to-treat (ITT) analysis). 
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CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 72 of 93 
PRE TREATMENT  
 
Hydration schedule for cisplatin 
The hydration and electrolyte regimen (KCl +/- MgSO4) for cisplatin administration will be 
determined by locally agreed pharmacy procedures and guidelines.  
The following is recommended: 
 
KCL 20 mmol and MgSO4 8 mmol during the one hour cisplatin infusion followed by 500 mls 
0.9% saline over 30 minutes prior to the gemcitabine 
However, alternative local schedules are acceptable. 
 
Anti-emetics 
The following schedules are optional; alternatively anti-emetics should be given according to 
local practice. 
 
Gemcitabine & Cisplatin  
Pre chemo on day 1  
8 mg dexamethasone iv plus  
1 mg Granisetron or  
4 mg Ondansetron  
Day 2  
4 mg dexamethasone PO plus  
1 mg Granisetron PO  
Day 3  
4 mg dexamethasone PO  
Days 1-5  
Domperidone 20 mg qid PRN  
Metoclopramide 10 mg tid PO  
 
 
RECOMMENDED CRITERIA FOR DOSE ADJUSTMENTS AND DEFERRING 
SUBSEQUENT TREATMENT COURSES  
 
Dose adjustments and/or deferring chemotherapy treatment administrations will be dependent 
upon the full blood count taken prior to each treatment day and on the assessment of renal 
function as well as total bilirubin value.  
 
In order to proceed with administration of full dose of gemcitabine on day 1 and day 8 of each 
cycle the following are required: WBC ≥ 2x10
9, ANC ≥ 1x10
9 and platelets ≥ 100,000/mm
3 
and total bilirubin ≤ 30 µmol/L (1.75 mg/dL).   
 
If gemcitabine is deferred, the cisplatin will also be deferred (i.e. cisplatin will not be 
administered as a single agent).  
 
In the event of a delay due to total bilirubin > 30 µmol/L (1.75 mg/dL) is more than 3 weeks and 
in the absence of biliary obstruction, treatment may still be resumed when the total bilirubin 
reduces to ≤ 30 µmol/L (1.75 mg/dL). Treatment will be resumed at Day 1 of the next treatment 
cycle. After the 3 weeks delay and during the extended delay period, total bilirubin should be 
assessed at least once every TWO weeks until recovery, or disease progression, patient choice 
or intolerance or permanent discontinuation at investigators discretion. Prophylactic treatment 
with steroids, ursodeoxycholic acid and ciprofloxacin should be considered if there is 2 weeks 
or greater delay due to total bilirubin > 30 µmol/L (1.75 mg/dL). Refer to Section7.1.3 Hepatic 
Complications for further consideration. 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 73 of 93 
 
Prior to administration of cisplatin on each treatment day adequate renal function must be 
demonstrated with a calculated creatinine clearance ≥ 45ml/min.  
 
Treatment on both arms will be deferred for toxicity by one week only (note this does not apply 
to biliary tract obstruction see section 12.3). If a second deferral is required, the treatment week 
in question is omitted and the patient will move on to the next treatment point (not necessarily 
next cycle).  
 
For example: A patient has received cycle 3 day 1 (C3D1) of treatment and is due cycle 3 day 8 
(C3D8): 
 
Gemcitabine & Cisplatin 
No deferral 
C3D1 
C3D8 
C3D15 
 
i.e. as per protocol 
Treatment given 
√ 
√ 
χ 
(rest) 
 
 
1-week deferral 
C3D1 
C3D8 
C3D8 
C3D15 
i.e. cycle 3D8 is given 1 week late 
Treatment given 
√ 
χ 
√ 
χ 
(rest) 
 
2-week deferral 
C3D1 
C3D8 
C3D8 
C4D1 
i.e. cycle 3D8 is omitted altogether and *next 
cycle starts (which is C4D1) 
Treatment given 
√ 
χ 
χ 
√* 
 
 
RECOMMENDED ADJUSTMENTS 
 
Haematological toxicity 
 
Gemcitabine in both treatment arms will be dose-reduced or delayed if haematological toxicity 
occurs. The dose to be administered will depend on the FBC result on the day of treatment. 
 
WBC 
(x109/L) 
 
ANC 
(x109/L) 
 
Platelets 
(x1000/mm3) 
Gemcitabine 
Dose 
Cisplatin 
Dose 
≥ 2 
and 
≥ 1 
and 
≥ 100 
Full 
Full 
1-1.9 
and/or 0.5-0.9 
and/or 50-99 
75% dose 
Full 
< 1 
and/or < 0.5 
and/or < 50 
Delay* 
Delay 
 
*If delay is > 3 weeks for haematological toxicity, the patient will be withdrawn from treatment and 
followed according to protocol as shown in section 13.1. Study Calendar. 
 
 
NB: the dose of gemcitabine will be re-escalated to full dose upon recovery of haematological 
toxicity despite a previous dose reduction in order to maintain the dose-intensity of therapy. 
 
Renal toxicity 
 
Cisplatin dosage will depend on renal function 
 
 
 
 
Cisplatin  
Gemcitabine 
Estimated GFR ≥ 45ml/min 
full dose  
full dose 
Estimated GFR < 45ml/min* omit 
 
full dose 
 Repeat the creatinine clearance assessment (consider using the more accurate isotope GFR 
method, if not available 24 hour urine creatinine clearance could be used) ensuring the patient 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 74 of 93 
is adequately hydrated prior to this test and further cisplatin administration. Proceed with 
cisplatin if the repeated reading is ≥ 45ml/min, otherwise cisplatin is to be omitted until 
recovery of renal function. If cisplatin has to be omitted, continue with gemcitabine dosing 
according to FBC. If a sudden increase in creatinine occurs, haemolytic uraemic syndrome 
should be ruled out. 
 
 
Other toxicity 
No dose reduction/modification is required for: 
Alopecia (any grade) 
 
Lethargy (grade 1-2)  
 
Nausea/vomiting (grade 1-2)  
May have been reduced from grade 3-4 by 
appropriate use of anti-emetics  
Oedema (grade 1-2)  
Give postural advice, consider appropriate diuretics  
 
Recommended dose-modifications* for: 
 
Lethargy (grade 3-4) 
Reduce gemcitabine by 25% 
Nausea/vomiting (grade 3-4)  
Ensure optimal use of antiemetics (according to local 
policy)  
Delay until recovery to baseline, then:  
Omit cisplatin first. If it recurs reduce gemcitabine 
by 25%.  
Peripheral neuropathy  
(grade 1-2)  
Delay cisplatin until recovery to baseline, then 
continue at full dose. If it recurs, treat as for grade 3-
4. Continue with gemcitabine (full dose).  
Peripheral neuropathy  
(grade 3-4)  
Omit cisplatin from further treatment. Continue with 
gemcitabine (full dose).  
Oedema (grade 3-4)  
Dipstick urine test for protein followed by full 24-
hour urinary protein estimation if result ≥ +  
Delay until recovery to baseline (with use of 
appropriate diuretics). Then reduce gemcitabine by 
25%.  
Tinnitus  
No dose modification required if full recovery 
between cycles.  
Omit cisplatin if no recovery between cycles 
Continue gemcitabine (full dose)  
For increases in bilirubin and other liver function tests, refer to Section 7.1.3 
 
Stop allocated treatment for:  
 
 
Lethargy (grade 3-4)** 
Which has not responded to dose modification 
Nausea/vomiting (grade 3-4)**  
Which has not responded to optimal anti-emetics or 
dose reduction  
Oedema (grade 3-4)  
Which has not responded to dose modification and 
use of appropriate diuretics  
Pulmonary toxicity (grade 2-4)  
Supportive therapy (high dose steroids) should be 
initiated immediately  
 
*Investigator discretion as to whether a particular non-haematological toxicity requires a dose reduction or treatment 
delay 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 75 of 93 
**If delay is > 3 weeks for non-haematological toxicity (excluding biliary tract obstruction, see section 12.3 
Supportive Treatment 
 
In the event of a delay or interruption to trial treatment for reasons other than toxicity or disease 
related problems, treatment should continue. Resume treatment at Day 1 of the next treatment 
cycle. Patients who discontinue allocated treatment will still be included in evaluation of toxicity, 
response to treatment and survival. 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 76 of 93 
APPENDIX 6 
Recommended acquisition guidelines for CT scanning 
 
CT Acquisition Guidelines 
For the purpose of baseline screening and response assessment the following tables describe the 
preferred parameters to be used for computed tomography (CT) imaging of the chest, abdomen 
and pelvis.  
 
CT images are to be acquired from the lung apices to the symphysis pubis. 1) Prior to patients 
entering this study; and 2) for the follow-up imaging performed on this study.  
See Section 13 Follow Up Study Assessments. 
 
Area covered: 
Lung apices to pubic symphysis 
Scan type: 
Spiral 
Scan direction: 
Cranial-caudal 
Injection rate: 
2cc/kg @ 4cc/second up to 150cc contrast maximum 
Saline chaser: 
30cc @ 4cc/second 
 
Phases:  
Non-contrast (lung, abdomen and pelvis) 
 
Arterial @ 35 seconds post injection (abdomen) 
 
Portal venous @ 70 seconds post injection (lung, abdomen, pelvis) 
 
Late phases /delayed @ 6-15 mins* post injection (abdomen) 
 
*The recommended time for the late phase is at least 10 mins (Adam, 
Parthasarathy & Miller 2015.) The duration of the late phase should be 
consistent throughout the study for each patient. 
 
 
Parameter 
Phase 
  
Non-
Contrast 
Arterial 
(35 sec post injection) 
Portal 
Venous  
(70 sec 
post 
injection) 
Late phases 
/ delayed 
(6-15 mins 
post 
injection) 
  
Recon 1 
Recon 1 
Recon 2 
Recon 3 
Recon 1 
Recon 1 
View 
Axial 
Axial 
Coronal 
Sagittal 
Axial 
Axial 
Slice Thickness 
5.0mm 
1.0mm 
1.0mm 
1.0mm 
3.0mm 
3.0mm 
Increment/Spacing 
2.5mm 
1.0mm 
1.0mm 
1.0mm 
2.0mm 
2.0mm 
Kernel 
B25f 
B25f 
B25f 
B25f 
B25f 
B25f 
Window 
Abdomen 
Abdomen 
Abdomen Abdomen Abdomen 
Abdomen 
 
In case MRI is the standard radiological assessment for ICC patients, it is permitted if, for an 
individual patient, during the entire course of the study, the same method of assessment and the 
same technique is used to characterize each identified and reported lesion at baseline and during 
follow-up.  
 
CT scan (chest-abdomen-pelvis) remains mandatory for assessments outside the liver.  


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
Confidential Sirtex Technology Pty Ltd                                                                                                                                                                 Page 77 of 93 
APPENDIX 7 
RECIST Assessments 
• RECIST 1.1 Guidelines  
 
All measurements should be recorded in metric notation, using callipers if clinically assessed.  
 
All baseline evaluations should be performed as closely as possible to the beginning of treatment 
start and never more than 28 days before beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
I. 
Measurable Lesions: 
• Tumour > 10 mm in longest diameter (LD) on an axial image on CT or MRI with ≤ 5 
mm reconstruction interval (> 20 mm with conventional techniques) 
• Lymph nodes ≥ 15 mm in short axis on CT (CT slice thickness ≤ 5 mm) 
 
1) Target Lesions: 
• Choose up to 5 lesions and up to 2 per organ 
• Add up longest diameters (LD) of non-nodal lesions (axial plane) 
• Add short axis diameters of nodes 
• This is the sum of longest diameter (SLD)  
• If the largest lesion cannot be measured reproducibly, select the next largest lesion which 
can be. 
The baseline sum diameter will be used as reference to further characterise any objective tumour 
regression in the measurable dimension of the disease. 
 
2) Non-Target Lesions 
• All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with 10 to < 15 mm short axis). 
 
They should be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
 
II. 
Evaluating Response at each Time point: 
• Measure previously chosen target lesions (even if they are no longer the largest) 
• Evaluate all previously identified non-target lesions 
• Look for new definite cancer lesions 
 
Target Lesion Evaluation 
• Measure LD (axial plane) for each target lesion 
• Measure short axis for target lymph nodes 
• Add these measurements to get the SLD 
• If too small to measure, a default value of 5 mm is assigned (if the lesion disappears 
completely, the measurement is recorded as 0 mm). 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
• 
Splitting or coalescent lesions: 
o If a target lesion fragments into multiple smaller lesions, the LDs of all fragmented 
po1iions are added to the sum 
o If target lesions coalesce, the LD of the resulting coalescent lesion is added to the sum 
Response 
Definition 
Complete 
Disappearance of all extranodal target lesions. All pathological lymph 
Response (CR) 
nodes must have decreased to < 10 llllll in sho1i axis. 
Paitial 
At least a 30% decrease in the SLD of target lesions, taking as 
Response (PR) 
reference the baseline sum of diameters 
Progressive 
SLD increased by at least 20% from the smallest value on study 
Disease (PD) 
(including baseline, if that is the smallest) 
The SLD must also demonstrate an absolute increase of at least 5 llllll. 
(Two lesions increasing from 2 nnn to 3 rmn, for example, does not 
qualify) 
Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
(SD) 
to qualify for PD 
Non-Tai·get Lesion Evaluation 
Response 
Definition 
Complete 
• Disappearance of all extranodal non-target lesions 
Response (CR) 
• All lymph nodes must be non-pathological in size ( < 10 mm sho1t 
axis) 
• N01malization of tumour marker level 
Non CR/Non PD 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumour marker level above the n01mal limits 
Progressive 
Unequivocal progression of existing non-tai·get lesions. (Subjective 
Disease (PD) 
judgement by experienced reader) 
Note: Elevated sernm tumour markers on their own are not sufficient evidence of progression 
and only imaging examinations can assess and confirm disease progression. 
New Lesions 
• 
Should be unequivocal and not attributable to differences in scanning technique or findings 
which may not be a tumour 
• 
If a new lesion is equivocal, continue to the next time point. If confomed then, PD is assessed 
at the date when the lesion was first seen. 
• 
Lesions identified in anatomic locations not scanned at baseline are considered new. 
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CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
RECIST: Response Criteria 
Time Point Response: Patients with Target(+/- non target) disease: 
T ar2et Lesions 
Non-Target lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all 
Non-PD 
No 
NE 
evaluated 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yes 
PD 
• 
Refined RECIST: Response Criteria 
The conventional RECIST was amended for the SHARP trial in order to prevent over-staging 
and non-accurate assessment of progression in the following instances: 
• 
Detection of lymph nodes in the hepatic hilum, as this may be seen in cinhotic patients and 
does not reflect cancer involvement. 
• 
Detection of ascites or pleural fluid at baseline or during follow-up, as this may reflect 
hydrosaline retention because of impaired liver function and not malignant spread. 
• 
Detection of macro regenerative nodules. Th.is may be observed in cinhotic livers and does 
not reflect progression, even if the nodules are larger than 1 cm. 
To prevent the above, the amendments state: 
• 
Lymph nodes are classified as malignant if their size exceeds 20 mm or if ru.terial 
vascularization is present. 
• 
For ascites or pleural effusion, in order to declare malignant, it should be proven by positive 
cytology. 
• 
New lesions outside the liver follow the same definitions as for RECISTl .1. New intrahepatic 
lesions have specific consideration: 
• 
<l 0 mm should be considered as equivocal and not progression. 
• 
~ 10 mm should be considered malignant if arterial hypervascularisation is present. 
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Table:  BCLC- refined RECIST  
Baseline lesion categorisation 
Measurable 
≥ 20 mm for conventional techniques 
≥ 10 mm with spiral (helical) CT scan or MRI 
Minimum lesion size 
20 mm or double the slice thickness (and gap if noncontiguous) on 
conventional technique 
10 mm or double the reconstruction thickness (and gap if 
noncontiguous) on spiral/helical CT or MRI 
Nonmeasurable 
All other lesions 
Smaller lesion (< 20 mm for conventional techniques or < 10 mm for 
spiral (helical) CT scan or MRI) 
Truly nonmeasurable lesions 
Lesion on chest X-rays 
Pleural effusion evidenced 
radiographically 
Will be classified as malignant only if pathology (cytology) proven 
Ascites 
Progressive disease may only be declared on the basis of a new or 
enlarging ascites if there is cytological confirmation of its malignant 
nature.  
New or enlarging ascites detected on imaging but without cytological 
proof of malignancy should not be assigned as progression. 
Portal vein thrombosis 
Malignant portal vein thrombosis should be considered nonmeasurable 
lesion. 
Malignant lymph nodes 
Lymph nodes detected at the portal hepatis should be considered as 
malignant if the lymph node longest diameter is at least 20 mm or show 
arterial enhancement. 
Lesion 
with 
prior 
local 
treatment 
Not valid as a target lesion 
Target lesion (TL) 
Selection rules 
Will not select TL if evidence of prior irradiation is apparent 
radiographically. Lesions with significant necrotic component or 
concomitant palliative radiotherapy should be excluded. 
Boundary 
Lesion with hypervascular component, that component must be 
included in the measurement. Hypervascular component is viable 
tumour. 
Measurement rules 
Tumour measurement performed on CT chest, abdomen, and pelvis. 
The longest diameter of the lesion should be measured even if the 
actual axis is different from the one used initially. If TL cannot be 
measured because of incomplete imaging, the TL will be limited 
“unknown” or “progressive disease.” Changes on pre-existing bone 
scan lesion will only have influence over OR. Only new bone lesions 
will be indicative of progressive disease. 
Nontarget lesion (NTL) 
Change on each lesion will be recorded as:  
Unequivocal progression (requires retrospective measurements and at 
least a doubling in LD from nadir for lesion < 2 cm and an increase by 
30% for lesion > 2 cm and inconclusive for progressive disease 
New lesions 
Will be recorded separately from target/nontarget 
≥ 1 cm in longest diameter and depicts arterial hypervascularisation = 
Progressive disease 
< 1 cm in longest diameter or not typical enhancement = Inconclusive 
progressive disease 


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New lesions smaller than 10 mm in longest diameter must be 
considered equivocal 
New lesions 10 mm or larger in longest diameter, but without 
hypervascularisation must be considered equivocal and inconclusive 
for progressive disease 
Response criteria 
Target lesion (TL) 
Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or nontarget) must have 
reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters 
of target lesions, taking as reference the baseline sum diameters.  
Progressive Disease (PD): At least a 20% increase in the sum of 
diameters of target lesions, taking into account the smallest sum on 
study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest 
sum diameters while on study.  
Lymph nodules 
Any pathological lymph nodes (whether target or nontarget) must have 
reduction in short axis to < 10 mm. 
Overall response in NTL 
NTL New lesion OR 
CR/No CR 
Incomplete response/SD/No SD 
PD Yes/No PD 
Any/Yes PD 
The appearance of one or more new lesions is also considered 
progression. 
Unequivocal Progression: There must be an overall level of substantial 
worsening in nontarget disease such that even in the presence of SD or 
PR in target disease, the overall tumour burden has increased 
sufficiently to merit discontinuation of therapy.  
Modest “increase” in the size of one or more nontarget lesions is 
usually not sufficient to qualify for unequivocal progression status. 
Confirmation criteria 
PR or CR, by CT or MRI scan of the chest, abdomen, and pelvis at 
least 4wk after. If the subject had evidence of bone disease at baseline, 
response cannot be confirmed if a bone scan was not performed.  
Tools for measuring lesions 
Clinical lesions 
Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using callipers. 
When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken because it is more objective 
and may also be reviewed at the end of the study.  
Ultrasound 
Will not be used to measure tumour lesion 
Endoscopy and laparoscopy 
Is not advised for tumour evaluation, but it can be used to confirm 
CR 
Tumour makers 
Are not reliable to assess response 
Abbreviations: BCLC, Barcelona Clinical Liver Cancer; CT, computed tomography; MRI, magnetic resonance imaging; RECIST, Response 
Evaluation Criteria In Solid Tumours. 
 
 


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APPENDIX 8 
EQ-5D Quality of Life Questionnaire 
 
The following four pages contain the Quality of Life questionnaire that is to be used by study 
participants during the course of the trial. The EQ-5D questionnaire is a tool that has been designed 
for rapid use in the clinical setting.  
 
EQ-5D is designed for self-completion by respondents and is ideally suited for use in clinics and 
face-to-face interviews. It is cognitively simple, taking only a few minutes to complete. Instructions 
to respondents are included in the questionnaire.  
 
The EQ-5D is used under license from the EuroQol group. The sample version shown here is the 
Australian English version. Sirtex has purchased the rights to use this document in all participating 
countries. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Health Questionnaire 
 
English version for Australia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Australia (English) © 1997 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
 
EQ-5D-3L 


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By placing a tick in one box in each group below, please indicate which 
statements best describe your own health state today. 
 
Mobility 
I have no problems in walking around 
❑ 
 
PLEASE TICK 
I have some problems in walking around 
❑ 
ONE BOX 
I am confined to bed 
❑ 
Personal Care 
I have no problems with personal care 
❑ 
 PLEASE TICK 
I have some problems washing or dressing myself 
❑ 
ONE BOX 
I am unable to wash or dress myself 
❑ 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities 
❑ 
PLEASE TICK 
I have some problems with performing my usual activities 
❑ 
ONE BOX 
I am unable to perform my usual activities 
❑ 
Pain/Discomfort 
I have no pain or discomfort 
❑ 
PLEASE TICK 
I have moderate pain or discomfort 
❑ 
ONE BOX 
I have extreme pain or discomfort 
❑ 
Anxiety/Depression 
I am not anxious or depressed 
❑ 
PLEASE TICK 
I am moderately anxious or depressed 
❑ 
ONE BOX 
I am extremely anxious or depressed 
❑ 
 
 
 
 
 
 
2 
Australia (English) © 1997 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
 


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3 
Australia (English) © 1997 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the 
worst state you can imagine is marked 0.  
 
We would like you to indicate on this scale how good or 
bad your own health is today, in your opinion. Please do 
this by drawing a line from the box below to whichever 
point on the scale indicates how good or bad your health 
state is today.
Your own 
health state 
today 
Best 
imaginable 
health state 
100 
0 
Worst 
imaginable 
health state 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
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APPENDIX 9 
World Medical Association Declaration of Helsinki 
WMA Declaration of Helsinki – Ethical Principles for Medical Research 
Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
            The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
The WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.  
 
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and standards. 
No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 


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12.       Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other health 
care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14.       Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value 
and if the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of participating 
in research must be ensured. 
 
Risks, Burdens and Benefits  
16.       In medical practice and in medical research, most interventions involve risks and burdens. 
           Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
           Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.            
 
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result from 
the research. 
 
Scientific Requirements and Research Protocols  
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals 
used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects 
and information regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
           In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
 
Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and approval to 
the concerned research ethics committee before the study begins. This committee must be transparent in 


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its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations of the country or countries 
in which the research is to be performed as well as applicable international norms and standards but these 
must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.  
           The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. No 
amendment to the protocol may be made without consideration and approval by the committee. After the 
end of the study, the researchers must submit a final report to the committee containing a summary of the 
study’s findings and conclusions.  
 
Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information. 
 
Informed Consent  
25.       Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she freely 
agrees. 
26.       In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study 
and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to withdraw consent 
to participate at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the information. 
           After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.       
           All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27.       When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately qualified 
individual who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorised representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the health 
of the group represented by the potential subject, the research cannot instead be performed with persons 
capable of providing informed consent, and the research entails only minimal risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent is able to 
give assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorised representative. The potential subject’s dissent should be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research  group. In such circumstances the physician 
must seek informed consent from the legally authorised representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible from the subject or a 
legally authorised representative. 


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31.       The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be impossible 
or impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested against those 
of the best proven intervention(s), except in the following circumstances: 
           Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
           Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to determine 
the efficacy or safety of an intervention  
           and the patients who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.  
           Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial 
in the trial. This information must also be disclosed to participants during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results must be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be accepted for 
publication. 
 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available. 
 
 


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APPENDIX 10 Abbreviations and Acronyms 
3D-CRT  
Three-dimensional Conformal Radiation Therapy 
5FU 
 
5-fluorouracil 
AASLD  
The American Association for the Study of Liver 
AE 
 
Adverse Event 
ADE 
 
Adverse Device Effect 
AFP 
 
Alpha-Fetoprotein 
AIMD 
 
Active Implantable Medical Device 
ALP 
 
Alkaline Phosphatase 
ALT 
 
Alanine Aminotransferase 
ANC 
 
Absolute Neutrophil Count 
ARTG 
 
Australian Register of Therapeutic Goods 
AST 
 
Aspartate Aminotransferase 
AVM 
 
Arterio-Venous Malformations 
BSA 
 
Body Surface Area 
BTC 
 
Biliary Tract Cancer 
CA 19-9   
Carbohydrate antigen 19-9 
CA 125  
Cancer antigen 125 
CEA 
 
Carcinoembryonic Antigen 
CIP 
 
Clinical Investigation Plan 
CIS 
 
Cisplatin 
CRA 
 
Clinical Research Associate 
CRF 
 
Case Report Form 
CRP 
 
C-Reaction Protein 
CSG 
 
Clinical Study Group 
 
CT 
 
Computed Tomography  
EASL 
 
The European Association for the Study of Liver 
EBRT 
 
External Beam Radiation Therapy 
EC 
 
Ethics Committee 
ECOG 
 
Eastern Cooperative Oncology Group 
eCRF 
 
electronic Case Report Form 
EC 
 
Ethics Committee 
EE 
 
Efficacy Evaluable 
ERC 
 
Endoscopic Retrograde Cholangiography 
ERCP 
 
Endoscopic Retrograde Cholangio-Pancreatography 
ESMO 
 
European Society for Medical Oncology 
EU 
 
European Union 
FBC 
 
Full Blood Count 
FOLFOX  
Oxaliplatin + leucovorin + 5-fluorouracil systemic chemotherapy 
FOLFOX6m 
modified FOLFOX6 
FOV 
 
Field of View 
FU 
 
Follow up 
FUDR 
 
Floxuridine 
GCP 
 
Good Clinical Practice 
GD 
 
Gastric-Duodenal 
GEM 
 
Gemcitabine 
GFR 
 
Glomerular Filtration Rate 
GGT 
 
Gamma-Glutamyl Transpeptidase 
HBV 
 
Hepatitis B Virus 
HCC 
 
Hepatocellular carcinoma 


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HCV 
 
Hepatitis C Virus 
HEENT  
Head, Eye, Ear, Nose and Throat 
ICC 
 
Intrahepatic Cholangiocarcinoma 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonisation 
IDSA 
 
Infectious Disease Society of America 
IDSMC  
Independent Data Safety Monitoring Committee 
IGRT 
 
Image Guided Radiotherapy 
IHAC 
 
Intra-Hepatic Arterial Chemotherapy 
IMRT 
 
Intensity Modulated Radiation Therapy 
IRB 
 
Institutional Review Board 
IRCP 
 
International Commission on Radiological Protection 
ISO 
 
International Standards Organization 
ISO 14155 
Clinical Investigation of Medical Devices for Human Use 
ITT 
 
Intention To Treat 
mITT 
 
modified Intention To Treat 
IWRS 
 
Interactive Web Response System 
LC 
 
Local Control 
LD 
 
Longest Diameter 
LG 
 
Left Gastric 
LH 
 
Left Hepatic 
LLN 
 
Lower Limit of Normal 
LN 
 
Lymph Node 
LPFS 
 
Liver-Progression Free Survival 
LV 
 
Leucovorin (folinic acid) 
 
 
MAA 
 
Macro-Aggregated Albumin 
METAVIR 
Meta-analysis of Histological Data in Viral Hepatitis 
MIRD 
 
Medical Internal Radiation Dose 
MRI 
 
Magnetic Resonance Imaging 
NCIC CTC 
National Cancer Institute of Canada Common Toxicity Criteria 
NCRI 
 
National Cancer Research Institute 
NICE 
 
National Institute for Health and Care Excellence 
NTL 
 
Nontarget Lesion 
ORR 
 
Overall Response Rate 
OS 
 
Overall Survival 
PET 
 
Positron Emission Tomography 
PFS 
 
Progression Free Survival 
PMA 
 
Pre-Market Approval 
PRISMA  
Preferred Reporting Items for Systematic Reviews and Meta-Analyses 
PTC 
 
Percutaneous Transhepatic Cholangiography 
PTCD 
 
Percutaneous Transhepatic Cholangio-Drainage 
RE 
 
Radioembolisation 
RECIST  
Response Evaluation Criteria In Solid Tumours 
REILD 
 
Radioembolisation Induced Liver Disease 
RH 
 
Right Hepatic 
ROI 
 
Region of Interest 
RT 
 
Radiotherapy 
SADE 
 
Serious adverse device effect 
SAE 
 
Serious Adverse Event 
SBRT 
 
Stereotactic Body Radiotherapy 
SIRT 
 
Selective Internal Radiation Therapy 


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SLD 
 
Sum of Longest Diameter 
SMA 
 
Superior Mesenteric Artery 
SPECT 
 
Single Photon Emission Computed Tomography 
SPL 
 
Splenic 
TGA 
 
Therapeutic Goods Administration 
TL 
 
Target Lesion 
TNC 
 
Too Numerous to Count 
TR 
 
Treatment Received = Safety Population 
TTP 
 
Time To Progression 
ULN 
 
Upper Limit of Normal 
WBC 
 
White Blood Count 
WHO 
 
World Health Organisation 
WMA 
 
World Medical Association 
 
RECIST outcome abbreviations 
CR 
 
Complete response 
NE 
 
Not Evaluable 
PR 
 
Partial response  
SD 
 
Stable disease 
PD 
 
Progressive disease 
 
Units of measurement 
GBq 
 
gigabequerel 
Gy 
 
Gray 
dL 
 
decilitre 
hr 
 
hour 
kg 
 
kilogram 
L 
 
litre 
mg 
 
milligram 
mL 
 
millilitre 
mSv 
 
millisieverts 
Sv 
 
microsieverts 
v 
 
volume 
 
 


CIP STX 0115 - SIRCCA Study, Rev 5, 12 Apr 2019 
 
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APPENDIX 11    NETHERLANDS SPECIFIC SAFETY REPORTING PROCEDURES 
Netherlands specific safety reporting procedures in accordance with the Medical Research 
Involving Human Subjects Act, Wet medisch-wetenschappelijk onderzoek met mensen (WMO) 
in the Netherlands. 
 
The sponsor will report all SAEs through the web portal Toetsing Online to the accredited METC 
(Medisch Ethische Toetsings Commissie) that approved the protocol, at the following 
timeframes:  
 
1. SAEs that result in death or are life threatening will be reported through the web portal 
Toetsing Online within 7 days after the sponsor has first knowledge of the serious adverse 
event, followed by a period of maximum of 8 days to complete the initial preliminary report.  
 
2. Unanticipated SAEs which are or are suspected to be related to a study procedure or to the 
medical device will be reported through the web portal Toetsing Online within a period of 
maximum 15 days after the sponsor has first knowledge of the serious adverse event.  
 
3. Anticipated SAEs which are or are suspected to be related to a study procedure or to the 
medical device will be reported periodically through the annual report.  
 
4. SAEs which are definitely not related to a study procedure or to the medical device will be 
reported periodically through the annual report  
 
The sponsor will submit a summary of the progress of the study (Annual progress report) to the 
accredited METC once a year. Information will be provided on the date of inclusion of the first 
subject, numbers of subjects included and numbers of subjects that have completed the study, 
serious adverse events/ serious adverse reactions, other problems, and amendments.  
 
Temporary halt for reasons of subject safety  
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or safety. 
The sponsor will notify the accredited METC with undue delay of a temporary halt including the 
reason for such an action. The study will be suspended pending further review by the accredited 
METC. The investigator will take care that all subjects are kept informed.