Clinical trial NCT02195011
Conditions: Colorectal Neoplasms
Keywords: Regorafenib 90Y Radioembolization SIR-Spheres Microspheres Metastatic Colorectal Cancer Liver Metastases SIRT Refractory
Sponsor: SCRI Development Innovations, LLC
Start date: 2014-07-01; Completion date: 2017-06-04
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety of regorafenib, an antiangiogenic drug, when combined with radioembolization using SIR-Spheres® microspheres in the treatment of colorectal cancer (CRC) that has spread to the liver.

Detailed description:
Recent targeted therapies and treatment strategies have shown promise in colorectal cancer; however, elimination of disease remains a challenge once spread to the liver. Radioembolization using SIR-Spheres® microspheres (SIR-Spheres) to treat liver-only or liver-dominant metastatic colorectal cancer (mCRC) has been successful in this refractory setting. In this open-label study we will compare the safety of two treatment cohorts in which radioembolization will be administered using the device SIR-Spheres microspheres (90Y resin microspheres) in combination with regorafenib to patients with mCRC with liver metastases. The two treatment cohorts will be evaluated for safety, overall response (OR), progression-free survival (PFS), and overall survival (OS).

Arms: arm 1: Regorafenib (one cycle) followed by SIR-Spheres followed by re-initiation of regorafenib 2-4 weeks after SIR-Spheres.

Patients will take regorafenib 160 mg orally once daily on Days 1-21 of each 28-day treatment cycle. SIR-Spheres microspheres will then be administered to the patient by injection through a trans-femoral catheter into the hepatic artery. Treatment with regorafenib will be re-started 2-4 weeks after SIR-Spheres administration. arm 2: SIR-Spheres followed by regorafenib to start 2-4 weeks after SIR-Spheres.

SIR-Spheres microspheres will be administered to the patient by injection through a trans-femoral catheter into the hepatic artery. After SIR-Spheres microspheres have been administered, the treatment with regorafenib will be initiated 2-4 weeks after administration of SIR-Spheres. Patients will take regorafenib 160 mg orally once daily on Days 1-21 of each 28-day treatment cycle.
Interventions: intervention 1: SIR-Spheres intervention 2: Regorafenib
Intervention descriptions: intervention 1: Radioembolization will be administered once by injection through a trans-femoral catheter into the hepatic artery. intervention 2: All patients will take regorafenib 160mg orally once daily on Days 1-21 of each 28-day cycle.

Protocol documents:
Prot_000.pdf: 
 
CONFIDENTIAL 
This document is confidential and is the property of the SCRI Development Innovations, LLC.  No part of 
this document may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from SCRI Development Innovations, LLC. 
GI 189 
A Two Arm Safety Study of Regorafenib before or after SIR-Spheres® 
Microspheres (90Y) for the Treatment of Patients with Refractory Metastatic 
Colorectal Cancer and Liver Metastases 
 
SCRI INNOVATIONS STUDY NUMBER: 
GI 189 
STUDY DEVICE: 
SIR-Spheres®1 Microspheres 
SPONSOR: 
SCRI Development Innovations, LLC 
(SCRI Innovations) 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
STUDY CHAIR: 
Andrew Kennedy, MD 
Sarah Cannon Research Institute (SCRI) 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
STUDY CO-CHAIR: 
Johanna Bendell, MD 
Sarah Cannon Research Institute (SCRI) 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
MEDICAL MONITOR 
D.K. Strickland, MD 
SCRI Innovations 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-901-309-2572 
asksarah@scresearch.net 
DATE FINAL: 
16 December 2013 
AMENDMENT 1 DATE:    
 
 
          15 April 2014 
 
 
                                                 
 
1  SIR
-Spheres is a registered trademark of Sirtex SIR-Spheres Pty Ltd 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
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Clinical Study Statement of Compliance 
A Two Arm Safety Study of Regorafenib before or after SIR-Spheres® 
Microspheres (90Y) for the Treatment of Patients with Refractory Metastatic 
Colorectal Cancer and Liver Metastases 
 
 
This clinical study shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but not 
be limited to: 
 
International Conference on Harmonisation (ICH) Guidelines on Good Clinical 
Practice (GCP) 
 
Ethical principles that have their origins in the Declaration of Helsinki  
 
Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 812, Investigational Device Exemptions 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA)  
 
As the Study Chair and/or Principal Investigator, I understand that my signature on the 
protocol constitutes my agreement and understanding of my responsibilities to conduct the 
clinical study in accordance to the protocol and applicable regulations.  Furthermore, it 
constitutes my understanding and agreement that any changes initiated by myself, without 
prior agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such. 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
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Clinical Study Principal Investigator Signature Page 
A Two Arm Safety Study of Regorafenib before or after SIR-Spheres® 
Microspheres (90Y) for the Treatment of Patients with Refractory Metastatic 
Colorectal Cancer and Liver Metastases 
 
 
SCRI INNOVATIONS STUDY NUMBER: 
GI 189 
STUDY DRUG(S): 
SIR-Spheres® Microspheres 
DATE FINAL: 
16 December 2013 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:        15 April 2014 
 
 
__________________________ 
__________________________         ______________  
Principal Investigator Name 
Please Print 
 
Principal Investigator Signature 
 
Date 
 
 
Please retain a copy of this page for your study files and return the original signed and dated 
form to: 
 
SCRI Development Innovations, LLC 
3322 West End Avenue, Suite 900 
Attn:  GI 189 Study Team  
Nashville, TN 37203 
 
 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
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SCRI Innovations GI 189 Clinical Study Summary of Changes 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:        15 April 2014 
Global Changes 
In-text references to appendices have been reordered to adjust for the change of Appendix E to A 
and Appendix F to B. 
Informed consent forms for both cohorts have been adjusted to reflect updates to the protocol.   
Section 3.1 Inclusion Criteria  
and Synopsis 
10. Male patients with female partners of childbearing potential and women female patients of 
childbearing potential are required to use two forms of acceptable contraception, including one 
barrier method, during their participation in the study and for 30 days following last dose.  Male 
patients must also refrain from donating sperm during their participation in the study. 
Section 5 Study Design, Section 5.4 Correlative Testing 
and Synopsis 
Blood samples will be collected from all patients prior to the hepatic angiogram and 99mTc 
MAA lung shunt scan, on Day 8 after SIR-Spheres treatment, and Day 30 (pre-dose) after 
SIR-Spheres treatment (see Section 5.1). prior to SIR-Spheres administration on Day 1, Day 8, 
and Day 30 (pre-dose) following SIR-Spheres treatment.    
Cytokine analyses will include, but not be limited to, the following: 
Section 5 Study Design Figure 1 GI 189 Schema 
Cohort 1 Regorafenib then SIR-Spheres (n=25) 
CYCLE 
1 
 
 
2 
2 
 
3* 
3 
 
 
4 
4 
WEEK 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Regorafenib 
160 mg PO daily 
X 
X 
X 
- 
- 
- 
X 
X 
X 
X- 
X 
- 
SIR-Spheres 
- 
- 
- 
 
X 
- 
- 
- 
- 
- 
- 
- 
Regorafenib - 160 mg orally once daily for Days 1-21 of a 28-day cycle followed by a  
1 week washout, then treatment with SIR-Spheres microspheres followed by a 2-week rest*,  
followed by re-initiation of regorafenib.  *If liver function toxicities are present,  
patient may be rechecked weekly for 2 additional weeks to allow for appropriate resolution of liver function 
toxicities prior to re-starting regorafenib.


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
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SCRI Innovations GI 189 Clinical Study Summary of Changes 
AMENDMENT NUMBER: 
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AMENDMENT DATE:        15 April 2014 
Cohort 2 SIR-Spheres then Regorafenib (n=25) 
CYCLE 
1 
 
2* 
 
2 
 
3 
3 
 
 
4 
4 
WEEK 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
SIR-Spheres 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Regorafenib 
160 mg PO daily 
- 
- 
X 
X 
X 
- 
X 
X 
X 
X- 
X 
- 
Treatment with SIR-Spheres microspheres followed by a 2-week rest*  
then regorafenib initiated - 160 mg orally once daily for Days 1- 21 of each 28-day cycle. * If liver  
function toxicities (LFTs) are present, patient may be rechecked weekly for  2 additional weeks  
and reinitiation of regorafenib may be delayed until appropriate resolution of liver function toxicities LFTs.     
Section 7 Study Assessments and Evaluations 
Overview 
The Screening physical examination, medical history, ECOG PS, complete blood counts (CBC), 
differential and platelets, comprehensive metabolic profile (CMP), and prothrombin time/partial 
thromboplastin time/international normalized ratio (PT/PTT/INR) should be done ≤21 days prior 
to initiation of treatment.  However, if these initial examinations are obtained within 72 hours of 
Cycle 1 Day 1 they do not have to be repeated on Cycle 1 Day 1. 
Section 7.2 Baseline Assessments 
This section has been listed separately for the two cohorts as Section 7.3.1 for Cohort 1 and 
Section 7.4.1 for Cohort 2.  
Section 7.2 Patient Assessment for SIR-Spheres 
 Cohort 1 patients will have these assessments performed during week 4 5 prior to SIR-
spheres treatment.   
 Cohort 2 patients will be assessed at Screening 7-4 days prior to SIR-Spheres 
treatment on CID1. 
Section 7.3.1 Baseline Study Assessments 
The following information will be collected and procedures will be performed for each 
patient at Screening ≤21 days prior to initiation of treatment unless otherwise noted: 
 Written informed consent prior to any other study-related procedures (≤28 days 
prior to initiation of treatment) 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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AMENDMENT NUMBER: 
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AMENDMENT DATE:        15 April 2014 
Section 7.3.1 Baseline Study Assessments (continued) 
 Medical history 
 Physical examination, measurements of height (first visit), weight, and vital signs 
(resting heart rate, respiratory rate, and oral temperature) 
 Blood pressure (BP) 
 ECOG PS (Appendix D) 
 Concomitant medication review 
 CBC (complete blood count) including hemoglobin, hematocrit, white blood cell 
(WBC) with 3-part differential, and platelets 
 CMP to include: glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), alkaline phosphatase (ALP), AST, ALT, 
total bilirubin, total protein, and albumin plus lactate dehydrogenase (LDH), and 
phosphorous. 
 PT/PTT/INR 
 Serum or urine pregnancy test (must be performed within 72 hours prior to the 
initiation of treatment) 
 Disease assessments: 
o CT scan chest, abdomen, and pelvis (≤28 days prior to treatment) 
o CEA tumor marker 
Section 7.3.2 Cycle 1, Day 1  
 AE assessment 
Section 7.3.4 Cycle 1, Day 22 (assessments to be completed ≤7 days prior to SIR-Spheres 
treatment) 
 Physical examination, weight, and vital signs 
 BP 
 ECOG PS 
 AE assessment 
 Concomitant medication review 
 CBC


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
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SCRI Innovations GI 189 Clinical Study Summary of Changes 
AMENDMENT NUMBER: 
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AMENDMENT DATE:        15 April 2014 
Section 7.3.4 Cycle 1, Day 22 (assessments to be completed ≤7 days prior to SIR-Spheres 
treatment) (continued) 
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 Biomarker blood sample collection prior to the hepatic angiogram and 99mTc MAA 
lung shunt scan 
 CEA tumor marker 
The following tests will be obtained 7-4 days prior to SIR-Spheres treatment: 
 Hepatic angiogram 
 
99mTc MAA lung shunt scan 
Section 7.3.5 Cycle 2, Day 1 (±72 hours) (Day of SIR-Spheres treatment) 
 SIR-Spheres treatment 
 BP 
 Physical examination, weight, and vital signs  
 BP 
 ECOG PS 
 AE assessment   
 Concomitant medication review 
 CBC    
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 Biomarker blood sample collection 
 CEA tumor marker 
Section 7.3.6 Cycle 2, Day 8 
 Biomarker blood sample collection (following SIR-Spheres treatment) 
Section 7.4.6 Cycle 2, Day 15 
and Schedule of Assessments – Cohort 1 table 
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
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SCRI Innovations GI 189 Clinical Study Summary of Changes 
AMENDMENT NUMBER: 
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AMENDMENT DATE:        15 April 2014 
Section 7.4.7 Cycle 2, Day 22 (if LFT toxicity persists) 
 CMP 
Section 7.3.7 Cycle 3 and Beyond, Day 1 (±72 hours) 
Regorafenib may not start until the patient’s hematologic, liver and renal functions have been re-
confirmed as eligible according to the Section 3.1 by the Investigator.  Therefore, the 
regorafenib cycle starts on the day that treatment begins.  If liver function toxicities are 
present, patient may be rechecked weekly for 2 additional weeks.  Those patients with 
persistent liver function toxicities after this time will come off study, but will be followed 
until resolution.   
 Biomarker blood sample collection (Day 30 [pre-dose] only following SIR-Spheres 
treatment) 
Section 7.4 Study Treatment Assessments – COHORT 2  
SIR-Spheres followed by 2-4 week rest then regorafenib 
Section 7.4.1 Baseline Study Assessments 
The following information will be collected and procedures will be performed for each patient at 
Screening ≤21 days prior to initiation of treatment unless otherwise noted.  If tThe following 
aremust be repeated or performed ≤within 7 days of Cycle 1 Day 1 they do not have to be 
repeated to document Cycle 1 Day 1 assessments prior to SIR-Spheres treatment unless 
otherwise noted: 
 Written informed consent prior to any other study-related procedures (≤28 days 
prior to initiation of treatment) 
 Medical history 
 Physical examination, measurements of height (first visit), weight, and vital signs 
(resting heart rate, respiratory rate, and oral temperature) 
 Blood pressure (BP) 
 ECOG PS (Appendix D) 
 Concomitant medication review 
 CBC (complete blood count) including hemoglobin, hematocrit, white blood cell 
(WBC) with 3-part differential, and platelets  


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
Page 10 of 98 
 CMP to include: glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), alkaline phosphatase (ALP), AST, ALT,  
SCRI Innovations GI 189 Clinical Study Summary of Changes 
AMENDMENT NUMBER: 
 1 
AMENDMENT DATE:        15 April 2014 
Section 7.4.1 Baseline Study Assessments (continued) 
 total bilirubin, total protein, and albumin plus lactate dehydrogenase (LDH), and 
phosphorus.  
 PT/PTT/INR 
  Serum or urine pregnancy test (must be performed within 72 hours prior to the 
initiation of treatment) 
 Biomarker blood sample collection prior to the hepatic angiogram and 99mTc MAA 
lung shunt scan, which will be obtained 7-4 days prior to SIR-Spheres treatment 
 Disease assessments: 
o CT scan chest, abdomen, and pelvis (≤ 28 days prior to treatment)  
o CEA tumor marker    
Section 7.4.2 Cycle 1, Day 1 (Day of SIR-Spheres treatment) 
 SIR-Spheres treatment 
 AE assessment 
 Biomarker blood sample collection 
 Medical History 
 Physical examination, measurements of height (first visit), weight, and vital signs (resting 
heart rate, respiratory rate, and oral temperature) 
 BP 
 ECOG PS 
 Concomitant medication review 
 CBC 
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 Serum or urine pregnancy test (must be performed within 72 hours prior to the initiation 
of treatment) 
 CEA tumor marker 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
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SCRI Innovations GI 189 Clinical Study Summary of Changes 
AMENDMENT NUMBER: 
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AMENDMENT DATE:        15 April 2014 
Section 7.4.3 Cycle 1, Day 8 
 Biomarker blood sample collection (following SIR-Spheres treatment) 
 Section 7.5.3 Cycle 1, Day 15 
 CMP  
 PT/PTT/INR (for patients receiving Coumadin therapy) 
Section 7.5.4 Cycle 1, Day 22 (if LFT toxicity persists) 
 CMP 
Section 7.4.4 Cycle 2, Day 1 (±72 hours) 
Regorafenib may not start until the patient’s hematologic, liver and renal functions have been re-
confirmed as eligible according to Section 3.1 by the Investigator.  Therefore, the regorafenib 
cycle starts on the day that treatment begins.  If liver function toxicities are present, patient 
may be rechecked weekly for 2 additional weeks.   Those patients with persistent liver 
function toxicities after this time will come off study, but will be followed until resolution.   
 Section 8.1.3 Precautions and Risks Associated with SIR-Spheres® Microspheres 
There is some evidence that there is a decrease in leucocyte levels, with a nadir eight 8 weeks 
after implantation.  This has been evident in both first line and refractory studies. with studies 
reporting a The median number of leukocytes was of 3.55 x 109/L (3.55 x 103/µL) (NCIC CTC3 
gGrade 1).  Leukocyte levels recover from this point, with the median value rising to normal 
levels 4-8 weeks after the decline.   
Please refer to PMA P990065 SIR-Spheres® microspheres for a comprehensive review of prior 
clinical, laboratory and animal investigations concerning the device.   
Section 8.2 Regorafenib 
Regorafenib is to be administered in accordance with the terms of its marketing authorization 
recommendations in the approved labelling and in accordance with institutional standard of 
practice.  
Section 10.1 Statistical Design 
The safety of two treatment cohorts will be evaluated in the open-label study.  The 
administration sequence of radioembolization with SIR-Spheres to the patient with and 
regorafenib is different in the two treatment cohorts.  


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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SCRI Innovations GI 189 Clinical Study Summary of Changes 
AMENDMENT NUMBER: 
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AMENDMENT DATE:      15 April 2014 
Appendix E A: Schedule of Assessments – Cohort 1 – Regorafenib then SIR-Spheres then 
Regorafenib 
Cycle 1 Day 22 and Cycle 2 Day 1 
Following assessments added to C1D22 and removed from C2D1: physical exam, ECOG 
performance status, adverse event evaluation, concomitant medication review, CBC, CMP, 
PT/PTT/INR, biomarker blood sample collection, tumor marker, hepatic angiogram, and 99mTc 
MAA lung shunt scan. 
Appendix A E: Schedule of Assessments tables  
Footnotes: 
h Biomarker samples (see Section 5.4) will be collected prior to SIR-Spheres administration on 
Day 1, Day 8, and Day 30 (pre-dose) following SIR-Spheres treatment. from all patients prior to 
the hepatic angiogram and 99mTc MAA lung shunt scan, which will be obtained 7-4 days prior to  
Appendix A E: Schedule of Assessments tables  
SIR-Spheres treatment [see Section 7.2]), on Day 8 after SIR-Spheres radiation, and Day 30 
(pre-dose) after SIR-Spheres radiation.  
f If LFTs liver function toxicities are present after a 2 week rest, then patients may must be 
rechecked weekly for 2 additional weeks.   
o Cohort 1 pPatients will be assessed 7-4 days prior to SIR-Spheres treatment to determine the 
suitability for SIR-Spheres (see Section 7.2).  
q The Cycle 1 Day 22 physical examination, ECOG performance status, CBC, CMP, and 
PT/PTT/INR, tumor marker (CEA), adverse event evaluation, and concomitant medication 
review to be completed ≤7 days prior to SIR-Spheres radiation treatment.   
Appendix F B: Schedule of Assessments – Cohort 2-SIR-Spheres then Regorafenib  
Baseline assessment of biomarker blood sample collection added. 
Cycle 1 Day 1 assessments removed.  
Footnotes 
b The Screening physical examination, update of medical history, ECOG performance status, CBC, CMP, 
and PT/PTT/INR, serum or urine pregnancy test and concomitant medication review and tumor marker 
(CEA) should be done ≤21 days prior to initiation of treatment.  However, if These initial examinations 
are obtained within 72 hours of Cycle Day 1 they do not have to be repeated on Cycle 1 Day 1.  These 
initial examinations must be repeated or performed ≤7 days of Cycle 1 Day 1 to document Cycle 1 
Day 1 assessments prior to SIR-Spheres treatment.  CT scans to document measurable or evaluable 
disease (i.e. tumor measurement) and tumor marker (CEA) should be performed ≤28 days prior to 
initiation of treatment.  Cohort 2


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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AMENDMENT NUMBER: 
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AMENDMENT DATE:      15 April 2014 
Appendix F B: Schedule of Assessments – Cohort 2-SIR-Spheres then Regorafenib 
(continued) 
 pPatients will be assessed at Screening (4-7 days prior to SIR-Spheres treatment) to 
determine the suitability for SIR-Spheres (see Section 7.2).   
f If LFTs liver function toxicities are present after a 2 week rest, then patients may must be 
rechecked weekly for 2 additional weeks prior to Regorafenib treatment on C2D1.   
h Biomarker samples (see Section 5.4) will be collected prior to SIR-Spheres administration on 
Day 1, Day 8, and Day 30 (pre-dose) following SIR-Spheres treatment. from all patients prior to 
the hepatic angiogram and 99mTc MAA lung shunt scan, which will be obtained 7-4 days prior to 
SIR-Spheres treatment [see Section 7.2]), on Day 8 after SIR-Spheres radiation, and Day 30 
(pre-dose) after SIR-Spheres radiation.  
p Blood pressure is required Cycle 3 Day 8.  Cycle 4 and beyond, blood pressure will be 
required Day 1 only.


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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GI 189 PROTOCOL SYNOPSIS 
Title of Study: 
A Two Arm Safety Study of Regorafenib before or after SIR-Spheres® Microspheres (90Y) 
for the Treatment of Patients with Refractory Metastatic Colorectal Cancer and Liver 
Metastases 
SCRI Innovations 
Study Number: 
GI 189 
Sponsor: 
SCRI Development Innovations, LLC 
Study Duration: 
The total duration of the study is planned to be 16 months. 
Phase of Study:  II 
Study Centers: 
This study will be conducted at approximately 5 sites in the United States in the SCRI 
network.   
Number of 
Patients: 
Up to 50 patients are planned to be enrolled in this study. 
Objectives: 
Primary Objective 
The primary objective of this study is: 
 
To evaluate the safety of two treatment cohorts combining regorafenib and SIR-
Spheres microspheres (SIR-Spheres) radioemoblization in patients with refractory 
metastatic colorectal cancer (mCRC) with liver metastasis. 
Secondary Objectives 
The secondary objective of this study is: 
 
To evaluate the overall response rate (ORR), progression-free survival (PFS), and 
overall survival (OS) of patients with refractory mCRC when treated with 
combination SIR-Spheres and regorafenib in the two sequencing cohorts 
Exploratory Objectives 
The exploratory objective of this study is: 
 
To evaluate the status of exploratory biomarkers and correlate with clinical 
outcomes of patients treated in one of two SIR-Spheres and regorafenib cohorts. 
 
Study Design: 
This is an open-label study comparing the safety of two treatment cohorts in which 
radioembolization will be administered using the device SIR-Spheres microspheres (90Y 
resin microspheres) in combination with regorafenib to patients with mCRC with liver 
metastases.  The two treatment cohorts will be evaluated for safety, ORR, PFS, and OS.  
Twenty-five patients will be treated in each cohort.  The first cohort will complete 
enrollment before the second cohort opens.  There will be no randomization or blinding.  
Blood samples will be collected from all patients prior to the hepatic angiogram and 99mTc 
MAA lung shunt scan, on Day 8 after SIR-Spheres treatment, and Day 30 (pre-dose) after 
SIR-Spheres treatment (see Section 5.1).  Expressions of cytokines and proteins will be 
measured to explore potential biomarkers that may correlate with clinical outcome. 
Study Drugs, 
Doses, and Modes 
of Administration: 
Two treatment cohorts will be evaluated sequentially as follows:     
Cohort 1 
Regorafenib (one cycle) followed by SIR-Spheres followed by re-initiation 
of regorafenib 2-4 weeks after SIR-Spheres 
Cohort 2 
SIR-Spheres followed by regorafenib to start 2-4 weeks after SIR-Spheres 
All patients will take regorafenib, orally once-a-day, on Days 1-21 of a 28-
day treatment cycle.  Twenty-five patients will be treated in each cohort.   


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Page 15 of 98 
GI 189 PROTOCOL SYNOPSIS 
Inclusion Criteria: 
1. Histologically confirmed metastatic adenocarcinoma of the colon or rectum. 
2. Patients who have been previously treated with or are not candidates for fluorouracil, 
oxaliplatin, irinotecan, and if Kras wild-type, anti EGFR therapy 
3. Considered an appropriate candidate for regorafenib therapy. 
4. Measurable disease or evaluable disease as measured by Response Evaluation 
Criteria in Solid Tumors (RECIST) version 1.1 (Appendix C). 
5. Measurable computed tomography (CT) scan evidence of liver metastases which are 
not treatable by surgical resection or local ablation with curative intent at the time of 
study entry. 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0-1 
(Appendix D). 
7. Adequate hematologic function defined as: 
- 
Absolute neutrophil count (ANC) ≥1500/μL 
- 
Hemoglobin (Hgb) ≥9 g/dL (pre-enrollment transfusion allowed)  
- 
Platelets  ≥75,000/µL 
8. Adequate liver function defined as: 
- 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 x the upper limit of normal (ULN) or  <5 x ULN if due to hepatic 
metastases 
- 
Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin 
elevation due to Gilbert’s disease or a similar syndrome involving slow 
conjugation of bilirubin) 
9. Adequate renal function defined as serum creatinine ≤1.5 mg/dL (133 μmol/L) OR 
calculated creatinine clearance ≥50 mL/min. 
10. Male patients with female partners of childbearing potential and female patients of 
childbearing potential are required to use two forms of acceptable contraception, 
including one barrier method, during their participation in the study and for 30 days 
following last dose.  Male patients must also refrain from donating sperm during 
their participation in the study (Appendix E). 
11. Life expectancy ≥ 3 months. 
12. Age ≥18 years. 
 
13. Ability to understand the nature of this study and give written informed consent. 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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GI 189 PROTOCOL SYNOPSIS 
Exclusion 
Criteria: 
1. Most recent chemotherapy ≤14 days and ≥Grade 1 chemotherapy-related side 
effects, with the exception of alopecia.  
2. Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to 
initiation of study treatment.  For study drugs for which 5 half-lives is ≤21 days, a 
minimum of 10 days between termination of the study drug and administration of 
study treatment is required. 
3. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to 
starting study drug or has not recovered from side effects of such therapy.   
4. Previous radiation delivered to the upper abdomen. 
5. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
6. Previously untreated brain metastases.  Patients who have received radiation or 
surgery for brain metastases are eligible if therapy was completed at least 2 weeks 
previously and there is no evidence of central nervous system disease progression, 
mild neurologic symptoms, and no requirement for chronic corticosteroid therapy.  
7. Leptomeningeal metastases or spinal cord compression due to disease. 
8.  Pregnant or lactating.  
9. Evidence of ascites, cirrhosis, portal hypertension, or thrombosis as determined by 
clinical or radiologic assessment. 
10. History of abdominal fistula or gastrointestinal perforation ≤6 months prior to 
beginning study treatment. 
11. Serious non-healing wound, active ulcer, or untreated bone fracture. 
12. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of oral 
therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, 
and malabsorption syndrome). 
13. Any of the following cardiac diseases currently or within the last 6 months: 
- 
 Unstable angina pectoris 
- 
Congestive heart failure (NYHA ≥ Grade 2 [Appendix F]) 
- 
Conduction abnormality not controlled with pacemaker or medication 
- 
Significant ventricular or supraventricular arrhythmias (patients with 
chronic rate-controlled atrial fibrillation in the absence of other cardiac 
abnormalities are eligible) 
- 
Valvular disease with significant compromise in cardiac function 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Page 17 of 98 
GI 189 PROTOCOL SYNOPSIS 
Exclusion 
Criteria: 
(continued) 
14. Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] >180 
mmHg or diastolic blood pressure (DBP) >100 mmHg) (patients with values 
above these levels must have their blood pressure (BP) controlled with medication 
prior to starting treatment). 
15. Serious active infection at the time of treatment, or another serious underlying 
medical condition that would impair the ability of the patient to receive protocol 
treatment. 
16. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C. 
17. Presence of other active cancers, or history of treatment for invasive cancer ≤5 
years.  Patients with Stage I cancer who have received definitive local treatment 
and are considered unlikely to recur are eligible.  All patients with previously 
treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with 
history of non-melanoma skin cancer. 
18. Use of strong CYP34A inducers or inhibitors (see Appendix G). 
19. The herbal medications St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng will not be 
allowed during study treatment.  Patients should stop using these herbal 
medications 7 days prior to first dose of study drug. 
20. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
21. Inability or unwillingness to comply with study and/or follow-up procedures 
outlined in the protocol. 
Correlative 
Testing: 
 
 
Blood samples will be collected from all patients prior to the hepatic angiogram and 99mTc 
MAA lung shunt scan, on Day 8 after SIR-Spheres treatment, and Day 30 (pre-dose) after 
SIR-Spheres treatment (see Section 7.2).  Expressions of cytokines and proteins will be 
measured to explore potential biomarkers that may correlate with clinical outcome. 
Cytokine analyses will include, but not be limited to, the following:  VEGFA, VEGFC, 
VEGFD, FGF2, HGF, EGF, PDGF-AA, PDGF-AB/BB, MMP-9, sVEGFR-2, E-selectin, 
VCAM-1, ICAM-1, MIF, TNFα, IFN-α and -γ, LIF, TGF-α, TGF-β1, Angiopoietin-2, 
Endoglin, IGF, Osteopontin, GM-CSF, G-CSF, M-CSF, SCGF-β, SCF, Beta-NGF, PlGF, 
MCP-1, MCP-3, RANTES, MIP-1α, MIP-1β, MIG, Eotaxin, IP-10, SDF-1α, GRO-α, 
CTACK, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 p40, IL-12 p70, 
IL-16, CA9 and HIF-1 alpha.  
 
Protein expression in blood samples will be measured by proteomics platform. 
Statistical 
Methodology: 
There is no formal hypothesis testing in this study. The sample size of 50 patients (25 in 
each cohort) is based on clinical practicalities rather than statistical reasoning, in order to 
evaluate the safety of the 2 different sequences in treatment administration of SIR-Spheres 
microspheres and regorafenib. With 25 patients per cohort, the 95% confidence interval for 
the response rate estimate would be no more than 21%. 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
Page 18 of 98 
GI 189 CONTACT INFORMATION 
SCRI Innovations  
Contact Information: 
SCRI Development Innovations;, LLC 
(SCRI Innovations) 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
Study Chair: 
Andrew Kennedy, MD 
Sarah Cannon Research Institute (SCRI) 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
Study Co-Chair: 
Johanna Bendell, MD 
Sarah Cannon Research Institute (SCRI) 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-877-MY-1-SCRI 
asksarah@scresearch.net 
 
Medical Monitor 
D.K. Strickland, MD 
SCRI Innovations 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
1-901-309-2572 
asksarah@scresearch.net 
Safety Dept. Phone # / Fax #: 
Safety Dept. Email: 
1-615-329-7358/1-866-807-4325 
CANN.SAE@scri-innovations.com 
Regulatory Phone #:  
Regulatory Email: 
1-877-MY-1-SCRI  
SCRIRegulatory@scresearch.net 
SCRI Innovations Enrollment  Phone #: 
SCRI Innovations Enrollment Fax #: 
1-877-MY-1-SCRI 
1-866-699-0258 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Page 19 of 98 
LIST OF ABBREVIATIONS 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT   
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR  
Adverse reaction 
AST   
Aspartate aminotransferase 
CBC 
Complete blood count 
CEA 
Carcinoembryonic antigen 
CFR 
Code of Federal Regulations 
CMP 
Comprehensive metabolic profile 
CRC 
Colorectal cancer 
CRC 
Complete remission 
CT 
Computerized tomography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LFT 
Liver Function Test 
mCRC 
metastatic Colorectal Cancer 
MRI 
Magnetic resonance imaging 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
Overall Response rate 
OS 
Overall Survival 
PD 
Progressive disease 
PHI 
Protected health information 
PFS 
Progression-free survival 
PMA 
Premarket approval 
PR 
Partial response 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SCRI 
Sarah Cannon Research Institute 
SD 
Stable disease 
SIRT 
Selective internal radiation therapy 
ULN 
Upper limit of normal 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................. 24 
1.1 
Background ........................................................................................................... 24 
1.2 
Rationale for the Study .......................................................................................... 25 
2. 
STUDY OBJECTIVES ......................................................................................... 25 
2.1 
Primary Objectives ................................................................................................ 25 
2.2 
Secondary Objective.............................................................................................. 25 
2.3 
Exploratory Objectives .......................................................................................... 25 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION ...................... 26 
3.1 
Inclusion Criteria ................................................................................................... 26 
3.2 
Exclusion Criteria .................................................................................................. 27 
3.3 
Discontinuation from Study Treatment ................................................................. 28 
4. 
STUDY REGISTRATION.................................................................................... 29 
5. 
STUDY DESIGN .................................................................................................. 29 
5.1 
Treatment Plan ...................................................................................................... 32 
5.2 
Treatment Duration ............................................................................................... 33 
5.3 
Concomitant Medications...................................................................................... 33 
5.3.1 
Permitted Concomitant Medications ..................................................................... 33 
5.3.2 
Prohibited Concomitant Medications .................................................................... 34 
5.4 
Correlative Studies ................................................................................................ 34 
6. 
DOSE MODIFICATIONS .................................................................................... 35 
6.1 
Dose Modifications Due to Hematologic Toxicity ............................................... 35 
6.2 
Regorafenib Dose Modifications for Non-Hematologic Toxicity ........................ 36 
6.2.1 
Regorafenib Dose Modifications for Abnormal Liver Function Tests ................. 36 
6.2.2 
Regorafenib Dose Modifications for Hand-Foot Skin Reaction ........................... 37 
6.2.3 
Regorafenib Dose Modifications for Hypertension .............................................. 39 
6.3 
Other Regorafenib-Related Grade 3 or 4 Non-Hematologic Toxicities ................ 41 
7. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 42 
7.1 
Overview ............................................................................................................... 42 
7.2 
Patient Assessment for SIR-Spheres ..................................................................... 42 
7.3 
Study Treatment Assessments - COHORT 1 ........................................................ 42 
7.3.1 
Baseline Study Assessments ................................................................................. 42 
7.3.2 
Cycle 1, Day 1 ....................................................................................................... 43 
7.3.3 
Cycle 1, Day 8 and 15 ........................................................................................... 44 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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7.3.4 
Cycle 1, Day 22 (assessments to be completed ≤7 days prior to SIR-Spheres 
treatment)............................................................................................................... 44 
7.3.5 
Cycle 2, Day 1   ..................................................................................................... 44 
7.3.6 
Cycle 2, Day 8 ....................................................................................................... 45 
7.3.7 
Cycle 3 and Beyond, Day 1 (±72 hours) ............................................................... 45 
7.3.8 
Cycle 3 and Beyond, Day 15 ................................................................................. 45 
7.4 
Study Treatment Assessments – COHORT 2 ....................................................... 45 
7.4.1 
Baseline Study Assessments ................................................................................. 45 
7.4.2 
Cycle 1, Day 1  ...................................................................................................... 46 
7.4.3 
Cycle 1, Day 8 ....................................................................................................... 46 
7.4.4 
Cycle 2, Day 1 (±72 hours) ................................................................................... 46 
7.4.5 
Cycle 2, Day 8 and 15 ........................................................................................... 47 
7.4.6 
Cycle 2, Day 22 ..................................................................................................... 47 
7.4.7 
Cycle 3 and Beyond, Day 1 (±72 hours) ............................................................... 47 
7.4.8 
Cycle 3, Day 8 ....................................................................................................... 48 
7.4.9 
Cycle 3 and Beyond, Day 15 ................................................................................. 48 
7.5 
Response Assessment Week 6 and Week 12 after SIR-Spheres, and then 
every 8 Weeks ....................................................................................................... 48 
7.6 
End-of-Treatment Visit ......................................................................................... 48 
7.7 
Follow-Up ............................................................................................................. 49 
7.7.1 
Follow-up for Patients Who Discontinue Prior to Disease Progression ............... 49 
7.7.2 
Survival Follow-Up ............................................................................................... 49 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................... 49 
8.1 
SIR-Spheres® Microspheres .................................................................................. 49 
8.1.1 
Labeling, Packaging, and Supply .......................................................................... 49 
8.1.2 
Preparation and Administration of SIR-Spheres® Microspheres .......................... 50 
8.1.3 
Precautions and Risks Associated with SIR-Spheres® Microspheres ................... 50 
8.2 
Regorafenib ........................................................................................................... 52 
8.2.1 
Labeling, Packaging, and Supply .......................................................................... 52 
8.2.2 
Preparation and Administration of Regorafenib ................................................... 52 
8.2.3 
Precautions and Risks Associated with Regorafenib ............................................ 52 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 52 
10. 
STATISTICAL CONSIDERATIONS .................................................................. 52 
10.1 
Statistical Design ................................................................................................... 52 
10.2 
Sample Size Considerations .................................................................................. 53 
10.3 
Analysis Population ............................................................................................... 53 
10.4 
Data Analysis ........................................................................................................ 53 
10.4.1 
Demographics and Baseline Characteristics ......................................................... 54 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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10.4.2 
Efficacy Analysis .................................................................................................. 54 
10.4.3 
Early Safety Monitoring and Stopping Rules........................................................ 54 
10.4.4 
Safety Analysis ...................................................................................................... 55 
10.5 
Analysis Time Points............................................................................................. 55 
10.5.1 
Final Analysis ........................................................................................................ 55 
11. 
SAFETY REPORTING AND ANALYSES ......................................................... 55 
11.1 
Definitions ............................................................................................................. 56 
11.1.1 
Adverse Events ...................................................................................................... 56 
11.1.2 
Serious Adverse Event .......................................................................................... 56 
11.1.3 
Adverse Reaction .................................................................................................. 57 
11.1.4 
Suspected Adverse Reaction ................................................................................. 57 
11.1.5 
Recording and Reporting of Adverse Events ........................................................ 57 
11.1.6 
Assessment of Adverse Events.............................................................................. 58 
11.2 
Serious Adverse Event Reporting by Investigators ............................................... 59 
11.3 
Recording of Adverse Events and Serious Adverse Events .................................. 59 
11.3.1 
Diagnosis versus Signs and Symptoms ................................................................. 59 
11.3.2 
Persistent or Recurrent Adverse Events ................................................................ 60 
11.3.3 
Abnormal Laboratory Values ................................................................................ 60 
11.3.4 
Deaths .................................................................................................................... 60 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 60 
11.3.6 
Pre-Existing Medical Conditions .......................................................................... 61 
11.3.7 
New Cancers.......................................................................................................... 61 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 61 
11.3.9 
Study Drug Overdose ............................................................................................ 62 
11.4 
Sponsor Serious Adverse Event Reporting Requirements .................................... 62 
11.4.1 
Sponsor Assessment of Unexpected Drug Events ................................................ 62 
11.4.2 
Sponsor Reporting for Clinical Studies Under an Investigational Device 
Exemption ............................................................................................................. 63 
11.4.3 
Sponsor Assessment of Unexpected Adverse Device Effects ............................... 63 
12. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ............ 63 
12.1 
Institutional Review Board Approval.................................................................... 64 
12.2 
Regulatory Approval ............................................................................................. 64 
12.3 
Informed Consent .................................................................................................. 64 
12.3.1 
Confidentiality ....................................................................................................... 65 
12.4 
Financial Information ............................................................................................ 66 
13. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 66 
13.1 
Amendments to the Protocol ................................................................................. 66 
13.2 
Documentation Required to Initiate the Study ...................................................... 66 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Page 23 of 98 
13.3 
Study Documentation and Storage ........................................................................ 67 
13.4 
Data Collection ...................................................................................................... 69 
13.5 
Study Monitoring, Auditing, and Inspecting ......................................................... 69 
13.6 
Quality Assurance and Quality Control ................................................................ 69 
13.7 
Disclosure and Publication Policy ......................................................................... 70 
14. 
REFERENCES ...................................................................................................... 71 
15. 
APPENDICES ....................................................................................................... 73 
LIST OF TABLES 
Table 1 
Regorafenib Dose Levels for Dose Modifications due to Toxicities ....... 35 
Table 2 
Regorafenib Dose Modifications for Hematologic Toxicities ................. 36 
Table 3 
Regorafenib Dose Modifications for Abnormal Liver Function Tests .... 36 
Table 4 
Regorafenib Dose Modifications for Hand-Foot Skin Reaction.............. 37 
Table 5 
Regorafenib Dose Modifications for Hypertension ................................. 40 
Table 6 
Dose Modifications for Regorafenib Non-Hematologic Toxicities ......... 41 
LIST OF FIGURES 
Figure 1 
GI 189 Schema ......................................................................................... 31 
LIST OF APPENDICES 
Appendix A:  
Schedule of Assessments – Cohort 1- Regorafenib then SIR-Spheres 
then Regorafenib ...................................................................................... 73 
Appendix B:  
Schedule of Assessments - Cohort 2-SIR-Spheres then Regorafenib ..... 76 
Appendix C:  
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1... 79 
Appendix D:  
ECOG Performance Status Criteria ......................................................... 84 
Appendix E:  
Guidelines for Women of Childbearing Potential and Fertile Male 
Patients ..................................................................................................... 85 
Appendix F: 
New York Heart Association (NYHA) Classification of Cardiac 
Disease ..................................................................................................... 87 
Appendix G:  
Common CYP3A4 Inhibitors and Inducers ............................................. 88 
Appendix H:  
Radiosensitization Study of Regorafenib and SIR-Spheres 
Microspheres ............................................................................................ 89 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
Page 24 of 98 
 
1. 
INTRODUCTION 
The American Cancer Society estimates that 142,820 new cases of colorectal cancer (CRC) will 
be diagnosed in the United States in 2013.  Although new treatments and frequent screenings 
have decreased mortality rates over the past 30 years, it is estimated that 50,830 patients will 
succumb to the disease in 2013.  Colorectal cancer remains the third most frequently diagnosed 
cancer in the United States and is responsible for 9% of all cancer deaths (American Cancer 
Society 2013).  
The population of patients with refractory metastatic colorectal cancer (mCRC) in the U.S. is 
around 25,000 patients.  Once patients have exhausted available standard therapies, their average 
survival is 4-6 months, and many have a performance status of Eastern Cooperative Oncology 
Group (ECOG) 1.  Findings from previous Phase III trials of panitumumab versus best 
supportive care (BSC) and cetuximab versus BSC, in patients with refractory mCRC suggested a 
median progression-free survival (PFS) of two months and overall survival (OS) of 
approximately 5 months (Van Cutsem et al. 2007, Jonker et al. 2007).  Recently, regorafenib 
([Stivarga] Bayer HealthCare Pharmaceuticals, Inc.) was approved for the treatment of patients 
with mCRC.  This was based on an improvement in OS of 6.4 versus 5.0 months (HR 0.77).  The 
PFS of patients on regorafenib was 1.9 months versus 1.7 months for placebo (Grothey et al. 
2012).  Antiangiogenic drugs like regorafenib have been thought to act primarily as tumor-static 
agents by preventing the growth of new tumor blood vessels.  Other antiangiogenic agents such 
as bevacizumab have been and are being evaluated in the maintenance setting during first line 
therapy for mCRC.   
1.1 
Background 
Recent targeted therapies and treatment strategies have shown promise in CRC but elimination 
of disease once spread to the liver remains a challenge.  The main cause of death in over 50% of 
CRC patients is liver metastases (Silverberg 1977).  Preoperative chemotherapy may improve 
resectability but may also impact overall survival.  Postoperative complications have been 
associated with decreased long-term survival after surgery for CRC with liver metastases with 
curative intent (Mavros et al. 2013).  
Radioembolization also referred to as selective internal radiation therapy (SIRT) enables 
multiple hepatic metastases to be targeted in a single procedure (Hendlisz et al. 2010).  Through 
fluoroscopic guidance, radioembolization can be achieved with the insertion of an intra-vascular 
catheter in the groin threaded through the arteries until it reaches the hepatic artery.  Yttrium- 90 
(90Y) microspheres are released through the catheter to lodge in the small vessels that feed the 
tumor, stopping blood flow and emitting radiation.  Radioembolization aims to deliver target 
radiation to all tumors in the liver while limiting the dose to the liver parenchyma (Kennedy et al. 
2012). 
SIR-Spheres® microspheres (90Y-resin microspheres) are approved by the Food and Drug 
Administration (FDA), and a number of safety and efficacy studies have been conducted in 
patients with mCRC with liver metastases.   


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Page 25 of 98 
A randomized study of 46 mCRC patients with liver metastases revealed that a single hepatic 
arterial injection of 90Y-resin microspheres combined with intravenous (IV) infusion 
5-fluorouracil (5-FU) improved time to overall disease progression.  Forty-four eligible patients 
were randomized to Arm A (n = 23) IV infusion 5-FU 300 mg/m2 on days 1-14 every 3 weeks; 
or Arm B (n = 21) radioembolization plus IV infusion 5-FU 225 mg/m2 on days 1 through 14 
then 300 mg/m2 days 1-14 every 3 weeks.  Treatment continued until hepatic progression and 
cross-over to radioembolization was permitted for patients in Arm A.  Ten patients in Arm A 
crossed-over at progression.  Median OS was 7.3 and 10.0 months in arms A and B, respectively 
(Hendlisz et al. 2010).  
1.2 
Rationale for the Study 
Radioembolization using SIR-Spheres microspheres (SIR-Spheres) to treat liver-only or liver-
dominant mCRC has been successful in this refractory setting.  The combination of regorafenib 
and SIR-Spheres is an attractive option as an anti-tumor and maintenance treatment for the 
refractory CRC population. 
The proper sequencing of this combination of regorafenib and SIR-Spheres is currently unclear.  
We propose this two arm study (25 patients in each arm) to evaluate the safety of the 
combination of regorafenib and SIR-Spheres, with one cohort of patients receiving regorafenib 
for three weeks followed by a one week hold of regorafenib (regorafenib half-life is 28 hours, 
one week to allow for washout), followed by SIR-Spheres treatment, followed by re-initiation of 
regorafenib two to four weeks later, and the other cohort of patients receiving SIR-Spheres 
followed by the initiation of regorafenib two to four weeks later. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objective of this study is: 
 To evaluate the safety of two treatment cohorts combining regorafenib and SIR-Spheres 
in patients with refractory mCRC with liver metastasis. 
2.2 
Secondary Objective  
The secondary objective of this study is: 
 To evaluate the overall response rate (ORR), progression-free survival (PFS), and OS of 
patients with refractory mCRC when treated with combination SIR-Spheres and 
regorafenib in the two sequencing cohorts. 
2.3 
Exploratory Objectives 
The exploratory objective of this study is: 
 To evaluate the status of exploratory biomarkers and correlate with clinical outcomes of 
patients treated in the two SIR-Spheres and regorafenib cohorts. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Page 26 of 98 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION 
3.1 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in the research study: 
1. Histologically confirmed metastatic adenocarcinoma of the colon or rectum. 
2. Patients who have been previously treated with or are not candidates for fluorouracil, 
oxaliplatin, irinotecan, and if Kras wild-type, anti EGFR therapy 
3. Considered an appropriate candidate for regorafenib therapy. 
4. Measurable disease as measured by Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 (Appendix C). 
5. Measurable computed tomography (CT) scan evidence of liver metastases which are not 
treatable by surgical resection or local ablation with curative intent at the time of study 
entry. 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1 
(Appendix D). 
7. Adequate hematologic function defined as: 
- Absolute neutrophil count (ANC) ≥1500/μL 
- Hemoglobin (Hgb) ≥9 g/dL (pre-enrollment transfusion allowed) 
- Platelets  ≥75,000/µL 
8. Adequate liver function defined as: 
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x the 
upper limit of normal (ULN) or  <5 x ULN if due to hepatic metastases 
- Total bilirubin ≤1.5 x ULN (unless the patient has Grade 1 bilirubin elevation due 
to Gilbert’s disease or a similar syndrome involving slow conjugation of 
bilirubin) 
9. Adequate renal function defined as serum creatinine ≤1.5 mg/dL (133 μmol/L) OR 
calculated creatinine clearance ≥50 mL/min. 
10.  Male patients with female partners of childbearing potential and female patients of 
childbearing potential are required to use two forms of acceptable contraception, 
including one barrier method, during their participation in the study and for 30 days 
following last dose.  Male patients must also refrain from donating sperm during their 
participation in the study (Appendix E). 
11. Life expectancy ≥ 3 months. 
12. Age ≥18 years. 
13. Ability to understand the nature of this study and give written informed consent. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Most recent chemotherapy ≤14 days and ≥Grade 1 chemotherapy-related side effects, 
with the exception of alopecia.  
2. Use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to initiation of 
study treatment.  For study drugs for which 5 half-lives is ≤21 days, a minimum of 
10 days between termination of the study drug and administration of study treatment is 
required. 
3. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) 
administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting 
study drug or has not recovered from side effects of such therapy.   
4. Previous radiation delivered to the upper abdomen. 
5. Major surgical procedures ≤28 days of beginning study drug, or minor surgical 
procedures ≤7 days.  No waiting required following port-a-cath placement. 
6. Previously untreated brain metastases.  Patients who have received radiation or surgery 
for brain metastases are eligible if therapy was completed at least 2 weeks previously and 
there is no evidence of central nervous system disease progression, mild neurologic 
symptoms, and no requirement for chronic corticosteroid therapy.  
7. Leptomeningeal metastases or spinal cord compression due to disease. 
8.  Pregnant or lactating.  
9. Evidence of ascites, cirrhosis, portal hypertension, or thrombosis as determined by 
clinical or radiologic assessment. 
10. History of abdominal fistula or gastrointestinal perforation ≤6 months prior to beginning 
study treatment. 
11. Serious non-healing wound, active ulcer, or untreated bone fracture. 
12. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption, distribution, metabolism, or excretion of oral therapy 
(e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, and 
malabsorption syndrome). 
13. Any of the following cardiac diseases currently or within the last 6 months: 
- Unstable angina pectoris 
- Congestive heart failure (NYHA ≥ Grade 2 [Appendix F]) 
- Conduction abnormality not controlled with pacemaker or medication 
- Significant ventricular or supraventricular arrhythmias (patients with chronic rate-
controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible) 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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- Valvular disease with significant compromise in cardiac function 
14. Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] >180 mmHg or 
diastolic blood pressure (DBP) >100 mmHg) (patients with values above these levels 
must have their blood pressure (BP) controlled with medication prior to starting 
treatment). 
15. Serious active infection at the time of treatment, or another serious underlying medical 
condition that would impair the ability of the patient to receive protocol treatment. 
16. Known diagnosis of human immunodeficiency virus, hepatitis B, or hepatitis C. 
17. Presence of other active cancers, or history of treatment for invasive cancer ≤5 years.  
Patients with Stage I cancer who have received definitive local treatment and are 
considered unlikely to recur are eligible.  All patients with previously treated in situ 
carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma 
skin cancer. 
18. Use of strong inducers or inhibitors of CYP34A (see Appendix G). 
19. The herbal medications St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng will not be 
allowed during study treatment.  Patients should stop using these herbal medications 
7 days prior to first dose of study drug. 
20. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 
21. Inability or unwillingness to comply with study and/or follow-up procedures outlined in 
the protocol. 
3.3 
Discontinuation from Study Treatment 
Patients will be discontinued from study treatment for any of the following reasons: 
 
Disease progression 
 
Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
 
Conditions requiring therapeutic intervention not permitted by the protocol 
 
Intercurrent illness (this will be at the investigator’s discretion) 
 
Inability of the patient to comply with study requirements or lost-to-follow-up 
 
Patient requests to discontinue treatment 
 
Patient withdraws consent from the study   
 
Pregnancy 
After discontinuation from protocol treatment, patients must be followed for adverse events 
(AEs) for 30 days after their last dose of study drug.  All new AEs occurring during this period 
must be reported and followed until resolution, unless, in the opinion of the investigator, these 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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values are not likely to improve, because of the underlying disease.  In this case, the investigators 
must record his or her reasoning for this decision in the patients’ medical records and as a 
comment in the electronic Case Report Form (eCRF). 
All patients who have Grade 3 or 4 laboratory abnormalities (per National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.0 insert current version 
number) (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE), at the time of discontinuation must be 
followed until the laboratory values have returned to Grade 1 or 2, unless it is, in the opinion of 
the investigator, not likely that these values are to improve.  In this case, the investigator must 
record his or her reasoning for making this decision in the patients’ medical records and as a 
comment on the eCRF. 
4. 
STUDY REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks, and 
discomforts.  Human protection committee (Institutional Review Board/Ethics Committee) 
approval of this protocol and consent form is required.  Eligible patients who wish to participate 
in the study and sign consent will be enrolled into the study. 
Registration must occur prior to the initiation of protocol therapy.  Patients eligible to participate 
in the study may be enrolled through the SCRI Development Innovations (SCRI Innovations) 
Central Enrollment Desk.  The enrollment desk may be reached at the following: 
CANN.SCRIInnovationsEnr@scri-innovations.com OR FAX to: 1-866-346-1062 or 615-524-
4012.  Monday through Friday, 8:30 a.m. to 4:30 p.m., Central Standard Time.  Patient 
registration will be confirmed via email within 24 hours, or by the next business day. 
5. 
STUDY DESIGN 
This is an open-label study comparing the safety of two treatment cohorts in which 
radioembolization will be administered using the device SIR-Spheres in combination with 
regorafenib to patients with mCRC with liver metastases.  The two treatment cohorts will be 
evaluated for safety, ORR, PFS, and OS.  Twenty-five patients will be treated in each cohort.  
The first cohort will complete enrollment before the second cohort opens.  There will be no 
randomization or blinding.  
A safety review for toxicity by the Medical Monitor will occur after the first 10 patients have 
been enrolled in each cohort and treated with one cycle of regorafenib and SIR-spheres 
(combination therapy) to assess the frequency of ≥ Grade 3 adverse events and all SAEs.  
Accrual will not be halted while the analysis is being conducted.   
Stopping Rules Due to Toxicities of Combination Therapy 
Stopping rules due to toxicities assessed as related to combination therapy by the Medical 
Monitor will be defined as follows: 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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 
A patient death considered to be caused by AEs of combination therapy 
 
A patient with Grade 4 AST, ALT, or irreversible hepatic failure assessed as related to 
combination therapy; 
 
More than 2 patients that develop Grade 3 AST, ALT, or total bilirubin assessed as 
related to combination therapy; 
 
More than 2 patients develop Grade 3 bleeding in the lung, stomach, small intestine, or 
liver assessed as related to combination therapy. 
If the early stopping rules are met or safety signals emerge from the group of the first 10 patients 
treated with combination therapy in each cohort, patient recruitment will discontinue and the 
study will be reassessed.  Any outcome of these safety reviews will be communicated in a timely 
manner to the participating investigators so that they may notify their IRBs.   
Blood samples will be collected from all patients prior to the hepatic angiogram and 99mTc MAA 
lung shunt scan, on Day 8 after SIR-Spheres treatment, and Day 30 (pre-dose) after SIR-Spheres 
treatment (see Section 5.1).  Expressions of cytokines and proteins will be measured to explore 
potential biomarkers that may correlate with clinical outcome. The study schema is presented in 
Figure 1.


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Figure 1 
GI 189 Schema 
Cohort 1  Regorafenib then SIR-Spheres  (n=25) 
CYCLE 
1 
 
 
 
2 
 
3* 
 
 
 
4 
 
WEEK 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
Regorafenib 
160 mg PO daily 
X 
X 
X 
- 
- 
- 
X 
X 
X 
- 
X 
 
SIR-Spheres 
- 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
 
Regorafenib - 160 mg orally once daily for Days 1-21 of a 28-day cycle followed by a  
1 week washout, then treatment with SIR-Spheres microspheres followed  
by a 2 week rest*, followed by re-initiation of regorafenib. 
*If liver function toxicities are present, patient may be rechecked weekly for 2 additional weeks  
to allow for appropriate resolution of liver function toxicities prior to re-starting regorafenib. 
 
NOTE:  COHORT 1 ENROLLMENT WILL BE COMPLETED BEFORE COHORT 2 OPENS TO ENROLLMENT 
 
Cohort 2  SIR-Spheres then Regorafenib  (n=25) 
 
CYCLE 
1 
 
2* 
 
 
 
3 
 
 
 
4 
 
WEEK 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
SIR-Spheres 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
 
Regorafenib 
160 mg PO daily 
- 
- 
X 
X 
X 
- 
X 
X 
X 
- 
X 
 
Treatment with SIR-Spheres microspheres followed by a 2 week rest*  
then regorafenib initiated - 160 mg orally once daily for Days 1- 21 of each 28-day cycle.    
*If liver function toxicities are present, patient may be rechecked weekly for 2 additional weeks and initiation of regorafenib may be delayed until 
appropriate resolution of liver function toxicities. 
Continue 
treatment; 
re-evaluate 
every 8 
weeks until 
PD or 
intolerance 
due to side 
effects 
Stable 
Disease 
or Better 
Restage at 6 
and 12 
Weeks after 
SIR-
Spheres  
completion 
Restage at 
6 and 12 
Weeks 
after SIR-
Spheres  
Stable 
Disease 
or Better 
Continue 
treatment; 
re-evaluate 
every 8 
weeks until 
PD or 
intolerance 
due to side 
effects 
Progressive 
Disease – Off 
Study 
 
Progressive 
Disease – Off 
Study 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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5.1 
Treatment Plan 
 
Radioembolization using SIR-Spheres Microspheres 
Patients must be assessed with a hepatic angiogram and “break-through” scan to determine 
suitability for SIR-Spheres.   
Hepatic Angiogram 
The patient will undergo a preliminary angiogram of the liver to determine the vascular 
anatomy of the liver.  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.  The hepatic angiogram 
should be performed together with the ‘break-through’ scan and results must be available 
prior to radioembolization with SIR-Spheres (see Appendix Appendix A/Appendix B). 
Liver-Lung Break-Through Nuclear Scan 
In order to mitigate the possibility of including patients who exhibit excessive liver-to-lung 
shunting a nuclear medicine ‘break-through’ scan using 99mTechnetium (Tc) macroaggregated 
albumin will be performed in all patients prior to SIR-Spheres treatment.  Excessive liver-to-lung 
shunting resulting in radiation damage to the lungs has not been observed in any case of 
colorectal metastatic liver disease treated since the premarket approval (PMA) of SIR-Spheres 
microspheres for mCRC in 2003. 
If either the hepatic angiogram or the liver-lung break through nuclear scan shows that a patient 
is ineligible to receive SIR-Spheres, then the patient will be removed from study and replaced. 
SIR-Spheres Microspheres Administration 
SIR-Spheres microspheres will be administered by a certified radiation oncologist, interventional 
radiologist, or nuclear medicine physician to the patient by injection through a trans-femoral 
catheter into the hepatic artery.  All areas of tumor within the liver will be targeted with SIR-
Spheres microspheres which usually involves treating both lobes of the liver.  However, it is vital 
that the SIR-Spheres microspheres are not delivered to other organs such as the duodenum, 
stomach, pancreas etc. 
If the metastases are limited to only one lobe, the radiologist can insert the catheter selectively 
into the lobar artery supplying only that lobe that contains the metastases.  The SIR-Spheres 
microspheres will then be delivered only to the lobe containing the metastases with sparing of 
the other normal lobe. The SIR-Spheres microspheres are injected slowly into the hepatic artery 
to avoid reflux back down the hepatic artery and placement in the pancreas, stomach and other 
organs. 
After SIR-Spheres microspheres have been administered, the patient will be monitored closely 
during the following 2 week rest period prior to starting regorafenib (see Section 7).  If liver 
function toxicities are present, the patient may be rechecked weekly for 2 additional weeks. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Regorafenib Administration 
  
All patients entering this study will receive regorafenib at a dose of 160 mg orally once daily on 
Days 1-21 of each 28 day cycle.   
Patients will be instructed to take regorafenib with a low-fat breakfast that contains less than 
30% fat.  Examples of a low-fat breakfast include 2 slices of white toast with 1 tablespoon of 
low-fat margarine and 1 tablespoon of jelly, and 8 ounces of skin milk (319 calories and 8.2 
grams fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 
cup of coffee or tea (520 calories and 2 grams fat).  The time of day for administration of 
regorafenib should be consistent.    
If the patient misses a dose of study drug, the patient should take the dose as soon as possible, 
but not less than 12 hours before the next dose is due for once daily dosing.  If the next dose is 
due in less than 12 hours for once daily the patient should skip the missed dose and take the next 
dose as scheduled. 
If vomiting occurs after taking the study medication, the patient should be instructed not to 
retake the dose.  Patients should take the next scheduled dose of regorafenib.  If vomiting persists 
the patient should contact the investigator. 
No routine prophylactic anti-emetics will be given.  However, antiemetics may be administered 
with nausea and vomiting when they occur, and may be given prophylactically afterwards. 
5.2 
Treatment Duration 
Patients will be evaluated for toxicity at the start of each 28-day cycle of regorafenib.  Patients 
will be restaged at 6 weeks and 12 weeks after SIR-Spheres in both cohorts, and every 8 weeks 
thereafter, with imaging, laboratory chemistries, and tumor markers as defined in Appendix A 
and Appendix BError! Reference source not found..  Patients will continue on treatment until 
progression as defined in Appendix C or intolerance to side effects.  
5.3 
Concomitant Medications 
Patients will be instructed not to take any additional medications during the course of the study 
without prior consultation with the research team.  At each visit, the patient will be asked about 
any new medications he is taking or has taken after the start of the study drug. 
5.3.1 
Permitted Concomitant Medications 
Premedication with anti-emetics is allowed according to standard practice guidelines.  At each 
visit, the patient will be asked about any new medications he is taking or has taken after the start 
of the study drug. 
All concomitant medications and significant non-drug therapies taken ≤14 days prior to the start 
of study drug should be recorded. 
Medications may be administered for maintenance of existing conditions prior to study 
enrollment or for a new condition that develops while on study, including but not limited to the 
following: 
 Use of bisphosphonates and receptor activator of nuclear factor kappa-B ligand 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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(RANKL) inhibitors like denosumab.  Treatment with these agents must begin 1 day 
prior to study treatment or after treatment is initiated.  Treatment with these agents cannot 
be initiated on Cycle 1 Day 1.  
 Full dose Coumadin is allowed if required for the treatment of thromboembolic disease 
occurring after the patients have initiated study treatment.  INR must be followed and 
managed on Day 1 and 15 of each treatment cycle. 
 Low molecular weight heparin is allowed. 
 Erythropoietic and granulocyte colony-stimulating factor (G-CSF) agents according to 
standard guidelines.  Neutropenia/fever should be managed according to accepted 
guidelines. 
Other medications considered necessary for the patient’s safety and well-being may be given at 
the discretion of the investigator with the exception of those listed in Section 5.3.2. 
5.3.2 
Prohibited Concomitant Medications 
The following treatments are prohibited while in this study: 
 No other investigational therapy should be given to patients.  No anticancer agents other 
than the study medications should be given to patients.  If such agents are required for a 
patient, then the patient must first be withdrawn from the study. 
 Avoid concomitant use of strong CYP34A inducers (e.g., rifampin, phenytoin, 
carbamazepin, phenobarbital, and St John’s wort).  For the most updated information, visit 
the following website:  http://medicine.iupui.edu/clinpharm/ddis/.  (see Appendix G) 
 Avoid concomitant use of strong CYP34A inhibitors (e.g., clarithromycin, grapefruit juice, 
itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole). For the most 
updated information, visit the following website:  
http://medicine.iupui.edu/clinpharm/ddis/.  (see Appendix G) 
 Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.  
Patients should stop using these herbal medications 7 days prior to first dose of regorafenib. 
5.4 
Correlative Studies 
Blood samples for biomarker testing will be collected from all patients prior to the hepatic 
angiogram and 99mTc MAA lung shunt scan, which will be obtained 7-4 days prior to SIR-
Spheres treatment (see Section 7.2), on Day 8 after SIR-Spheres treatment, and Day 30 (pre-
dose) after SIR-Spheres treatment.  Expressions of cytokines and proteins will be measured to 
explore potential biomarkers that may correlate with clinical outcome.  
Cytokine analyses will include, but not be limited to, the following:  VEGFA, VEGFC, VEGFD, 
FGF2, HGF, EGF, PDGF-AA, PDGF-AB/BB, MMP-9, sVEGFR-2, E-selectin, VCAM-1, 
ICAM-1, MIF, TNFα, IFN-α and -γ, LIF, TGF-α, TGF-β1, Angiopoietin-2, Endoglin, IGF, 
Osteopontin, GM-CSF, G-CSF, M-CSF, SCGF-β, SCF, Beta-NGF, PlGF, MCP-1, MCP-3, 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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RANTES, MIP-1α, MIP-1β, MIG, Eotaxin, IP-10, SDF-1α, GRO-α, CTACK, IL-1β, IL-2, IL-3, 
IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 p40, IL-12 p70, IL-16, CA9 and HIF-1 alpha.  
Protein expression in blood samples will be measured by proteomics platform.  
6. 
DOSE MODIFICATIONS 
If toxicity occurs, the toxicity will be graded utilizing the NCI CTCAE v4.0, and appropriate 
supportive care treatment will be administered to decrease the signs and symptoms thereof.  
Dose adjustments will be based on the organ system exhibiting the greatest degree of toxicity. 
6.1 
Dose Modifications Due to Hematologic Toxicity 
Dose reductions or holds and initiation of supportive care are allowed as clinically indicated by 
the treating physician.  Patients whose treatment is delayed due to toxicity will discontinue study 
drug or will proceed with the next cycle of treatment when toxicity has improved (as long as the 
toxicity resolves within 3 weeks) according to the dose modifications below.  Two dose 
reductions for toxicity will be allowed.  In addition, dose reductions will also be allowed based 
on clinical judgment of the treatment physician.  If persistent toxicity occurs despite two dose 
reductions, the patient will be removed from the study.   
Patients who require a treatment delay of more than 3 weeks due to treatment-related toxicity 
will be discontinued from study treatment, unless the treating physician and the Medical Monitor 
agree that continued treatment at lower doses is in the best interest of the patient.   
 
Table 1 
Regorafenib Dose Levels for Dose Modifications due to Toxicities  
Dose Level 
Regorafeniba 
0 
160 mg orally once daily 
-1  
120 mg orally once daily  
-2 
80 mg orally once daily 
a 
Two dose reductions are allowed for regorafenib.  Patients who require more than two dose reductions due to toxicity will 
be discontinued from the study. 
 
The regorafenib dose modifications for hematologic toxicities are below in Table 2. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Table 2 
Regorafenib Dose Modifications for Hematologic Toxicities 
Toxicity 
Regorafenib Dosea 
Grade 3 
And  
Recurrence of Grade 3 
Hold dose until recovery to ≤ Grade 2, then resume 
regorafenib at one lower dose level.   
Grade 4 
Hold dose until recovery to ≤ Grade 2, then resume 
regorafenib at one lower dose level, or discontinue at 
the discretion of the investigator after discussion with 
the Medical Monitor.   
a Any patient who requires a treatment delay of more than 3 weeks due to treatment-related toxicity will be discontinued from 
study treatment, unless the treating physician and the Medical Monitor agree that continued treatment at lower doses is in the 
best interest of the patient. 
 
6.2 
Regorafenib Dose Modifications for Non-Hematologic Toxicity 
6.2.1 
Regorafenib Dose Modifications for Abnormal Liver Function Tests   
Regorafenib has been associated with severe drug-induced liver injury with fatal outcome in 
previous studies.  Liver function tests (LFTs) will be monitored during study treatment as 
described in Error! Reference source not found. Appendix A and Error! Reference source 
not found.Appendix B.  Dose modifications for regorafenib are recorded in Table 3 below. 
Table 3 
Regorafenib Dose Modifications for Abnormal Liver Function Tests 
Toxicity 
Regorafenib Dose 
Baseline - Grade 1 
And Recurrence 
OR 
Baseline Grade 1 – Grade 2 
And Recurrence 
Treat on time and check AST, ALT and bilirubin 
2x/week for 2 weeks followed by weekly assessments 
for at least 4 weeks. 
Baseline - Grade 2 
 
Hold dose until ≤ Grade 1 and check AST, ALT and 
bilirubin 2x/week. 
Resume regorafenib at 1 lower dose level and check 
AST, ALT, bilirubin 2x/week for 2 weeks followed by 
weekly assessments for at least 4 weeks.a 
Recurrence of 
Baseline - Grade 2 
Discontinue regorafenibb. 
Baseline Any Grade-Grade 3 
 
Hold dose until ≤ Grade 1 for baseline - Grade 1 OR 
until Grade 2 if baseline was Grade 2. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Check AST, ALT and bilirubin 2x/week. 
Resume regorafenib at 1 lower dose level and check 
AST, ALT, bilirubin 2x/week for 2 weeks followed by 
weekly assessments for at least 4 weeks.a 
Note:  If ALT or AST >8 x ULN with a concomitant 
rise in bilirubin (of any degree) compared to previous 
bilirubin values, consider permanent discontinuation at 
the first occurrenceb. 
Recurrence of 
Baseline Any Grade-Grade 3 
Discontinue regorafenibb. 
Baseline Any Grade-Grade 4 
Discontinue regorafenibb 
a If all values remain stable for 2 full cycles, dose re-escalation may be considered at the discretion of the investigator.  After re-
escalation AST, ALT, and bilirubin should be checked 2x/week for 2 weeks, followed by weekly assessments for at least 4 
weeks.  
b In case of discontinuation, AST, ALT, and bilirubin should be checked 2x/week for 2 weeks, followed by weekly assessments 
until recovery to baseline. 
6.2.2 
Regorafenib Dose Modifications for Hand-Foot Skin Reaction 
Hand-foot skin reaction is a known adverse event for regorafenib.  The dose modifications are 
provided in Table 4 below.   
Table 4 
Regorafenib Dose Modifications for Hand-Foot Skin Reaction 
Toxicity 
Regorafenib Dose 
Grade 1 
Numbness, dysesthesia, paraesthesia, 
tingling, painless swelling, erythema 
or discomfort of the hands or feet 
which does not disrupt the patient’s 
normal activities 
Institute supportive measures immediately for 
symptomatic relief and continue treatment with the 
same dose level. 
Grade 2 
Painful erythema and swelling of the 
hands or feet and/or discomfort 
affecting the patient’s normal 
activities 
 
First and Second Occurrence - 
Institute supportive measures immediately for 
symptomatic relief and decrease regorafenib one dose 
level (see Table 1) 
 If toxicity does not return to Grade 0-1 despite dose 
reduction, interrupt regorafenib for a minimum of 7 
days until toxicity has resolved to Grade 0-1a. 
 If no improvement after 7 days, continue to hold 
until toxicity has resolved to Grade 0-1a,b. 
 When resuming treatment after a dose interruption, 
reduce regorafenib an additional dose level a.   


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Patients requiring >2 dose reductions will discontinue 
Grade 3 
Moist desquamation, ulceration, 
blistering or severe pain of the hands 
or feet, or severe discomfort that 
causes the patient to be unable to 
work or perform activities of daily 
living 
 
First and Second Occurrence - 
Institute supportive measures immediately for 
symptomatic relief and interrupt regorafenib for a 
minimum of 7 days and until toxicity resolved to Grade 
0-1 (see Table 1). 
 When resuming treatment after dose interruption, 
decrease regorafenib by one dose level a. 
Patients requiring >2 dose reductions will discontinue 
protocol therapy.   
aIf toxicity returns to Grade 0-1 after dose level reduction, dose re-escalation is permitted at the discretion of the investigator 
bIf no recovery after 3 weeks of holding drug, patients should go off study unless in the opinion of the investigator & SCRI 
Innovations Medical Monitor, there is reason to believe that the patient is still experiencing clinical benefit. 
 
The following supportive measurements should be considered for prevention and treatment of 
hand-foot skin reaction: 
Control of callouses: 
Before initiating treatment with regorafenib - 
 Check condition of hands and feet 
 Suggest a manicure/pedicure, when indicated 
 Recommend pumice stone use for callous or rough spot removal 
During regorafenib treatment - 
 Avoid pressure points 
 Avoid items that rub, pinch or create friction 
Use of creams: 
The following non-urea based creams should be applied liberally - Cetaphil, Aveeno, Udderly 
Smooth, Gold Bond, Norwegian Formula, and Eucerin. 
The following keratolytic creams should be used sparingly and only to affected (hyperkeratotic) 
areas - urea-based creams and salicylic acid 6%. 
Approximately 5-8% of Α-hydroxy acids-based creams provide gentle chemical exfoliation.  
These creams should be applied liberally two times each day. 
Topical analgesics like lidocaine 2% to be considered for pain control. 
Topical corticosteroids like clobetasol 0.05% should be considered for subjects with Grade 2 or 3 
hand-foot skin reaction.  Avoid systemic steroids. 
Cushions: 
Protect tender areas by doing the following -  
 Use socks/gloves to cover moisturizing creams 
 Wear well-padded footwear 
 Use insole cushions or inserts (e.g., silicon, gel) 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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 Foot soaks with tepid water and Epsom salts 
6.2.3 
Regorafenib Dose Modifications for Hypertension 
The dose modification table for treatment-emergent hypertension should be followed.  Blood 
pressure measurements will be followed closely and appropriate treatment to effectively control 
hypertension is highly recommended.


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Table 5 
Regorafenib Dose Modifications for Hypertension 
Toxicity 
Antihypertensive Therapy 
Regorafenib Dose 
Grade 1 
Prehypertension 
(systolic BP 120 – 139 
mm Hg or diastolic BP 
80 - 89 mm Hg) 
None 
No dose modification. 
Increase blood pressure monitoring. 
Grade 2 
Systolic BP 140 – 159 
mm Hg or diastolic 
BP 90 -99 mm Hg, 
 
OR 
 
Symptomatic increase 
by >20 mm Hg 
(diastolic) if 
previously within 
normal limits 
Treat with the aim to achieve 
diastolic BP ≤90 mm Hg: 
If BP previously within normal 
limits, start antihypertensive 
monotherapy. 
If patient already on anti-
hypertensive medication, 
titrate up the dose. 
No dose modification. 
If symptomatic, hold regorafenib until 
symptoms resolve AND diastolic BP ≤ 90 mm 
Hga. 
When regorafenib is restarted, continue at the 
same dose level. 
Grade 3 
Systolic BP ≥ 160 mm 
Hg or diastolic 
BP ≥100 mm Hg 
OR 
More than one drug or 
more intensive therapy 
than previously used 
indicated 
Treat with the aim to achieve 
diastolic BP ≤90 mm Hg: 
Start antihypertensive 
medication. 
AND/OR 
Increase current 
antihypertensive medication 
AND/OR 
Add additional 
antihypertensive medications. 
Hold regorafenib until diastolic BP ≤ 90 mm 
Hg, and if symptomatic, until symptoms 
resolvea. 
When regorafenib is restarted, continue at the 
same dose level. 
If BP is not controlled with the addition of 
new or more intensive therapy, reduce by 1 
dose levelb. 
If Grade 3 hypertension recurs despite dose 
reduction and antihypertensive therapy, 
reduce another dose levelc. 
Grade 4 
Life-threatening 
consequences (e.g. 
Malignant 
hypertension, transient 
or permanent 
neurologic deficit, 
hypertensive crisis) 
Discontinue treatment. 
a Subjects requiring a delay of > 4 weeks should go off protocol therapy 
b If blood pressure remains controlled for at least one full cycle, dose re-escalation is permitted at the investigator’s discretion. 
c Subjects requiring > 2 dose level reductions should go off protocol therapy 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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6.3 
Other Regorafenib-Related Grade 3 or 4 Non-Hematologic Toxicities 
The dose reduction guidelines for non-hematologic toxicities are shown in Table 6.  If a Grade 
3 non-hematologic toxicity that is expected to be manageable and reversible with dose reduction 
occurs, treatment with regorafenib should be held until the toxicity resolves to ≤ Grade 1.  If the 
Grade 3 non-hematologic toxicity lasts longer than 7 days, study drug will be discontinued.  
Patients with Grade 3 non-hematologic toxicity lasting ≥ 7 days that does not resolve to 
 Grade 1 within 3 weeks should also be removed from the study, unless the treating physician 
and the Medical Monitor agree that continued treatment at lower doses is in the best interest of 
the patient.  If a Grade 4 non-hematologic toxicity occurs, study drug will be discontinued. 
If Grade 3 or 4 non-hematologic toxicity other than nausea, vomiting, or alopecia occurs, 
treatment with regorafenib should be held, and should be resumed at 1-level dose reduction(s) 
(see Table 1) as soon as the toxicity resolves to ≤ Grade 1.  Dose reductions will also apply for 
nausea and vomiting if the toxicity is Grade 3 or 4 and persists for 7 days after maximal 
antiemetic prophylaxis. 
 
Table 6 
Dose Modifications for Regorafenib Non-Hematologic Toxicities 
Toxicity 
Regorafenib Dosea 
Grade 1 and Grade 2 
No dose modificationsa. 
Grade 3b 
 
Hold dose until recovery to ≤ Grade 2 (for AEs in 
Cycle 1: resolution to ≤ Grade 1), then resume 
regorafenib at one lower dose level.   
For AEs occurring in Cycle 2 or later the investigator 
may consider a retreatment at the dose Level 0. 
If subject experiences a second Grade 3 toxicity, 
withhold dose until toxicity is ≤ Grade 2, then reduce 
1 dose level and resume treatment. 
Grade 4b 
Discontinue treatment.  For certain toxicities such as 
laboratory assessments (e.g., lipase increase without 
signs of a clinical pancreatitis), a decision about the 
further continuation and dose of treatment has to be 
determined after discussion between investigator and 
the sponsor.   
aThe investigator may consider lowering the regorafenib dose level in the case of Grade 1-2 toxicities which interfere with the 
activities of daily life, such as long lasting fatigue, anorexia, etc.   
bSubjects who develop Grade 3 hyperlipasemia or hyperamylasemia without clinical or other evidence of pancreatitis, or Grade 
3/Grade 4 hypophosphatemia may continue study treatment without interruption if this is deemed medically acceptable by the 
investigator.  Relevant diagnostic measures to exclude other adverse events leading to hyperlipasemia, hyperamylasemia, or 
hypophosphatemia will be mandatory before dosing of regorafenib is continued. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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7. 
STUDY ASSESSMENTS AND EVALUATIONS 
7.1 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedules of Assessments for the two cohorts in this study are shown in Appendix A 
Error! Reference source not found. and Appendix BError! Reference source not found..   
Informed consent must be obtained ≤28 days prior to initiation of treatment and before any 
protocol-specific procedures are performed.  The Screening physical examination, medical 
history, ECOG PS, complete blood counts (CBC), differential and platelets, comprehensive 
metabolic profile (CMP), and prothrombin time/partial thromboplastin time/international 
normalized ratio (PT/PTT/INR) should be done ≤21 days prior to initiation of treatment.  A 
pregnancy test must be performed within 72 hours of Cycle 1 Day 1.  CT scan of the chest, 
abdomen, and pelvis should be performed ≤28 days prior to initiation of treatment, as should a 
carcinoembryonic antigen (CEA) tumor marker.  
Cohort 1 and Cohort 2 patients will be assessed to determine suitability for SIR-Spheres. These 
assessment tests will be obtained 7-4 days prior to SIR-Spheres treatment.  Cohort 1 patients will 
have these assessments performed during week 4 prior to SIR-spheres treatment.  Cohort 2 
patients will be  assessed at Screening.   
Patients need to fast for 6 hours before receiving SIR-Spheres treatment. 
Imaging studies to be submitted for central review are listed in Section 13.3. 
7.2 
Patient Assessment for SIR-Spheres 
Cohort 1 and Cohort 2 patients will be assessed to determine suitability for SIR-Spheres.  
The following tests will be obtained 7-4 days prior to SIR-Spheres treatment.   
 Hepatic angiogram 
 
99mTc MAA lung shunt scan 
Cohort 1 patients will have these assessments performed during week 4 prior to SIR-spheres 
treatment.   
Cohort 2 patients will be at assessed at Screening 7-4 days prior to SIR-Spheres treatment on 
CID1. 
7.3 
Study Treatment Assessments - COHORT 1 
7.3.1 
Baseline Study Assessments 
The following information will be collected and procedures will be performed for each patient at 
Screening ≤21 days prior to initiation of treatment unless otherwise noted: 
 Written informed consent prior to any other study-related procedures (≤28 days prior to 
initiation of treatment) 
 Medical history 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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 Physical examination, measurements of height (first visit), weight, and vital signs (resting 
heart rate, respiratory rate, and oral temperature) 
 Blood pressure (BP) 
 ECOG PS (Appendix D) 
 Concomitant medication review 
 CBC (complete blood count) including hemoglobin, hematocrit, white blood cell (WBC) 
with 3-part differential, and platelets  
 CMP to include: glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), alkaline phosphatase (ALP), AST, ALT, total 
bilirubin, total protein, and albumin plus lactate dehydrogenase (LDH), and phosphorus.  
 PT/PTT/INR 
  Serum or urine pregnancy test (must be performed within 72 hours prior to the initiation 
of treatment) 
 Disease assessments: 
 CT scan chest, abdomen, and pelvis (≤ 28 days prior to treatment)  
 CEA tumor marker    
 
7.3.2 
Cycle 1, Day 1  
If the following are performed within 72 hours of Cycle 1 Day 1 they do not have to be repeated: 
 Medical history   
 Physical examination, measurements of weight, and vital signs (resting heart rate, 
respiratory rate, and oral temperature) 
 BP 
 ECOG PS 
 Concomitant medication review 
 CBC  
 CMP  
 PT/PTT/INR 
 Serum or urine pregnancy test (must be performed within 72 hours prior to the initiation 
of treatment)  
 CEA tumor marker 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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7.3.3 
Cycle 1, Day 8 and 15 
 Physical examination, weight, and vital signs  
 BP 
 ECOG PS 
 AE assessment   
 Concomitant medication review 
 CBC    
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
7.3.4 
Cycle 1, Day 22 (assessments to be completed ≤7 days prior to SIR-Spheres 
treatment) 
 Physical examination, weight, and vital signs 
 BP 
 ECOG PS 
 AE assessment   
 Concomitant medication review 
 CBC    
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 Biomarker blood sample collection prior to the hepatic angiogram and 99mTc MAA lung 
shunt scan 
 CEA tumor marker 
The following tests will be obtained 7-4 days prior to SIR-Spheres treatment: 
 Hepatic angiogram 
 
99mTc MAA lung shunt scan 
7.3.5 
Cycle 2, Day 1   
SIR-Spheres may not be administered until the patient’s hematologic, liver and renal function 
assessments performed per Section 7.3.4 have been re-confirmed as eligible according to Section 
3.1 by the Investigator. 
 SIR-Spheres treatment 
 BP 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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7.3.6 
Cycle 2, Day 8  
 BP 
 AE assessment   
 CMP 
 Biomarker blood sample collection (following SIR-Spheres treatment) 
7.3.7 
Cycle 3 and Beyond, Day 1 (±72 hours) 
Regorafenib may not start until the patient’s hematologic, liver and renal functions have been re-
confirmed as eligible according to the Section 3.1 by the Investigator.  Therefore, the regorafenib 
cycle starts on the day that treatment begins.  If liver function toxicities are present, patient may 
be rechecked weekly for 2 additional weeks.  Those patients with persistent liver function 
toxicities after this time will come off study, but will be followed until resolution.   
 
 Physical examination, weight, and vital signs 
 BP  
 ECOG PS 
 AE assessment   
 Concomitant medication review 
 CBC  
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 Biomarker blood sample collection (Day 30 (pre-dose)  following SIR-Spheres treatment) 
 CEA tumor marker 
7.3.8 
Cycle 3 and Beyond, Day 15   
 PT/PTT/INR (for patients receiving Coumadin therapy) 
7.4 
Study Treatment Assessments – COHORT 2  
7.4.1 
Baseline Study Assessments 
The following information will be collected and procedures will be performed for each patient at 
Screening ≤21 days prior to initiation of treatment unless otherwise noted.  The following must 
be repeated or performed ≤7 days of Cycle 1 Day 1 to document Cycle 1 Day 1 assessments 
prior to SIR-Spheres treatment unless otherwise noted:  


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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 Written informed consent prior to any other study-related procedures (≤28 days prior to 
initiation of treatment) 
 Medical history 
 Physical examination, measurements of height (first visit), weight, and vital signs (resting 
heart rate, respiratory rate, and oral temperature) 
 Blood pressure (BP) 
 ECOG PS (Appendix D) 
 Concomitant medication review 
 CBC (complete blood count) including hemoglobin, hematocrit, white blood cell (WBC) 
with 3-part differential, and platelets  
 CMP to include: glucose, blood urea nitrogen (BUN), creatinine, sodium, potassium, 
chloride, calcium, carbon dioxide (CO2), alkaline phosphatase (ALP), AST, ALT, total 
bilirubin, total protein, and albumin plus lactate dehydrogenase (LDH), and phosphorus.  
 PT/PTT/INR 
  Serum or urine pregnancy test (must be performed within 72 hours prior to the initiation 
of treatment) 
 Biomarker blood sample collection prior to the hepatic angiogram and 99mTc MAA lung 
shunt scan, which will be obtained 7-4 days prior to SIR-Spheres treatment 
 Disease assessments: 
o CT scan chest, abdomen, and pelvis (≤ 28 days prior to treatment)  
o CEA tumor marker    
7.4.2 
Cycle 1, Day 1  
 SIR-Spheres treatment 
7.4.3 
Cycle 1, Day 8  
 AE assessment   
 CMP 
 Biomarker blood sample collection (following SIR-Spheres treatment) 
7.4.4 
Cycle 2, Day 1 (±72 hours)  
Regorafenib may not start until the patient’s hematologic, liver and renal functions have been re-
confirmed as eligible according to Section 3.1 by the Investigator.  Therefore, the regorafenib 
cycle starts on the day that treatment begins.  If liver function toxicities are present, patient may 
be rechecked weekly for 2 additional weeks.  Those patients with persistent liver function 
toxicities after this time will come off study, but will be followed until resolution.   


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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 Physical examination, weight, and vital signs  
 BP 
 ECOG PS 
 AE assessment   
 Concomitant medication review 
 CBC  
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 CEA tumor marker 
 Biomarker blood sample collection (Day 30 following SIR-Spheres treatment only) 
7.4.5 
Cycle 2, Day 8 and 15 
 Physical examination, weight, and vital signs 
 BP 
 ECOG PS 
 AE assessment   
 Concomitant medication review 
 CBC 
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 
7.4.6 
Cycle 2, Day 22  
 BP 
7.4.7 
Cycle 3 and Beyond, Day 1 (±72 hours)  
 Physical examination, weight, and vital signs  
 BP 
 ECOG PS 
 AE assessment   
 Concomitant medication review 
 CBC  


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 CEA tumor marker    
7.4.8 
Cycle 3, Day 8 
 BP 
7.4.9 
Cycle 3 and Beyond, Day 15 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 
7.5 
Response Assessment Week 6 and Week 12 after SIR-Spheres, and then every 8 
Weeks  
Patients will be reassessed for response according to RECIST v1.1 (Appendix C) at Weeks 6 and 
12 after SIR-Spheres with CT scans in both cohorts.  After completing SIR-Spheres and 2 cycles 
of regorafenib patients may continue regorafenib treatment alone, if tumor response is stable or 
better.  Patients continuing treatment after Week 12 will have response re-assessed at 8-week 
intervals (±1 week).  Patients with progressive disease (PD) or unacceptable toxicity will be 
discontinued from the study.     
The following assessment will be performed:   
o 
CT scan of chest, abdomen, and pelvis.  If CT chest is normal at baseline this does 
not have to be repeated with each restaging unless there is a clinical reason to do so.  
If a CT scan is not possible, then an MRI may be used. 
As noted above in the Day 1 assessments for all cycles, CEA tumor markers must be assessed on 
Day 1 of each cycle and at the End-of-Treatment visit.  
7.6 
End-of-Treatment Visit 
Patients are permitted to continue treatment with regorafenib until disease progression, or the 
patient is discontinued due to unacceptable toxicity or decision to discontinue treatment by the 
patient or the study physician.    
If treatment is discontinued because of toxicity or any other reason(s) at a treatment visit and no 
study treatment is administered, that visit may fulfill the End-of-Treatment visit. 
After withdrawal from or completion of protocol treatment, patients must be followed for any 
new AEs for 30 calendar days after the last dose of study drug. 
The following end-of-treatment visit procedures will be performed. 
 Physical examination, weight, and vital signs  
 BP 
 ECOG PS 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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 AE assessment   
 Concomitant medication review 
 CBC 
 CMP 
 PT/PTT/INR (for patients receiving Coumadin therapy) 
 Disease assessment 
 
CT scan of chest, abdomen and pelvis   
 
CEA tumor marker   
7.7 
Follow-Up 
7.7.1 
Follow-up for Patients Who Discontinue Prior to Disease Progression 
Patients discontinuing treatment for any reason other than PD will be monitored for evidence of 
disease progression.  Patients will be followed every 3 months (±1 month) for up to a maximum 
of 6 months after the last patient has been enrolled on study for disease progression.  
Assessments at these visits will be performed as described in Appendix A Error! Reference 
source not found. and Appendix BError! Reference source not found.. 
7.7.2 
Survival Follow-Up 
After disease progression is documented, patients will be followed every 3 months (±1 month) 
for survival (e.g., date and cause of death) for up to a maximum of 6 months after the last patient 
has enrolled on study or death whichever comes first.  Patients may be contacted during 
outpatient visits or by telephone. 
8. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
8.1 
SIR-Spheres® Microspheres 
SIR-Spheres microspheres are to be administered in accordance with the terms of its marketing 
authorization and in accordance with institutional standard of practice.  Please refer to the US 
Package Insert http://www.sirtex.com/us/clinicians/package-insert for detailed information on 
how to prepare and administer SIR-Spheres microspheres. 
8.1.1 
Labeling, Packaging, and Supply 
Each site will procure a supply of SIR-Spheres microspheres, which is commercially available. 
All study medications must be kept in a secure place under appropriate storage conditions.  
Storage conditions for SIR-Spheres microspheres can be found in the relevant US Package 
Insert.  The expiration date on the label must not be exceeded. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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The Sponsor or its representatives must be granted access on reasonable request to check drug 
storage, dispensing procedures, and accountability records. 
8.1.2 
Preparation and Administration of SIR-Spheres® Microspheres 
SIR-Spheres microspheres should be prepared and administered in accordance with the terms of 
its marketing authorization.  . 
8.1.3 
Precautions and Risks Associated with SIR-Spheres® Microspheres 
Overall, the incidence of complications after SIR-Spheres microspheres therapy, if patients are 
selected appropriately and target (i.e. liver) delivery is performed meticulously, is low. 
Gastroduodenal complications occur in less than 10% of those treated (Bester et al. 2011; 
Kennedy et al. 2006;Stubbs et al. 2004) and are largely preventable.  
A life-threatening complication, progressive pulmonary insufficiency secondary to radiation-
induced lung fibrosis can be avoided by excluding from treatment with SIR-Spheres 
microspheres any patient with marked hepato-pulmonary shunting (Leung et al. 1995). There 
have been rare reported occurrences of this complication since that time. 
The gallbladder also may receive SIR-Spheres microspheres through a patent cystic artery 
leading to radiation cholecystitis. In order to avoid this potential complication, infusion distal to 
the cystic artery is preferred, however the risk of radiation cholecystitis requiring 
cholecystectomy is low (Liu et al. 2005). 
Gastric and duodenal ulceration have been reported to occur after the use of SIR-Spheres 
microspheres and 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 with routine coil embolization 
of the extra-hepatic visceral arteries before infusion of SIR-Spheres microspheres (Liu et al. 
2005).  
Radioembolization induced liver disease (REILD) is a rare complication following selective 
internal radiation therapy (SIRT) with 90Y microspheres. REILD is characterised by a well-
defined constellation of temporal, clinical, biochemical and histopathologic findings. REILD 
typically manifests approximately 4-8 weeks post-SIRT and is characterised 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 
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 that may resemble veno-occlusive 
disease.  
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 (<1.5 L) and 
elevated bilirubin (1.2 mg/dL) at baseline. It is relevant to note that REILD is indeed very rare in 
the setting of an otherwise healthy liver and is largely confined to patients with a well-known 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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liver condition such as cirrhosis or who have been exposed to any form of potential liver insult, 
most usually prior chemotherapy. Patients presenting with small liver volumes (< 2.0 L) and low 
proportional tumour burden (< 0.20) may be at higher risk of developing REILD independent of 
other factors; appropriate dose recommendations per the study protocol should be strictly 
adhered to in these cases.  
The treatment of REILD may comprise tapering high dose corticosteroids and ursodeoxicolic 
acid. 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. 
Apart from the above listed major complications2 other side effects and complications include: 
In approximately one-third of patients, administration of SIRT causes immediate short term 
abdominal pain requiring narcotic analgesia. 
 
Post SIRT treatment lethargy and mild nausea are common symptoms and can last up to ten days 
and may require medication. 
 
Most patients develop a mild fever that may last for several days following SIRT administration. 
This fever does not require treatment. 
The most common potential serious complications result from either (1) inadvertent 
administration of SIR-Spheres microspheres into the gut resulting in gastritis/duodenitis or (2) 
radiation induced liver disease resulting from a radiation overdose to the normal liver 
parenchyma.  The incidence rate of gastritis/duodenitis can be reduced by experience and 
meticulous attention to the administration procedure so as to ensure that there is a minimal 
chance of SIR-Spheres microspheres entering small arteries supplying the gut. Radiation induced 
liver disease is largely, but not totally, preventable by using correct SIR-Spheres microspheres 
doses and making allowances for dose reduction when there is increased risk of causing radiation 
damage such as in pre-existing liver damage, poor liver reserve or small volume tumour mass in 
the liver. The reported incidence of gastritis/duodenitis is <10%, while the reported rate of 
radiation induced liver disease is < 1%. 
Rare complications that have been reported include acute pancreatitis resulting from SIR-
Spheres microspheres refluxing back down the hepatic artery and lodging in the pancreas and 
liver abscess from infection of necrotic tumour. Previously reported radiation pneumonitis has 
not been observed where appropriate treatment workup and dose reductions are followed. 
There is some evidence that there is a decrease in leucocyte levels, with a nadir eight weeks after 
implantation. This has been evident in both first line and refractory studies.The median number 
of leukocytes was 3.55 x 109/L  (NCIC CTC3 Grade 1). Leukocyte levels recover from this 
point, with the median value rising to normal levels 4-8 weeks after the decline.  
                                                 
 
2  Unpublished data, Sirtex Technology Pty Ltd 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Please refer to the US Package Insert for detailed information on the risks associated with the use 
of SIR-Spheres microspheres. 
8.2 
Regorafenib 
Regorafenib is to be administered in accordance with the recommendations in the approved 
labelling and in accordance with institutional standard of practice.  Please refer to the US 
Package Insert   http://labeling.bayerhealthcare.com/html/products/pi/Stivarga_PI.pdf for 
detailed information on how to prepare and administer Regorafenib. 
8.2.1 
Labeling, Packaging, and Supply 
Regorafenib is commercially available and will be purchased by the patient or a third party. 
8.2.2 
Preparation and Administration of Regorafenib 
A link to the full US Package Insert is provided in Section 8.2. 
8.2.3 
Precautions and Risks Associated with Regorafenib 
Please refer to the US Package Insert for detailed information on the risks associated with the use 
of Regorafenib. 
8.2.3.1 
In-Vitro Radiosensitization Study of Regorafenib and Radiation in 
Adenocarinoma Cell Lines 
The radiosensitization of the Regorafenib / radiotherapy combination was evaluated in 
adenocarcinoma cell lines. The purpose of the study was to determine the extent to which 
Regorafenib would potentiate the tumoricidal effect of radiation. Colorectal adenocarcinoma cell 
lines were subjected to selected combinations of regorafenib concentrations and exposure to 
radiation. The addition of regorafenib to radiation did not enhance radiosensitization irrespective 
of the timing or temporal sequencing of the two agents. Moreover, there was no dose-dependent 
relationship observed in the radiosensitization of cancer cell lines. Based on the results of this 
study, Regorafenib is not an intrinsic radiosensitizer in colorectal cancer cells.  A detailed report 
of study findings is included in Appendix H.   
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Response and progression will be evaluated in this study using the Response Evaluation Criteria 
in Solid Tumors (RECIST) Version 1.1 (see Appendix C).  Lesions are either measurable or non-
measurable according to the criteria.  The term “evaluable” in reference to measurability will not 
be used, as it does not provide additional meaning or accuracy. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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10. 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Design 
The safety of two treatment cohorts will be evaluated in this open-label study.  The 
administration sequence of radioembolization with SIR-Spheres and regorafenib is different in 
the two treatment cohorts.  The treatment cohorts are:  
Cohort 1 
Regorafenib (one cycle) followed by SIR-Spheres followed by re-initiation of 
regorafenib 2-4 weeks after SIR-Spheres 
Cohort 2 
SIR-Spheres followed by regorafenib to start 2-4 weeks after SIR-Spheres 
Enrollment to Cohort 1 will be completed before Cohort 2 begins enrolling patients.  All patients 
will take regorafenib, orally once-a-day, on Days 1-21 of a 28-day treatment cycle.  Twenty-five 
patients will be treated in each cohort.   
Primary Objective  
The primary objective of the study is to evaluate the safety of two treatment cohorts combining 
regorafenib and SIR-Spheres in patients with refractory mCRC with liver metastasis. 
Secondary Objectives 
The secondary objectives of the study are to evaluate the overall response rate (ORR), 
progression free survival (PFS), and OS of patients with refractory mCRC when treated with 
combination SIR-Spheres and regorafenib in the two sequencing cohorts. 
Exploratory Objectives 
The exploratory objectives will evaluate the status of biomarkers and correlate the clinical 
outcomes of patients treated in the two SIR-Spheres and regorafenib cohorts. 
10.2 
Sample Size Considerations 
There is no formal hypothesis testing in this study. The sample size of 50 patients (25 in each 
cohort) is based on clinical practicalities rather than statistical reasoning, in order to evaluate the 
safety of the 2 different sequences in treatment administration of SIR-Spheres microspheres and 
regorafenib.  
With 25 patients per cohort, the 95% confidence interval for the response rate estimate would be 
no more than 21%. 
10.3 
Analysis Population 
The following analysis populations will be used: 
 Intent-To-Treat Population (ITT) is defined as all patients who have started study 
treatment (Radioembolization with SIR-Spheres 90Y or regorafenib). 
 Safety Population is defined as all patients who have received at least one dose of study 
treatment.  In this instance, the ITT and safety populations would consist of the same 
patients. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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Date of Amendment #1:  15 April 2014  
 
 
 
 
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10.4 
Data Analysis 
Descriptive statistics, including mean, median, standard deviations and ranges for all continuous 
measures will be tabulated and reported.  Percentages and frequencies for all categorical 
measures will also be presented.  Time to events endpoints will be reported using Kaplan-Meier 
estimates, with 95% confidence intervals for median time to event.  
10.4.1 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized for each cohort.  Data to 
be tabulated will include demographic features such as age, sex and race, as well as disease-
specific characteristics. 
The number and percentages of patients screened, treated, completed the treatment/study and 
withdrawn from treatment/study for any reasons will be presented overall and also by cohort. 
10.4.2 
Efficacy Analysis 
All efficacy analyses will be performed using the Intent-To-Treat Population.  
 Overall Response Rate (ORR) is defined as the proportion of patients with observed CR 
or PR (i.e. 2 CRs or PRs at least 4 weeks apart) according to the RECIST 1.1 criteria.  
 
 Progression Free Survival (PFS), defined as the time from the first day of study drug 
administration (Day 1) to disease progression as defined by the RECIST v1.1 criteria, or 
death on study.  Patients who are alive and free from disease progression will be censored 
at the date of last adequate tumor assessment. 
 
 Overall Survival (OS), defined as the time from the first day of study drug administration 
(Day 1) to death.  Patients who are alive will be censored at the date of last known date 
alive. 
For ORR, the estimates and the associated 95% confidence interval (based on the Clopper-
Pearson method) in each treatment group will be calculated.   
For PFS and OS, Kaplan-Meier curves will be generated and the median time to event and the 
associated 95% confidence interval will be provided.   
10.4.3 
Early Safety Monitoring and Stopping Rules 
A safety review for toxicity by the Medical Monitor will occur after the first 10 patients have 
been enrolled in each cohort and treated with one cycle of regorafenib and SIR-spheres 
(combination therapy) to assess the frequency of ≥ Grade 3 adverse events and all SAEs.  
Accrual will not be halted while the analysis is being conducted.   
Stopping Rules Due to Toxicities of Combination Therapy 
Stopping rules due to toxicities assessed as related to combination therapy by the Medical 
Monitor will be defined as follows: 
 
A patient death considered to be caused by AEs of combination therapy 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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Date of Amendment #1:  15 April 2014  
 
 
 
 
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 
A patient with Grade 4 AST, ALT, or irreversible hepatic failure assessed as related to 
combination therapy; 
 
More than 2 patients that develop Grade 3 AST, ALT, or total bilirubin assessed as 
related to combination therapy; 
 
More than 2 patients develop Grade 3 bleeding in the lung, stomach, small intestine, or 
liver assessed as related to combination therapy. 
If the early stopping rules are met or safety signals emerge from the group of the first 10 patients 
treated with combination therapy in each cohort, patient recruitment will discontinue and the 
study will be reassessed.  Any outcome of these safety reviews will be communicated in a timely 
manner to the participating investigators so that they may notify their IRBs.   
10.4.4 
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of treatment-emergent 
AEs.  Treatment-emergent AEs are those with an onset on or after the initiation of therapy, and 
will be graded according to NCI CTCAE v 4.03  A copy of CTCAE scoring system may be 
downloaded from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf.  AEs that occur prior to initiation of therapy (after consent is 
signed, i.e. during mapping for SIR-Spheres treatment), will also be assessed. 
The AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA), and 
summarized using system organ class and preferred term by cohort for all patients in the Safety 
Population.  In addition, summaries of SAEs, AEs leading to treatment discontinuation, AEs by 
maximum NCI CTCAE grade, and AEs related to study treatment will also be presented by 
treatment cohort. 
Other safety endpoints including laboratory results will be summarized for all patients in the 
Safety Population.  
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
and they will be listed and summarized by treatment cohort. 
10.5 
Analysis Time Points 
10.5.1 
Final Analysis 
The final analysis of the study will occur 6 months after the last patient has been recruited into 
the study.   
11. 
SAFETY REPORTING AND ANALYSES 
Safety assessments will consist of monitoring and recording protocol-defined AEs and Serious 
AEs (SAEs), measurement of protocol-specified hematology, clinical chemistry, and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study drug. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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The Principal Investigator is responsible for recognizing and reporting AEs to the SCRI 
Innovations Safety Department (see Section 11.2).  It is the Sponsor’s responsibility to report 
relevant SAEs to the applicable local, national, or international regulatory bodies.  In addition, 
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) according to the policies of that IRB.  
 The Principal Investigator is also responsible for ensuring that every staff member involved in 
the study is familiar with the content of this section. 
11.1 
Definitions   
11.1.1 
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  An adverse event (also known as adverse 
experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporarily associated with the use of a drug, without any judgement about 
causality.  An adverse event can arise with any use of the drug (e.g., off-label use, use in 
combination with another drug) and with any route of administration, formulation, dose or 
including overdose. 
11.1.2 
Serious Adverse Event 
An AE or a suspected adverse reaction (SAR) is considered “serious” if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: 
 Death 
 A life-threatening AE (Note: the term “life-threatening” refers to an event/reaction 
in which the patient was at risk of death at the time of the event/reaction; it does not 
refer to an event/ reaction which hypothetically might have caused death if it were 
more severe) 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse.   
It is important to distinguish between “serious” and “severe” AE, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  Seriousness serves as the guide for defining regulatory 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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reporting obligations.  “Serious” is a regulatory definition and is based on patient/event outcome 
or action usually associated with events that pose a threat to a patient’s life or vital functions.  
For example, nausea which persists for several hours may be considered severe nausea, but may 
not be considered an SAE.  On the other hand, a stroke which results in only a limited degree of 
disability may be considered only a mild stroke, but would be considered an SAE.  Severity and 
seriousness should be independently assessed when recording AEs on the eCRF and SAEs on the 
SAE Report Form. 
11.1.3 
Adverse Reaction 
An adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset 
of all suspected adverse reactions where there is a reason to conclude that the drug caused the 
event. 
11.1.4 
Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event.  Reasonable possibility means that there is evidence to 
suggest a causal relationship between the drug and the adverse event.  A suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
11.1.5 
Recording and Reporting of Adverse Events 
Recording of Adverse Events 
All AEs of any patient during the course of the research study will be recorded in the eCRF, and 
the investigator will give his or her opinion as to the relationship of the AE to the study material 
or process (i.e., whether the event is related or unrelated to study drug administration, SIR-
Spheres microspheres or SIRT procedure). 
All AEs should be documented.  A description of the event, including its date of onset and 
resolution, whether it constitutes a serious adverse event (SAE) or not, any action taken (e.g., 
changes to study treatment), and outcome, should be provided, along with the investigator’s 
assessment of causality (i.e., the relationship to the study treatment[s]).  For an AE to be a 
suspected treatment-related event there should be at least a reasonable possibility of a causal 
relationship between the protocol treatment and the AE.  Adverse events will be graded 
according to the NCI CTCAE v4.0, and changes will be documented. 
If the AE is serious, it should be reported immediately to SCRI Innovations Safety Department.  
Other untoward events occurring in the framework of a clinical study are to be recorded as AEs 
(i.e., AEs that occur prior to assignment of study treatment that are related to a protocol-
mandated intervention, including invasive procedures such as biopsies, medication washout, or 
no treatment run-in). 
Any clinically significant signs and symptoms; abnormal test findings; changes in physical 
examination; hypersensitivity; and other measurements that occur will be reported as an AE, and 
collected on the relevant eCRF screen. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
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Test findings will be reported as an AE if: the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment, and/ or test findings require additional testing or surgical 
intervention, a test result or finding is associated with accompanying symptoms, or a test result is 
considered to be an AE by the investigator. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
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Date of Amendment #1:  15 April 2014  
 
 
 
 
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Reporting Period for Adverse Events 
All AEs regardless of seriousness or relationship to regorafenib and/or SIR-Spheres treatment 
(called study treatment), spanning from the start of study treatment, until 30 calendar days after 
discontinuation or completion of study treatment as defined by the clinical study for that patient, 
are to be recorded on the corresponding screen(s) included in the eCRF.   
All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization.  All new AEs occurring during this period must be reported and followed until 
resolution unless, in the opinion of the investigator, the AE or laboratory abnormality/ies are not 
likely to improve because of the underlying disease.  In this case, the investigators must record 
his or her reasoning for this decision in the patient’s medical record and as a comment on the 
eCRF screen.   
After 30 days of completion of protocol-specific treatment or discontinuation, only AEs, SAEs, 
or deaths assessed by the investigator as treatment related are to be reported. 
11.1.6 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug 
(see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Unrelated:  
No relationship between the experience and the administration of study 
device or drug; related to other etiologies such as concomitant medications 
or patient’s clinical state. 
Unlikely: 
 
The current state of knowledge indicates that a relationship is unlikely. 
Possibly Related: 
A reaction that follows a plausible temporal sequence from administration 
of the study device or drug and follows a known response pattern to the 
suspected study material.  The reaction might have been produced by the 
patient’s clinical state or other modes of therapy administered to the 
patient. 
Probably Related: 
A reaction that follows a plausible temporal sequence from administration 
of the study device or drug and follows a known response pattern to the 
suspected study material.  The reaction cannot be reasonably explained by 
known characteristics of the patient’s clinical state or other modes of 
therapy administered to the patient. 
Definite: 
There is a definite relationship between the experience and the 
administration of study device or drug. 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
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DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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11.2 
Serious Adverse Event Reporting by Investigators 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to SCRI Innovations Safety Department in order to comply with regulatory 
requirements.  Determination of life-threatening or serious is based on the opinion of either the 
Sponsor or the Investigator.   
Serious AEs may occur at any time from the start of study treatment through the 30 day period 
after the last dose of study drug.  The SCRI Innovations Safety Department must be notified 
of all SAEs, regardless of causality, within 24 hours of the first knowledge of the event by 
the treating physician or research personnel.   
To report a SAE, the SAE Report Form should be completed with the necessary information. 
The SAE report should be sent to SCRI Innovations Safety Department via fax or e-mail using 
the using the following contact information (during both business and non-business hours): 
SCRI Innovations Safety Department 
Safety Dept. Fax #:      1-866-807-4325 
Safety Dept. Email:     CANN.SAE@scri-innovations.com 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to SCRI Innovations Safety Department as soon as it is available; these reports 
should be submitted using the SCRI Innovations SAE Report Form.    
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) according to the policies of the responsible IRB. 
11.3 
Recording of Adverse Events and Serious Adverse Events 
11.3.1 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SAE Report Form and/or AE eCRF screen).  If a diagnosis is 
subsequently established, it should be reported as follow-up information is available.  If a 
diagnosis is determined subsequent to the reporting of the constellation of symptoms, the 
signs/symptoms should be updated to reflect the diagnosis. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as an 
SAE. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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11.3.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or the AE 
eCRF screen.  If a persistent AE becomes more severe or lessens in severity, it should be 
recorded on a separate SAE Report Form and/or AE eCRF screen. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE 
eCRF screen. 
11.3.3 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be collected on the relevant 
eCRF screen.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form or AE eCRF screen. 
Abnormal laboratory values will be reported as an AE if: the laboratory result requires an 
adjustment in the study drug(s) or discontinuation of treatment, and/ or laboratory findings 
require additional testing or surgical intervention, a laboratory result or finding is associated with 
accompanying symptoms, or a laboratory result is considered to be an AE by the investigator. 
11.3.4 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
Investigator solely to progression of disease will be recorded on the “Study Discontinuation” 
eCRF screen.  All other on study deaths, regardless of attribution, will be recorded on an SAE 
Report Form and expeditiously reported to the SCRI Innovations Safety Department. 
When recording a SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and Adverse Event screen of the eCRF.  If the cause of death is unknown and 
cannot be ascertained at the time of reporting, record “Death NOS” on the eCRF Adverse Event 
screen.  During post-study survival follow-up, deaths attributed to progression of disease will be 
recorded only on the “After Progressive Disease Follow-Up” eCRF screen. 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization or prolongation of pre-existing hospitalization should be 
documented and reported as an SAE unless specifically instructed otherwise in this protocol.  
There are some hospitalizations that do not require reporting as an SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
 Emergency Department or Emergency Room 


 
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 Outpatient or same-day surgery units 
 Observation or short-stay unit 
 Rehabilitation facility 
 Hospice or skilled nursing facility 
 Nursing homes, Custodial care or Respite care facility 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as a SAE to the SCRI Innovations 
Safety Department. 
11.3.6 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History eCRF screen.  A pre-existing medical 
condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF screen, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
11.3.7 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the seriousness criteria (see Section 11.1.2).  New primary cancers are those that 
are not the primary reason for the administration of the study treatment and have developed after 
the inclusion of the patient into the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the study, a Pregnancy Form (a paper report 
form, not available within the eCRF) should be completed and faxed to the SCRI Innovations 
Safety Department.  SCRI Innovations Safety Department should be notified expeditiously, 
irrespective of whether or not it meets the criteria for expedited reporting.  Abortions 
(spontaneous, accidental, or therapeutic) must also be reported to SCRI Innovations Safety 
Department. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the SCRI Innovations Safety Department immediately.  Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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11.3.9 
Study Drug Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to the SCRI Innovations Safety Department no greater 
than 24 hours from first knowledge of the event using the corresponding screens in the eCRF and 
following the same process described for SAE reporting (see Section 11.2) if the overdose is 
symptomatic. 
For information on how to manage an overdose of the study drug, see the Package Insert. 
11.4 
Sponsor Serious Adverse Event Reporting Requirements 
SCRI Innovations Safety Department will forward SAE information to Sirtex Medical within 1 
business day of SCRI Innovations Safety Department personnel becoming aware of the SAE. 
 
Sirtex Medical 
Jo Fladger 
Phone:  781-721-3844 
Fax:  877-221-0256 
Email: jfladger@sirtex.com 
SCRI Innovations is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating investigators, in accordance with International 
Conference on Harmonisation (ICH) guidelines, and FDA regulations 21CFR parts 312, 
812.140, 812.46.   
Sirtex Medical is responsible for determining reportablity of SAEs that a device has or may 
have caused or contributed to a death or serious injuries under the MDR (Medical Device 
Reporting) 21CFR Part 803.  Within 72 hours of receipt, Sirtex Medical will determine the 
relationship between the SAE and the device and they will notify the SCRI Innovations Safety 
Department.  SCRI Innovations Safety Department will complete the SAE report to the relevant 
regulatory authorities. 
11.4.1 
Sponsor Assessment of Unexpected Drug Events 
The Sponsor is responsible for assessing an adverse event or suspected adverse event as   
“unexpected”. 
An adverse event or suspected adverse reaction is considered “unexpected” when the following 
conditions occur: 
 Event(s) is not mentioned in the IB (or current US Package Insert) 
 Event(s) is not listed at the specificity or severity that has been observed 
 An event(s) is not consistent with the General Investigative Plan or in the current 
application 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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 Includes AEs or SARs that may be anticipated from the pharmacological properties of the 
study drug, or that occur with members of the drug class, but that have previously been 
observed under investigation 
When applicable, an unexpected adverse event may also apply to an event that is not listed in the 
current US Package Insert (USPI) or an event that may be mentioned in the USPI, but differs 
from the event because of greater severity or specificity.    
Known as Suspected Unexpected Serious Adverse Reactions (SUSAR), these events suspected 
(by the Investigator or Sponsor) to be related to the study drug, are unexpected (not listed in the 
Investigator’s Brochure or USPI), and are serious (as defined by the protocol) and require 
expedient submission to relevant health authorities within 7 days (fatal or life-threatening event) 
or 15 days (all serious events), or as defined by law.  The term SUSAR is used primarily in the 
reporting of events to regulatory authorities. 
Expected AEs are those events that are listed or characterized in the USPI or current IB. 
11.4.2 
Sponsor Reporting for Clinical Studies Under an Investigational Device 
Exemption 
All written IDE Safety Reports submitted to the FDA by the SCRI Innovations Safety 
Department must also be faxed to the company(ies) that are supporting the study: 
Sirtex Pty Ltd 
Fax:  877-221-0256 
11.4.3 
Sponsor Assessment of Unexpected Adverse Device Effects 
Any events determined by the PI to be unanticipated adverse device effects will be reported to the 
SCRI Innovations Safety Department as soon as possible but not more than 10 working days after 
the investigator first learns of the effect.  These unanticipated adverse device effects will be reported 
to the reviewing IRB, the FDA, and the study team as soon as possible but not more than 10 working 
days after the investigator first learns of the effect. 
Any unanticipated adverse device effect will be immediately evaluated by the Sponsor-investigator. 
Should it be determined the unanticipated adverse device effect presents an unreasonable risk to 
study subjects, the study or the part(s) of the study that presents that risk will be terminated as soon 
as possible but not later than 5 working days after the Sponsor-investigator first receives notice of the 
effect. 
12. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of Good Clinical Practice 
(GCP) outlined in the ICH E6 Tripartite Guideline and CFR Title 21 part 312, applicable 
government regulations, institutional research policies and procedures and any other local 
applicable regulatory requirement(s). 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
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12.1 
Institutional Review Board Approval 
The clinical study protocol, informed consent form (ICF), package inserts, available safety 
information, patient documents (e.g., study diary), patient recruitment procedures (e.g., 
advertisements), information about payments (i.e., Principal Investigator payments) and 
compensation available to the patients and documentation evidencing the Principal Investigator’s 
qualifications should be submitted to the IRB for ethical review and approval, prior to the study 
start. 
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to 
ensure appropriate, initial, and on-going, IRB study review.  The Principal Investigator/Sponsor 
(as appropriate) must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  Investigators 
will be advised by the Sponsor or designee whether an amendment is considered substantial or 
non-substantial and whether it requires submission for approval or notification only to an IRB. 
Safety updates for study drugs, will be prepared by the Sponsor or its representative as required, 
for distribution to the investigator(s) and submission to the relevant IRB. 
12.2 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities. 
12.3 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each consent form must include all of the relevant elements currently required by the 
FDA, as well as local county authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, to include the patient’s 
signature, will be provided by the investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to the 
patients, the patient’s consent to continue participation in the study should be obtained. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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12.3.1 
Confidentiality 
12.3.1.1 Patient Confidentiality 
Confidentiality of patient’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of following: 
 What protected health information (PHI) will be collected from patients in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws 
 The information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study 
 Whether the authorization contains an expiration date 
 The rights of a research patient to revoke his or her authorization 
In the event that a patient revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the investigator and institution permit authorized representatives of Sponsor, the regulatory 
authorities and the IRB direct access to review the patient’s original medical records at the site 
for verification of study-related procedures and data.  
Measures to protect confidentiality include: only a unique study number and initials will identify 
patients in the eCRF or other documents submitted to the Sponsor.  This information, together 
with the patient’s date of birth, will be used in the database for patient identification.  Patient 
names or addresses will not be entered in the eCRF.  No material bearing a patient’s name will 
be kept on file by Sponsor.  Patients will be informed of their rights within the ICF. 
12.3.1.2 Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the SCRI Innovations 
database, and shall be treated in compliance with all applicable laws and regulations.  When 
archiving or processing personal data pertaining to the investigator or sub investigator, SCRI 
Innovations shall take all appropriate measures to safeguard and prevent access to this data by 
any unauthorized party. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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12.4 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between the 
SCRI Innovations and applicable parties.  Any Investigator financial disclosures as applicable to 
21CFR Part 54.6 and 812.43 shall be appropriately provided. 
13. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
13.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor or its representative.  All amendments require review and approval of all 
pharmaceutical companies and the Principal Investigator supporting the study.  The written 
amendment must be reviewed and approved by the Sponsor, and submitted to the IRB at the 
investigator’s facility for the board’s approval. 
Amendments specifically involving change to study design, risk to patient, increase to dosing or 
exposure, patient number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB of record for the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by the 
Sponsor as applicable and IRB approval obtained, and specifically when an increase to dosing or 
patient exposure and/or patient number has been proposed; or, when the addition or removal of 
an Investigator is necessitated. 
Items requiring a protocol amendment with IRB and/or FDA or other regulatory authority’s 
approval which include but are not limited to the following: 
 Change to study design 
 Risk to patient 
 Increase to dose or patient exposure to drug 
 Patient number increase 
 Addition or removal of tests and / or procedures 
 Addition/removal of a new Investigator 
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, their consent to continue participation in the study 
should be obtained. 
13.2 
Documentation Required to Initiate the Study 
Before the study may begin certain documentation required by FDA regulations and ICH GCP 
must be provided by the Investigator.  The required documentation should be submitted to: 
SCRI Development Innovations, LLC 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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3322 West End Avenue, Suite 900 
Nashville, TN  37203 
Documents at a minimum required to begin a study in the US include, but are not limited to, the 
following: 
 A signature-authorized protocol and contract 
 A copy of the official IRB approval of the study and the IRB members list, if provided 
 Current Curricula Vitae for the principal investigator and any associate investigator(s) 
who will be involved in the study 
 Indication of appropriate accreditation for any laboratories to be used in the study and a 
copy of the normal ranges for tests to be performed by that laboratory 
 A signed Investigator agreement and curricula vitae (CVs) of participating investigators  
 A copy of the IRB-approved consent form (and patient information sheet, if applicable) 
containing permission for audit by representatives of  SCRI Innovations, the IRB, and the 
FDA and other regulatory agencies (as applicable) 
 Financial disclosure information for all investigators listed in the Investigator’s 
agreement (if applicable) 
 Site qualification reports, where applicable 
 Verification of Principal Investigator acceptability from local and/or national debarment 
list(s)  
13.3 
Study Documentation and Storage 
The Principal Investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties and should ensure that all persons assisting in the conduct of the study 
are informed of their obligations.  All persons authorized to make entries and/or corrections on 
the eCRFs are to be included on this document.  All entries in the patient’s eCRF are to be 
supported by source documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patient’s eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
The following imaging studies will be submitted for central review when available: 
1. CT/MRI and SPECT MAA study (DICOM) used to calculate 90Y activity prescription 
used to treat patient.  Patient identifiers must be removed and replaced by the patient’s 
unique trial number. 
2. Bremsstrahlung SPECT study (DICOM) obtained after 90Y treatment. Patient identifiers 
must be removed and replaced by the patient’s unique trial number. 


 
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3. CT/MRI studies (DICOM) obtained at 6 & 12 weeks post 90Y as per protocol follow up.  
Patient identifiers must be removed and replaced by the patient’s unique trial number. 
The Principal Investigator and each study staff member is responsible for maintaining a 
comprehensive and centralized filing system  (e.g., regulatory binder or investigator study file 
[ISF]) of all study-related (essential) documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced.  The ISF should contain as a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 8, 21 CFR Part 312.57, and Part 
812.140, including key documents such as the IB and any amendments, protocol and any 
amendments signed ICFs, copies of completed CRFs, IRB approval documents, patient 
identification lists, enrollment logs, delegation of authority log, staff qualification documents, 
laboratory normal ranges, records relating to the study drug including accountability records.  
Drug accountability records should, at a minimum, contain information regarding receipt, 
shipment, and disposition.  Each form of drug accountability record, at a minimum, should 
contain Principal Investigator name, date drug shipped/received, date, quantity and batch/code, 
or lot number for identity of each shipment.  In addition, all original source documents 
supporting entries in the CRF must be maintained and be readily available. 
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6, Part 812.43 and Part 312.57 for no less than 2 years after the last 
marketing application has been approved by FDA; or, in the event that the marketing application 
has not been approved by FDA, for no less than 2 years after the last shipment / delivery of the 
drug for investigational use is discontinued and FDA has been notified of the discontinuation. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62 and Part 812.140 for no less than 2 years 
after the last marketing application has been approved by FDA; or, in the event that the 
marketing application has not been approved by FDA, for no less than 2 years after the last 
shipment / delivery of the drug for investigational use is discontinued and FDA has been notified 
of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records e.g., eCRF records, and medical 
records), all original, signed ICFs, and copies of all eCRF records, SAE Reporting forms, source 
documents, detailed records of treatment disposition, and related essential regulatory documents.  
The documents listed above must be retained by the investigator for as long as needed to comply 
with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval).  Sponsor will notify the 
investigator(s)/institutions(s) when the study-related records are no longer required. 
If the investigator relocates, retires, or for any reason withdraws from the study, both the Sponsor 
and its representative should be prospectively notified.  The study records must be transferred to 
an acceptable designee, such as another investigator, another institution, or to the Sponsor.  The 
investigator must obtain the Sponsor’s written permission before disposing of any records, even 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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if retention requirements have been met.  All study files will be maintained by the Sponsor 
throughout the study, and will be transferred to the Sponsor at the conclusion of the study. 
13.4 
Data Collection 
The study eCRFs are the primary data collection instrument for the study.  Electronic case report 
forms will be completed using the English language and should be kept current to enable the 
Sponsor to review the patients’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, patient number, and date of birth will 
identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to SCRI 
Innovations and replaced instead with the patient number and patient’s initials.  The investigator 
will maintain a personal patient identification list (patient numbers with corresponding patient 
identifiers) to enable records to be identified and verified as authentic.  Patient data/information 
will be kept confidential, and will be managed according to applicable local, state, and federal 
regulations. 
All data requested in the eCRF system must be supported by and be consistent with the patient’s 
source documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or “Unknown”.  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided. 
The investigator will review and electronically sign and date each patient eCRF casebook 
indicating that the data in the eCRF has been assessed.  Each completed eCRF will be signed and 
dated by the Principal Investigator, once all data for that patient is final. 
13.5 
Study Monitoring, Auditing, and Inspecting 
The investigator will permit study-related monitoring, quality audits, and inspections by the 
Sponsor or its representative(s), government regulatory authorities, and the IRB of all study-
related documents (e.g., source documents, regulatory documents, data collection instruments, 
case report forms).  The investigator will ensure the capability for inspections of applicable 
study-related facilities.  The investigator will ensure that the study monitor or any other 
compliance or Quality Assurance reviewer is given access to all study-related documents and 
study-related facilities. 
At the Sponsor’s discretion, Source Document Verification may be performed on all data items 
or a percentage thereof. 
Participation as an investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the IRB and the Sponsor or its representative(s). 
13.6 
Quality Assurance and Quality Control 
Each study site shall be required to have Standard Operating Procedures to define and ensure 
quality assurance/control processes for study conduct, data generation & collection, recording of 
data/documentation and reporting according to the protocol, GCP and any applicable local, 
national or international regulations. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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13.7 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication strategy. 
Inclusion of the investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the study.  The investigator acknowledges that the study 
is part of a multi-center study and agrees that any publication by the investigator of the results of 
the study conducted at research site shall not be made before the first multi-center publication.  
In the event there is no multi-center publication within fifteen (15) months after the study has 
been completed or terminated at all study sites, and all data has been received, the investigator 
shall have the right to publish its results from the study, subject to the notice requirements 
described herein and subject to acknowledgement of the Sponsor as appropriate.  Investigator 
shall provide the Sponsor thirty (30) days to review a manuscript or any poster presentation, 
abstract or other written or oral material which describes the results of the study for the purpose 
only of determining if any confidential or patentable information is disclosed thereby.  If the 
Sponsor requests in writing, the investigator shall withhold any publication or presentation an 
additional sixty (60) days solely to permit the Sponsor to seek patent protection and to remove 
any SCRI Innovations Confidential Information from all publications. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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14. 
REFERENCES 
Bester et al. 2011 
Bester L. et al: Radioembolization versus standard care of hepatic metastases: Comparative 
retrospective cohort study of survival outcomes and adverse events in salvage patients.  J Vasc 
Interv Radiol 2011; 23:96–105.  
Eisenhauer et al. 2009 
Eisenhauer EA et al. New response evaluation criteria in solid tumours; revised RECIST 
guideline (version 1.1).  Eur J Cancer. 2009; 45 p. 228-47. 
Grothey et al. 2012 
Grothey A et al. Results of a phase III randomized, double-blind, placebo-controlled, 
multicentered trial (CORREC) of regorafenib plus best supportive care (BSC) versus placebo 
plus BSC in patients with metastatic colorectal cancer (mCRC) who have progressed after 
standard therapies.  Gastrointestinal Cancer Symposium. 2012. San Francisco, CA.  
Hendlisz et al. 2010 
Hendlisz A et al. Phase II trial comparing protracted intravenous fluorouracil infusion alone with 
or with Yttrium-90 resin microshperes radioembolization for liver-limited metastatic colorectal 
cancer refractory to standard chemotherapy. J Clin Oncol. 2010; 29.5643. 
Jonker et al. 2007 
Jonker DJ et al. Cetuximab for the treatment of colorectal cancer. N Eng J Med. 2007; 357(20): 
2040-8. 
Kennedy et al. 2006 
Kennedy A, Coldwell D, Nutting C et al. Resin 90Y-microsphere brachytherapy for unresectable 
colorectal liver metastases: Modern USA experience. Int J Radiat Oncol Biol Phys. 2006; 
65:412–425. 
Kennedy et al. 2012 
Kennedy A et al. Radioembolization for the treatment of liver tumors general principles.  Am J 
Clin Oncol. 2012; 35(1):91-9. 
Leung et al. 1995 
Leung T, Lau W, Ho S et al. Radiation pneumonitis after selective internal radiation treatment 
with intra-arterial yttrium-90-microspheres for inoperable hepatic tumours. Int J Rad Oncol Biol 
Phys 1995; 33;919-924 
Liu et al. 2005 
Liu D, Salem R, Bui J et al. Angiographic considerations in patients undergoing liver directed 
therapy. J Vasc Inter Radiol. 2005; 16:911-935. 
Mavros et al. 2013 
Mavros MN, et al. Impact of complications of long-term survival after resection of colorectal 
liver metastases.  Br J Surg. 2013;100(5):711-8. 


 
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Silverberg 1977  
Silverberg E. Cancer Statistics 1977. CA Cancer J Clin. 1977; 27(1):26-41. 
Stubbs et al. 2004 
Stubbs R, Wickremesekera S. Selective internal radiation therapy (SIRT): a new modality for 
treating patients with colorectal liver metastases. HPB 2004; 6:133 - 139 
Van Cutsem et al. 2007 
Van Cutsem E et al. Open-label phase III trial of panitumumab plus best supportive care 
compared with best supportive care alone in patients with chemotherapy-refractory metastatic 
colorectal cancer.  J Clin Oncol. 2007; 25(13):1658-64. 


 
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15. 
APPENDICES 
Appendix A:  Schedule of Assessments – Cohort 1- Regorafenib then SIR-Spheres then Regorafenib 
Procedures 
Screening 
Cohort 1 –Regorafenib then SIR-Spheres then Regorafenib  
End of 
Treatment  
Visitl 
Follow-Up 
Regorafenib 
SIR-Spheres 
Regorafenib 
Cycle 1 
Cycle 2 
Cycle 3 and Beyond 
Disease-Free 
Survivalm 
Survivaln 
Days 
Days 
Days 
Baselineb 
1b 
8 
15 
22q 
1 
8 
1 
8 
15 
 
 
 
TESTS & OBSERVATIONS 
 
Informed Consenta  
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs, 
height, weightc 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
Blood Pressure 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
Adverse event evaluation 
 
 
X 
X 
X 
 
X 
X 
 
 
X 
X 
 
Concomitant medication review 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LABORATORY TESTS 
 
CBC, including differential and 
plateletsd 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
CMPe 
X 
X 
X 
X 
X 
 
X 
Xf 
 
 
X 
X 
 
PT/PTT/INRg 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
 
Serum or urine pregnancy testi 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Biomarker blood sample collection  
 
 
 
 
Xh 
 
Xh 
Xh (day 
30) 
 
 
 
 
 
 


 
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Appendix A: Schedule of Assessments – Cohort 1- Regorafenib then SIR-Spheres then Regorafenib 
Procedures 
Screening 
Cohort 1 –Regorafenib then SIR-Spheres then Regorafenib 
End of 
Treatment  
Visitl 
Follow-Up 
Regorafenib 
SIR-Spheres 
Regorafenib 
Cycle 1 
Cycle 2 
Cycle 3 and Beyond 
Disease-Free 
Survivalm 
Survivaln 
Days 
Days 
Days 
Baselineb 
1b 
8 
15 
22q 
1 
8 
1 
8 
15 
 
 
 
DISEASE ASSESSMENT 
 
CT scan of the chest, 
abdomen, pelvisj,k  
X 
 
 
 
 
 
 
 
 
Xj 
Xj 
Xj 
 
Tumor marker (CEA)  
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Hepatic angiogram 
 
 
 
 
Xo 
 
 
 
 
 
 
 
 
99mTc MAA lung shunt scano 
 
 
 
 
Xo 
 
 
 
 
 
 
 
 
TREATMENT 
 
 
Regorafenib PO (Days 1-21)p 
 
Days 1-21 
 
 
Days 1-21 
 
 
 
SIR-Spheres 
 
 
 
 
 
X 
 
 
 
 
 
 
 


 
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Appendix A: 
Cohort 1 Schedule of Assessments (continued) 
 
a. Informed Consent must be obtained ≤28 days prior to the initiation of study treatment.   
b. The Screening physical examination, update of medical history, ECOG performance status, CBC, CMP, and PT/PTT/INR, and concomitant medication review should be done 
≤21 days prior to initiation of treatment.  However, if these initial examinations are obtained within 72 hours of Cycle 1 Day1 they do not have to be repeated on Cycle 1 Day 
1.  Scans to document measurable or evaluable disease (i.e., tumor measurement) and tumor marker (CEA) should be performed ≤28 days prior to initiation of treatment. 
c. Physical examinations will include measurements of height (Screening visit only), weight and vital signs (resting heart rate, respiratory rate, oral temperature).  Blood pressure 
should be monitored weekly for the first 6 weeks of regorafenib treatment and then every cycle, or more frequently, if clinically indicated. 
d. Hematology parameters include the following laboratory tests:  complete blood count including WBC with 3-part differential (total neutrophil count including bands, 
lymphocytes, monocytes) hemoglobin, hematocrit and platelets. 
e. CMP must include glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST, ALT, total bilirubin, total protein, and albumin plus LDH, phosphorus. 
f. If liver function toxicities are present after a 2 week rest, then patients may be rechecked weekly for 2 additional weeks.  Reinitiation of regorafenib must be delayed until 
appropriate resolution of liver function toxicities. 
g. PT/PTT/INR will be monitored in patients receiving Coumadin on Days 1, 8 (Cycle 1 only) and 15 of each treatment cycle.   
h. Biomarker samples (see Section 5.4) will be collected from all patients prior to the hepatic angiogram and 99mTc MAA lung shunt scan, which will be obtained 7-4 days prior to 
SIR-Spheres treatment (see Section 7.2) and on Day 8 after SIR-Spheres treatment and Day 30 (pre-dose) after SIR-Spheres treatment.  
i. Serum or urine pregnancy tests are to be conducted in women of childbearing potential within 72 hours of C1D1. 
j. CT scan of the chest, abdomen and pelvis will be obtained at baseline ≤28 days prior to the initiation of treatment.  Assessments required the same day of SIR-Spheres 
administration can be obtained ≤7 days prior to SIR-Spheres treatment.  Patients will be restaged on Week 6 and Week 12 after SIR-Spheres treatment according to RECIST 
v1.1.  All assessments should be performed within 7 days of the schedule day of assessment. Patients with stable disease or better may continue treatment with regorafenib.  
CEA tumor markers must be assessed on Day 1 of each cycle and at the End of Treatment visit.   
k. Patients determined to have stable disease or better at the Week 12 restaging continuing treatment will begin 28-day treatment cycles (21 days oral regorafenib followed by one 
week rest).  Patients will then be re-assessed according to RECIST v1.1 criteria every 8 weeks. 
l. All patients will undergo the End of Treatment visit assessments listed within 30 days after treatment ends due to completion of the planned study treatment period, or once a 
patient is discontinued due to unacceptable toxicity or decision to discontinue treatment by the patient or the study physician.  If treatment is discontinued because of toxicity or 
any other reason(s) at a treatment visit and no study treatment is administered, that visit may fulfill the End of Treatment visit.  After withdrawal from or completion of 
protocol treatment, patients must be followed for adverse events for 30 calendar days after the last dose of study drug. 
m. Patients will be followed every 3 months (±1 month) for up to a maximum of 6 months after the last patient has enrolled on study for toxicity and disease progression.    
n. After disease progression is documented, patients will be followed every 3 months (±1 month) for survival (e.g., date and cause of death) for up to a maximum of 6 months 
after the last patient has enrolled on study or death whichever comes first.  Patients may be contacted during outpatient visits or by telephone. 
o. Patients will be at assessed 7-4 days prior to SIR-Spheres treatment to determine the suitability for SIR-Spheres (see Section 7.2). 
p. Patients will self-administer regorafenib during Days 1-21. 
q. The Cycle 1 Day 22 physical examination, ECOG performance status, CBC, CMP, and PT/PTT/INR, tumor marker (CEA), adverse event evaluation, and concomitant 
medication review to be completed ≤7 days prior to SIR-Spheres radiation treatment.   


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Appendix B:  Schedule of Assessments - Cohort 2-SIR-Spheres then Regorafenib 
Procedures 
Screening 
Cohort 2 – SIR-Spheres then Regorafenib 
End of 
Treatment  
Visitl 
Follow-Up 
SIR-
Spheres 
Regorafenib 
Cycle 1 
Cycle 2 
Cycle 3 and Beyond 
Disease-
Free 
Survivalm 
Survivaln 
Days 
Days 
Days 
Baselineb 
1 
8 
1 
8 
15 
22 
1 
8 
15 
 
 
 
TESTS & OBSERVATIONS 
 
Informed Consenta  
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs, 
height, weightc 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
Blood Pressure 
X 
 
 
X 
X 
X 
X 
X 
Xp 
 
X 
X 
 
ECOG Performance Status 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
Adverse event evaluation 
 
 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
Concomitant medication review 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
LABORATORY TESTS 
 
CBC, including differential and 
plateletsd 
X 
 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
CMPe 
X 
 
X 
Xf 
X 
X 
 
X 
 
 
X 
X 
 
PT/PTT/INRg 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Serum or urine pregnancy test 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker blood sample collection  
Xh 
 
Xh 
Xh 
(day 
30) 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Page 78 of 98 
Appendix B:   Schedule of Assessments - Cohort 2-SIR-Spheres then Regorafenib (continued) 
Procedures 
Screening 
Cohort 2 – SIR-Spheres then Regorafenib 
End of 
Treatment  
Visitl 
Follow-Up 
SIR-
Spheres 
Regorafenib 
Cycle 1 
Cycle 2 
Cycle 3 and Beyond 
Disease-
Free 
Survivalm 
Survivaln 
Days 
Days 
Days 
Baselineb 
1 
8 
1 
8 
15 
22 
1 
8 
15 
 
 
 
DISEASE ASSESSMENT 
 
CT scan of the chest, abdomen, 
pelvisj,k  
X 
 
 
 
 
Xj 
 
 
 
 
Xj 
Xj 
 
Tumor marker (CEA)  
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Hepatic angiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
99mTc MAA lung shunt scan 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
 
SIR-Spheres 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Regorafenib PO (Days 1-21)o 
 
 
 
Days 1-21 
Days 1-21 
 
 
 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Appendix B: 
Cohort 2 Schedule of Assessments (continued) 
a. Informed Consent must be obtained ≤28 days prior to the initiation of study treatment.   
b. The Screening physical examination, update of medical history, ECOG performance status, CBC, CMP, and PT/PTT/INR, concomitant medication review and tumor marker 
(CEA) should be done ≤21 days prior to initiation of treatment.  These initial examinations must be repeated or performed ≤7 days of Cycle 1 Day 1 to document Cycle 1 Day 
1 assessments prior to SIR-Spheres treatment.  CT scans to document measurable or evaluable disease (i.e., tumor measurement)  should be performed ≤28 days prior to 
initiation of treatment.  Patients will be assessed at Screening (7-4 days prior to SIR-Spheres treatment) to determine the suitability for SIR-Spheres (see Section 7.2). 
c. Physical examinations will include measurements of height (Screening visit only), weight and vital signs (resting heart rate, respiratory rate, oral temperature).    Blood 
pressure should be monitored weekly for the first 6 weeks of regorafenib treatment and then every cycle, or more frequently, if clinically indicated. 
d. Hematology parameters include the following laboratory tests:  complete blood count including WBC with 3-part differential (total neutrophil count including bands, 
lymphocytes, monocytes) hemoglobin, hematocrit and platelets. 
e. CMP must include glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST, ALT, total bilirubin, total protein, and albumin plus LDH, phosphorus. 
f. If liver function toxicities are present after a 2 week rest, then patients may be rechecked weekly for 2 additional weeks prior to Regorafenib treatment on C2D1.  . 
g. PT/PTT/INR will be monitored in patients receiving Coumadin on Days 1, 8 (Cycle 2 only), and 15 of each treatment cycle.   
h. 
Biomarker samples (see Section 5.4) will be collected from all patients prior to the hepatic angiogram and 99mTc MAA lung shunt scan, which will be obtained 7-4 days prior to 
SIR-Spheres treatment [see Section 7.2]) and on Day 8 after SIR-Spheres treatment and Day 30 (pre-dose) after SIR-Spheres treatment.  
i. Serum or urine pregnancy tests are to be conducted in women of childbearing potential within 72 hours of C1D1.   
j. CT scan of the chest, abdomen and pelvis will be obtained at baseline ≤28 days prior to the initiation of treatment.  Assessments required the same day of SIR-Spheres 
administration can be obtained ≤7 days prior to SIR-Spheres treatment.  Patients will be restaged on Week 6 and Week 12 after SIR-Spheres treatment according to RECIST 
v1.1.  All assessments should be performed within 7 days of the schedule day of assessment. Patients with stable disease or better may continue treatment with regorafenib.  
CEA tumor markers must be assessed on Day 1 of each cycle and at the End of Treatment visit.   
k. Patients determined to have stable disease or better at the Week 12 restaging continuing treatment will begin 28-day treatment cycles (21 days oral regorafenib followed by one 
week rest).  Patients will be re-assessed according to RECIST v1.1 criteria every 8 weeks. 
l. All patients will undergo the End of Treatment visit assessments listed within 30 days after treatment ends due to completion of the planned study treatment period, or once a 
patient is discontinued due to unacceptable toxicity or decision to discontinue treatment by the patient or the study physician.  If treatment is discontinued because of toxicity or 
any other reason(s) at a treatment visit and no study treatment is administered, that visit may fulfill the End of Treatment visit. After withdrawal from or completion of protocol 
treatment, patients must be followed for adverse events for 30 calendar days after the last dose of study drug. 
m. Patients will be followed every 3 months (±1 month) for up to a maximum of 6 months after the last patient has enrolled on study for toxicity and disease progression.    
n. After disease progression is documented, patients will be followed every 3 months (±1 month) for survival (e.g., date and cause of death) for up to a maximum of 6 months 
after the last patient has enrolled on study or death whichever comes first.  Patients may be assessed during outpatient visits or contacted by telephone. 
o. Patients will self-administer regorafenib during Days 1-21. 
p. Blood pressure is required Cycle 3 Day 8.  Cycle 4 and beyond, blood pressure will be required Day 1 only. 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Appendix C:  Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Definitions 
Response and progression will be evaluated in this study using the Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1 (Eisenhauer et al. 2009).  Lesions are either measurable 
or non-measurable using the criteria provided below.  The term “evaluable” in reference to 
measurability will not be used, as it does not provide additional meaning or accuracy. 
Baseline Eligibility 
Measurable Disease: 
Tumor lesions:  Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a 
minimum size of: 
 
10 mm by CT by computerized tomography (CT scan slice thickness 
no greater than 5 mm). 
 
10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as non-
measurable). 
 
20 mm by chest x-ray. 
 
Skin lesions:  Documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
 
Malignant lymph nodes:  To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by 
CT scan.  At baseline and in follow-up, only the short axis will be measured 
and followed.  
Non-Measurable Disease: 
All other lesions, including small lesions (longest diameter <<10 mm or 
pathological lymph nodes with ≥10- to <<15-mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses, 
abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques.  
Target Lesions: 
The most reproducible measurable lesions, up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs should be 
identified as target lesions and recorded and measured at baseline.   
Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), should be representative of all involved organs, and in 
addition should be those that lend themselves to reproducible repeated 
measurements.  Pathological nodes which are defined as measurable and that 
may be identified as target lesions must meet the criterion or a short axis of 
≥15 mm by CT scan. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters. If lymph nodes are to be included in the sum, then as noted 
above, only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor 
response. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Non-Target Lesions: 
All other lesions should be identified as non-target lesions at baseline.  
Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up. 
Guidelines for Evaluation of Measureable Disease 
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment, as 
per protocol screening requirements. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
anti-tumor effect of a treatment. 
 
Clinical Lesions: 
Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter.  In 
the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest X-ray: 
Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, a CT scan is 
preferable. 
Conventional CT and MRI: 
CT, MRI:  CT is the best currently available and reproducible method to 
measure lesions selected for response assessment.  This guideline has 
defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5mm or less.  When CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).  
Ultrasound: 
When the primary study endpoint is objective response, ultrasound should 
not be used to measure tumor lesions.  It is, however, a possible alternative 
to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions, and thyroid nodules.  Ultrasound may also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination. 
Endoscopy and Laparoscopy: 
Use of endoscopy and laparoscopy for objective tumor evaluation has not yet 
been fully and widely validated.  Therefore, use of these techniques for 
objective tumor response should be restricted to validation purposes in 
specialized centers.  Such techniques can be useful in confirming complete 
pathological response when biopsies are obtained. 
Tumor Markers: 
Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper limit of normal, they must normalize for a subject to 
be considered in complete clinical response when all lesions have 
disappeared. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Cytology and Histology: 
Cytology and histology can be used to differentiate between partial response 
(PR) and complete response (CR) in rare cases (e.g., after treatment to 
differentiate between residual benign lesions and residual malignant lesions 
in tumor types such as germ cell tumors). 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR):  
Disappearance of all target lesions.   
Partial Response (PR):  
 
At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.. 
Stable Disease (SD):   
 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest (nadir) sum of diameters 
since the treatment started. 
Progressive Disease (PD):   
 
At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest (nadir) sum since the treatment started, or the 
appearance of one or more new lesions.  Requires not only 20% increase, but 
absolute increase of a minimum of 5 mm over sum. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor markers.  
All lymph nodes must be non-pathological in size (<<10 mm short axis). 
Stable Disease (SD):    
 
Persistence of one or more non-target lesions and/or persistence of tumor 
marker level above the normal limits. 
Progressive Disease (PD):  
 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  When the subject also has measurable disease, to 
achieve “unequivocal progression” on the basis of the non-target disease, 
there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of SD or PR in the target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy. 
 
Evaluation of Best Overall Response 
As detailed in Table 5 above, the best overall response is the best response recorded from the 
start of the treatment until disease progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment started).  In general, the subject’s best 
response assignment will depend on the achievement of both measurement and confirmation 
criteria.   
Confirmation of response (by repeat scans after 4 weeks or as specified in the protocol) is 
required for trials in which response rate is the primary endpoint, but is not required in 
randomized trials or trials with primary survival endpoints (i.e., where response is not a primary 
endpoint).


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
NO 
CR 
CR 
SD 
NO 
PR 
CR 
NE 
NO 
PR 
PR 
SD OR NE 
NO 
PR 
SD 
SD OR NE 
NO 
SD 
PD 
ANY 
YES OR NO 
PD 
ANY 
PD 
YES OR NO 
PD 
ANY 
ANY 
YES 
PD 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of a CR depends upon this determination, it is recommended that the 
residual lesion be investigated by fine needle aspirate or biopsy to confirm the CR status.  
When nodal disease is included in the sum of target lesions, and the nodes decrease to “normal” 
size (<<10 mm), they may still have a measurement reported on scans.  This measurement 
should be recorded even though the nodes are normal in order not to overstate progression, 
should it be based on increase in size of the nodes.  As noted earlier, this means that subjects 
with CR may not have a total sum of “zero” on the CRF. 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Appendix D:  ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
 
100 
Normal, no complaints, no evidence of 
disease. 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed << 50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about more 
than 50% of waking hours. 
 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >> 50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
 
40 
Disabled, requires special care and 
assistance 
 
30 
Severely disabled, hospitalization 
indicated.  Death no imminent. 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
20 
Very sick, hospitalization indicated.  Death 
not imminent. 
 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Appendix E: Guidelines for Women of Childbearing Potential and Fertile Male Patients 
 
Acceptable Contraception Methods:   
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective contraception during the study and for 2 months after 
stopping treatment.   
Highly effective contraception is defined as either: 
True Abstinence 
When this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Sterilization  
When a woman of childbearing potential has had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 
six weeks prior to study entry.  In case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment. 
Male Partner Sterilization When the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate. 
Use of a combination of any two of the following (one from a + one from b): 
a)  Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or established use of oral, injected or implanted hormonal 
methods of contraception. 
b)  Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository. 
 
Fertile male patients, defined as all males physiologically capable of conceiving offspring, 
with female partners of childbearing potential must use condoms plus spermicidal agent during 
the study treatment period and for 2 months after the last dose of study drug, and should not 
father a child during this period.   
Male patients must also refrain from donating sperm during their participation in the study. 
The following are acceptable forms of barrier contraception: 
 Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository 
Unacceptable Contraception Methods: for women of childbearing potential include: 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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 IUD progesterone T 
 Female condom 
 Natural family planning (rhythm method) or breastfeeding 
 Fertility awareness 
 Withdrawal 
 Cervical shield 
 
Pregnancies 
To ensure subject safety, each pregnancy in a subject on study treatment must be reported to 
the SCRI Innovations Safety Department within 24 hours of learning of its occurrence.  The 
pregnancy should be followed up for 3 months after the termination of the pregnancy to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and 
the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to SCRI Innovations Safety Department.  Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the study 
drug of any pregnancy outcome.  Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Women Not of Childbearing Potential are defined as Follows:   
 Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms).  
 Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy).   
 Women who are >45 years-of-age, not using hormone-replacement therapy and who 
have experienced total cessation of menses for at least 12 months OR who have a 
follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value 
<40 pg/mL (140 pmol/L). 
 Women who are >45 years-of-age, using hormone-replacement therapy and who have 
experienced total cessation of menses for at least 1 year OR who have had documented 
evidence of menopause based on FSH >40 mIU/mL and estradiol <40 pg/mL prior to 
initiation of hormone-replacement therapy. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
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DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Appendix F: New York Heart Association (NYHA) Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 
 
 
 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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Appendix G:  Common CYP3A4 Inhibitors and Inducers  
Inducers 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampicin 
Rofecoxib 
St. John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
Inhibitors 
Amiodarone 
Anastrozole 
Aprenavir 
Azithromycin 
Bromocriptine 
Cannabinoids 
Cimetidine 
Cisapride 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
Indinavir 
Isoniazid 
Itraconazole 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole 
Oxiconazole 
Paroxetine 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Telithromycin 
Troglitazone 
Troleandomycin 
Valproic acid 
Verapamil 
Zafirlukast 
Zileuton 


 
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STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
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Date of Amendment #1:  15 April 2014  
 
 
 
 
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Appendix H: Radiosensitization Study of Regorafenib and SIR-Spheres Microspheres 
 
Interim Report for Sirtex Medical from University of Oxford 
Screening of drugs to quantify radiosensitisation in cancer cell lines 
Author:  Dr R A Sharma, 6th August 2013 
Description of the Project 
 
This project aims to quantify the radiosensitisation exerted by drugs licensed for the treatment of 
metastatic colorectal cancer and hepatoma in a preclinical model system. 
A cellular viability assay has been developed to screen drugs for the quantification of intrinsic 
radiosensitisation (RS) in a semi-automated high-throughput format. The assay has been validated 
against the current gold standard in cells grown in vitro, clonogenic survival assays. The principal 
benefit of the cellular viability assay over clonogenic survival assays is that the former can be used 
to study multiple permutations of dose, temporal sequencing and timing of radiotherapy relative to 
drug treatment, and a variety of drug concentrations, all in a significantly shorter timescale than 
the use of traditional methodology. 
In the project proposed here, the principal investigator will demonstrate: 
1.  The degree of radiosensitisation affected by physiologically relevant concentrations of drugs 
licensed for treatment of colorectal cancer and hepatoma in cancer cell lines 
2.  The optimal temporal sequencing of each drug with radiotherapy 
3.  The most appropriate drug concentrations in cell lines to achieve optimal 
radiosensitisation. 


 
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Introduction 
Colorectal cancer is the second most common cancer in the developed world (NCI 2010). Although 
approximately half of cases may be treated with surgery alone, for more advanced stage cancers, 
including metastatic disease, patient outcomes remain poor. Selective internal radiotherapy (SIRT) 
permits high doses of radiotherapy to be delivered safely to liver metastases from colorectal cancer.  
Primary liver cancer, hepatocellular carcinoma (HCC), is not responsive to traditional chemotherapy 
making it difficult to treat when inoperable. Improving radiotherapy treatment for HCC may benefit 
from the combinations of radiotherapy with radiosensitising drugs. Although various 
chemotherapeutics may be used as radiosensitisers, it is not currently clear which radiosensitising 
agents are most appropriate to improve clinical response rates. 
In order to address this research deficit, we have developed a high-throughput assay for the 
identification of radiosensitising drugs to determine the most appropriate drugs to use with 
radiotherapy for specific cancers.  Historically, screening programmes for intrinsic 
radiosensitisers have assessed anti-proliferative activity of compound libraries in vitro in 4-day 
assays (Lally et al. 2010), or have performed RNA interference to look at the effect of gene 
expression on response to radiotherapy (Higgins et al. 2010). Neither method permits high- 
throughput screening for radiosensitisers in a manner that directly correlates with the gold 
standard in vitro, i.e. clonogenic assays - where the ability of single cells to form colonies after 
irradiation is directly measured to enable comparison of radiosensitivity of drugs in different cell 
lines.  Although it is the gold standard, clonogenic assays have major problems as the sole 
technique for assessing radiosensitivity.  They suffer from time-consuming methodology 
(2 weeks for colony growth) and the expense (a large number of plates and large volumes of 
media and drugs are required to obtain a single survival curve). Moreover, low plating efficiency 
for some cell lines can also be problematic (e.g. HepG2 hepatoma cells, which are difficult to test 
with traditional clonogenic survival assays) and in some cases cannot be overcome. To facilitate 
the identification of radiosensitising drugs, we developed an assay and confirmed that it could be 
used as a valid surrogate for clonogenic survival in vitro. This assay was then extended 
robotically to screen compound libraries for potential radiosensitising agents. 
Regorafenib is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, 
stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows antiangiogenic 
activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. We were asked by 
Sirtex to prioritise the testing of regorafenib in colorectal cancer cell lines with radiotherapy for 
this interim report. 


 
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Date of Amendment #1:  15 April 2014  
 
 
 
 
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Methods 
Cell culture.  Cell lines derived from colorectal adenocarcinoma (DLD1, RKO and HCT116) were 
cultured in Dulbecco’s modified essential medium (DMEM) supplemented with 10% foetal calf 
serum, 1x non-essential amino acids and 1x Pen/Strep (Gibco).  Cells were grown at 37ºC in a 
humidified incubator in 95% air with 5% CO2 and passaged twice weekly.  All experiments utilised 
exponentially growing cells with cell population doubling times of approximately 24 hours.  Cell cultures 
were renewed after every 15 passages 
Metabolic assays.  Proliferation assays were used to optimise cell lines to measure the effects of 
drugs and/ or radiation.  Cells were plated in serial dilutions on 96- or 384-well plates and treated 
with drugs and/ or radiation as appropriate.  After 24 hours, media was refreshed and cells allowed 
to proliferate for 5-6 cell doubling times.  As an indicator of cell proliferation after IR, metabolic 
activity in each well was measured using a coloured dye converted intracellularly into a yellow-
fluorescing form.  Cell culture media was replaced with DMEM containing 10 µg/ml dye.  After 
90 minutes, fluorescence was measured using a BMG Polarstar Optima plate reader. 
Clonogenic survival assay.  Cells were harvested, diluted to 10000 cells/ml and plated at 
appropriate cell numbers on 2 x 10 cm dishes/ radiation or drug dose.  After 5-6 hours for cell 
attachment, cells were treated with regorafenib for the timescales stated in the figure legends, and 
irradiated with 0-8 Gy radiation using a 137-Cs source at a dose rate of ~2Gy/ min.  Media were 
refreshed 24 hours after irradiation, and plates were incubated for 10-14 days.  Colonies were 
stained with 0.4% methylene blue in 100% methanol for colony counting, and results were used 
to generate clonogenic survival curves. 


 
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The following permutations of combination treatment were tested by metabolic assay: 
 
Cell line  
Regorafenib 
concentration 
range  
Timing of 
addition of 
drug tested  
HCT116 
(wild-type)  
0 – 40 μM  
24 hrs, 6 hrs 
and 1 hour 
pre-irradiation  
HCT116 
(wild-type)  
0 – 40 μM  
24 hrs, 6 hrs 
and 1 hour 
post-
irradiation  
HCT116 
(KRAS 
mutant)  
0 – 40 μM  
24 hrs pre-
irradiation  
DLD1 (wild-
type)  
0 – 40 μM  
24 hrs, 6 hrs 
and 1 hour 
pre-irradiation  
DLD1 (wild-
type)  
0 – 40 μM  
24 hrs, 6 hrs 
and 1 hour 
post-
irradiation  
DLD1 ( KRAS 
mutant)  
0 – 40 μM  
24 hrs pre-
irradiation  
RKO (BRAF 
mutant)  
0 – 40 μM  
24 hrs pre-
irradiation  
RKO (BRAF 
wild-type)  
0 – 40 μM  
24 hrs pre-
irradiation  


 
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STUDY DEVICE:  SIR-Spheres® 
  
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Date of Amendment #1:  15 April 2014  
 
 
 
 
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Results 
1. Measuring radiosensitivity 
The metabolic assay was optimised to measure radiosensitivity of regorafenib under different 
sequencing conditions (drug added 24 h before RT, drug added at same time as RT and drug 
added 24 h after RT). The data obtained for DLD1 and HCT116 colorectal cancer cells are 
shown in Figures 1 and 2, which are typical of the results for all cell lines tested under all 
conditions and permutations. There was no dose-dependent radiosensitisation observed. 
 
 
 
 
 
 
 
 
 
Figure 1 
 
Figure 1.  Regorafenib was added 24 h before radiotherapy treatment of DLD1 cells and cell 
proliferation measured by relative fluorescence obtained with dye on day 7 post-radiotherapy. 
There was no significant radiosensitisation observed.   IC50 values for drug alone (0 Gy), drug + 
3 Gy RT and drug + 6 Gy radiation were 3.2, 2.1 and 3.4 µM respectively (i.e. no significant 
difference without and with radiation). 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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Date of Amendment #1:  15 April 2014  
 
 
 
 
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Figure 2 
 
Figure 2.  Regorafenib was added 24 h before radiotherapy treatment of HCT116 cells and cell 
proliferation measured by relative fluorescence obtained with dye on day 7 post-radiotherapy. 
There was no significant radiosensitisation observed. 
2. Confirmation of results by clonogenic survival 
To confirm the lack of radiosensitisation in all 3 colorectal cancer cell lines, clonogenic survival 
assays were performed as described above.  All 3 colorectal cancer cell lines had sufficient 
plating efficiency for definitive conclusions to be made.  Results are shown in Figure 3, 
confirming that regorafenib does not cause any statistically significant radiosensitisation of 
colorectal cancer cell lines in this model system. 


 
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STUDY DEVICE:  SIR-Spheres® 
  
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Drug with radiation 
Drug with radiation 
 
 
 
 
 
Figure 3 
Figure 3.  Clonogenic survival assays for 3 colorectal cancer cell lines treated with regorafenib (10 or 
20 µM) plus radiotherapy (6 Gy).  Slight radiosensitisation of RKO cells was observed with 20 µM 
regorafenib plus radiation, but no statistically significant radiosensitisation was observed to justify 
further preclinical testing in vivo.  Results shown are mean values of three separate experiments. 
 
Conclusions 
We have applied 2 types of laboratory assay, including the gold standard test (clonogenic survival), to 
confirm that regorafenib is not an intrinsic radiosensitiser of colorectal cancer cells. This model system 
allows assessment of intrinsic radiosensitisation, but it should be noted that it cannot assess the 
antiangiogenic effect on radiosensitisation.  Such exploration would require in vivo experimentation in 
an animal model, which is beyond the scope of this study.  The rest of the project will test other 
approved drugs for intrinsic radiosensitisation of colorectal cancer cell lines and hepatoma cell lines 
and a further report will be issued in October 2013. 


 
CONFIDENTIAL 
STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
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References 
Dote H, Cerna D, Burgan WE, Carter DJ, Cerra MA, Hollingshead MG, Camphausen K, 
Tofilon PJ. Enhancement of in vitro and in vivo tumor cell radiosensitivity by the DNA 
methylation inhibitor zebularine. Clin Cancer Res. 11(12): 4571-4579 (2005). 
De Schutter H, Kimpe M, Isebaert S, Nuyts S. A systematic assessment of radiation dose 
enhancement by 5-Aza-2'-deoxycytidine and histone deacetylase inhibitors in head-and-
neck squamous cell carcinoma. Int. J. Radiation Oncology Biol. Phys. 73 (3): 904–912 
(2009). 
Freedberg DE, Rigas SH, Russak J, Gai W, Kaplow M, Osman I, Turner F, Randerson-
Moor JA, Houghton A, Busam K, Timothy Bishop D, Bastian BC, Newton-Bishop JA, 
Polsky D. Frequent p16-independent inactivation of p14ARF in human melanoma. J. Natl. 
Cancer Inst. 100: 784 – 795 (2008). 
Gao N, Hu YD, Cao XY, Zhou J, Cao SLJ. The exogenous wild-type p14ARF gene 
induces growth arrest and promotes radiosensitivity in human lung cancer cell lines. 
Cancer Res. Clin. Oncol. 127;359-367 (2001). 
Higgins GS, Prevo R, Lee YF, Helleday T, Muschel RJ, Taylor S, Yoshimura M, Hickson 
ID, Bernhard EJ, McKenna WG. A small interfering RNA screen of genes involved in 
DNA repair identifies tumor-specific radiosensitization by POLQ knockdown. Cancer Res, 
70(7):2984-93 (2010). 
Inui H, Oh KS, Nadem C, Ueda T, Khan SG, Metin A, Gozukara E, Emmert S, Slor H, 
Busch DB, Baker CC, DiGiovanna JJ, Tamura D, Seitz CS, Gratchev A, Wu WH, Chung 
KY, Chung HJ, Azizi E, Woodgate R, Schneider TD, Kraemer KH. Xeroderma 
pigmentosum-variant patients from America, Europe, and Asia. J Invest Dermatol.128(8): 
2055-2068 (2008). 
Johnson RE, Kondratick CM, Prakash S, Prakash L. hRAD30 mutations in the variant form 
of xeroderma pigmentosum. Science 285(5425): 263-265 (1999). 
Lally BE, Geiger GA, Kridel S, Arcury-Quandt AE, Robbins ME, Kock ND, Wheeler K, 
Peddi P, Georgakilas A, Kao GD, Koumenis C. Identification and biological evaluation of 
a novel and potent small molecule radiation sensitizer via an unbiased screen of a chemical 
library. Cancer Res. 67(18):8791-9 (2007). 
Lin Q, Clark AB, McCulloch SD, Yuan T, Bronson RT, Kunkel TA, Kucherlapati R. 
Increased susceptibility to UV-induced skin carcinogenesis in polymerase eta-deficient 
mice. Cancer Res. 66(1):87-94 (2006). 


 
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STUDY DEVICE:  SIR-Spheres® 
  
SCRI INNOVATIONS STUDY NUMBER: GI 189 
DATE OF ORIGINAL PROTOCOL:  16 December 2013 
Date of Amendment #1:  15 April 2014  
 
 
 
 
Version 2.0 
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NCI (2010) [online] Available at <http://www.cancer.gov/cancertopics/types/commoncancers> 
Martin LM, Marples B, Coffey M, Lawler M, Lynch TH, Hollywood D, Marignol. L. 
DNA mismatch repair and the DNA damage response to ionizing radiation: making 
sense of apparently conflicting data. Cancer Treat Rev 36(7):518-27 (2010). 
Masutani, C, Kusumoto R, Yamada A, Dohmae N, Yokoi M, Yuasa M, Araki M, Iwai S, 
Takio K, Hanaoka F. The XPV (xeroderma pigmentosum variant) gene encodes human 
DNA polymerase eta. Nature 399(6737): 700-704 (1999). 
Paz MF, Fraga MF, Avila S, Guo M, Pollan M, Herman JG, Esteller M. A systematic 
profile of DNA methylation in human cancer cell lines. Cancer Res. 63: 1114-1121 
(2003). 
Simon M, Voss D, Park-Simon TW, Mahlberg R, Köster G. Role of p16 and p14ARF in 
radio- and chemosensitivity of malignant gliomas. Oncology Reports 16: 127-132 
(2006). 
Slack A, Cervoni N, Pinard M, Szyf MM. Feedback regulation of DNA methyltransferase gene 
expression by methylation. Eur. J. Biochem. 264(1):191-9 (1999) 
 

SAP_001.pdf: 
 
 
GI 189 
Statistical Analysis Plan 
 
Version Draft 1.0, 22 MAY 2018 
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Master Statistical Analysis Plan Checklist  
for Investigator Initiated Trials 
 
 
 
 
 
 
A Two Arm Safety Study of Regorafenib before or after SIR-Spheres® Microspheres (90Y) for the 
Treatment of Patients with Refractory Metastatic Colorectal Cancer and Liver Metastases  
 
 
 
Sponsor: 
Sarah Cannon Development Innovations 
(Innovations) 
Study Drug: 
SIR-Spheres®  Microspheres 
Protocol Number: 
GI 189 
Prepared By: 
Innovations 
 


 
 
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Statistical Analysis Plan Checklist for Investigator Initiated Trials  
History of Changes 
 
This document has undergone the following changes: 
 
Version Number 
Version Date 
Description of Changes 
1.0 
22MAY2018 
Original document 
 


 
 
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1.1 Objectives 
 
Primary Objective: 
To evaluate the safety of two treatment cohorts combining regorafenib and SIR-Spheres 
microspheres (SIR-Spheres) radioemoblization in patients with refractory metastatic 
colorectal cancer (mCRC) with liver metastasis. 
Secondary Objectives: 
To evaluate the overall response rate (ORR), progression-free survival (PFS), and overall 
survival (OS) of patients with refractory mCRC when treated with combination SIR-
Spheres and regorafenib in the two sequencing cohorts. 
1.2 Study Design 
 
Study Type 
 Non-Randomized 
 Randomized (Allocation Ratio:      ) 
Details 
This is an open-label study comparing the safety of two treatment cohorts in which 
radioembolization will be administered using the device SIR-Spheres microspheres (90Y 
resin microspheres) in combination with regorafenib to patients with mCRC with liver 
metastases.  The two treatment cohorts will be evaluated for safety, ORR, PFS, and OS.  
Twenty-five patients will be treated in each cohort.  The first cohort will complete 
enrollment before the second cohort opens.  There will be no randomization or blinding.  
Blood samples will be collected from all patients prior to the hepatic angiogram and 
99mTc MAA lung shunt scan, on Day 8 after SIR-Spheres treatment, and Day 30 (pre-
dose) after SIR-Spheres treatment (see Section 5.1).  Expressions of cytokines and 
proteins will be measured to explore potential biomarkers that may correlate with clinical 
outcome. 
1.3.2 Randomization 
 
Randomization Type: 
 Open-Label           
 Single Blind           
 Double-Blind            
1.4 Timing of Analysis 
 
Planned Interim Analysis 
 Cohort Review / Dose Escalation 
 Safety Review 
 Interim Efficacy/Safety Analysis 
 Independent DMC/DSMB 
 Annual Report / Investigator Brochure (IB) 
 Abstract / Scientific Presentation (Oral/Poster) 
Final Analysis 
 6 months after last patient has been recruited into study 
1.5 Responsibilities 
 
Trial Statistician: 
Development of SAP and shells 
Review deliverables presented by statistical programmers 
PK Statistician: 
N/A 
Independent Statistician: 
N/A 


 
 
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1.6 Analysis Software 
 
Main statistical analysis: 
SAS Version 9.3 or above 
Other analysis software: 
None 
 
1.7 Coding 
 
 Adverse Events 
 Medical History 
 MedDRA:   
 Version                
 
 Most current release and update coding with new major releases 
 NCI-CTCAE Version       
 Concomitant Medication 
 Prior Therapy 
 Subsequent/Further 
Therapy 
 WHO-Drug:   
 Version                
 
 Most current release and update coding with new major releases 
3 Analysis Population 
 
Intent-To-Treat (ITT) 
Population definition: 
 All patients who have started treatment in the study 
 All patients who have been randomized in the study, regardless of whether they have 
received any treatment or not 
 All patients who have been randomized and have started treatment in the study 
 Other definition, specify:       
Per Protocol (PP) Population 
to be used in analysis: 
 Yes          
 No 
If yes, please specify the criteria for exclusion from the PP population: 
      
Safety (SAF) Population 
definition 
 All patients who have started treatment in the study. Patients will be analyzed according 
to the actual treatment they have received. 
 Other definition, specify:       
Other Analysis Population 
definition: 
N/A 
4 Baseline Value Definitions 
 
 
Last value prior to first date of study drug treatment 
5/6 Efficacy 
 
Response Criteria Used: 
 RECIST 1.0          
 RECIST 1.1         
 Cheson 2007 
 Modified RECIST – specify:               
 Other criteria, Specify:       


 
 
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Efficacy Assessment 
Timepoints: 
Assessed during treatment at week 6 and week 12. Patients continuing treatment after 
week 12 will be assessed at 8 week intervals. Patients with progressive disease (PD), 
unacceptable toxicity, or who withdraw consent will be removed from the study. 
Patients will be assessed at end of treatment visit 
During follow-up, patients will be assessed every 3 months up to 6 months. 
Efficacy Endpoints: 
 
 
Endpoint 
Primary Analysis 
Population 
Other Analysis 
Population 
Primary 
Overall Response 
Rate (ORR) 
ITT Population 
      
Secondary 
Progression-Free 
Survival (PFS) 
Overall Survival (OS) 
ITT Population 
      
  
Definition of Terms: 
 
 Response 
 Complete Response + Partial Response as best observed response 
 Complete Response + Partial Response, confirmed with 4 weeks apart.  
 Other criteria, specify:       
 Clinical Benefit 
 Complete Response + Partial Response + Stable Disease as best observed 
response 
 Complete Response + Partial Response (confirmed with       weeks apart) + 
Stable Disease (at least       weeks from start of treatment)  
 Other criteria, specify:       
      
 Progression 
As defined in Appendix C of the protocol. 
 Subsequent Therapy 
      
 Treatment Failure 
      
Definition of Endpoints: 
Start Date:  
 Date of Randomization         
 Date of First Treatment 
End Date (specify for all pertinent endpoints): 
Overall Survival: Event = Death 
Situation 
Date of Event or Censoring 
Outcome 
Death 
Date of death 
Event 
Alive on date of data cutoff 
Date last known alive 
Censored 
Alive before date of data cutoff, but status 
unknown on date of data cutoff (e.g. lost to 
follow-up) 
Date last known alive 
Censored 


 
 
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Progression-Free Survival: Event = Progression or Death  
Situation 
Date of Event or Censoring 
Outcome 
No baseline assessment 
Date of first treatment 
Censored 
Progression documented between scheduled 
visits 
First date of evaluated 
overall response = PD 
Event 
No progression 
Date of last evaluable 
tumor assessment 
Censored 
Treatment discontinuation for adverse event 
or other reason 
Date of last evaluable 
tumor assessment 
Censored 
Death before first PD assessment 
Date of death 
Event  
Death before the next scheduled tumor 
assessment 
Date of death 
Event  
Death after one missed tumor assessment 
but before second missed tumor assessment 
Date of death 
Event  
Death after two or more missed tumor 
assessment 
Date of last evaluable 
tumor assessment 
Censored 
 Overall Response Rate (ORR) 
Default: Estimates of rates in each treatment arm 
 Difference in rates & 95% confidence interval between treatment arms 
 p-value, specify statistical test:       
 Disease Control Rate (DCR) 
 Clinical Benefit Rate (CBR) 
 Early Progression Rate (EPR) 
 Time To Progression (TTP) 
Default: Estimates of medians in each treatment arm 
 Other quartiles or percentages of survival required, specify: probability evaluated at 
6 month intervals 
 Hazard ratio & 95% confidence interval between treatment arms, unstratified 
 p-value, specify statistical test:       
 Hazard ratio & 95% confidence interval between treatment arms, stratified (specify 
stratification factor(s)):       
 p-value, specify statistical test: 
 Progression-Free Survival 
(PFS) 
 Overall Survival (OS) 
 Duration of Response 
 Duration of Stable Disease 
 Time To Treatment Failure 
(TTF) 
 Other, Specify: 
 
7 Safety 
 
Adverse Events 
Definition of Treatment-Emergent Adverse Event (TEAE): any adverse event (AE) that 
starts or worsens after the start of the first dose of study treatment up to 30 days post 
last dose. 
Laboratory Data 
Data will be summarized by: 
 NCI-CTCAE for CTCAE-gradable parameters, and H/L for non-CTCAE-Gradable 
parameter 


 
 
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 H/L for all lab parameters 
 
Tier 1 Study – Tables, Figures & Listings 
Standard TFLs 
Table No 
Description 
Variables/Analyses To Be Included 
Subgroup Analyses 
Table 1 
Summary of Demographics and 
Disease Characteristics 
 Age: Median, Min, Max 
 Age Group:       
 Sex 
 Race 
 ECOG 
 Other, specify: Primary diagnosis, 
KRAS, BRAF 
Safety Analysis Set 
Table 2 
Summary of Metastatic Involvement at 
study entry 
 Histology 
 Disease Staging 
 Time from Diagnosis 
 Other, specify: sites of metastatic 
involvement (count and percent of 
patients per involved site) 
Safety Analysis Set 
Table 3 
Summary of Regorafenib Exposure and 
Treatment Modifications 
Treatment duration, number of patients 
with each treatment modification, 
reasons for dose modifications 
Safety Analysis Set 
Table 4 
Summary of SIR-Spheres Exposure 
Activity delivered to liver (mCi), lung 
shunt fraction, total tumor volume (mL): 
number of patients, Mean, SD, Median, 
Min, Max 
Treatment planning (left, right, whole): 
number and percent of patients 
Safety Analysis Set 
Table 4 
Summary of Treatment 
Discontinuations 
Number of patients with treatment 
discontinuation, reasons for treatment 
discontinuation 
Safety Analysis Set 
Table 5 
Summary of Best Overall Response 
Best overall response: Complete 
response (CR), Partial response (PR), 
Stable disease (SD), progressive 
disease (PD), not evaluable (NE) 
Objective response rate (ORR) (CR + 
PR): ORR, 95% Confidence interval 
CR and PR confirmed 
ITT Population/Efficacy 
Analysis Set 
Table 6 
Summary of Progression-Free Survival 
Kaplan-Meier  
Number of patients with events, 
Number of patients censored, Median, 
25th and 75th percentiles for progression 
free survival [months (95% CI)] 
Probability of events evaluated in 6 
month intervals 
ITT Population/Efficacy 
Analysis Set 
Table 7 
Summary of Overall Survival 
Kaplan-Meier 
ITT Population/Efficacy 
Analysis Set 


 
 
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Confidential 
 
Standard TFLs 
Table No 
Description 
Variables/Analyses To Be Included 
Subgroup Analyses 
Number of patients with events, 
Number of patients censored, Median, 
25th and 75th percentiles for overall 
survival [months (95% CI)] 
Probability of events evaluated in 6 
month intervals 
Table 8 
Summary of Treatment-Related 
Adverse Events 
Sarah Cannon/Modified CTCAE coding 
By CTCAE grade 
Safety Analysis Set 
 
Figure 
No 
Description 
Variables/Analyses To Be Included 
Subgroup Analyses 
Figure 1 
Progression-Free Survival 
Timescale to be used on horizontal 
axis: 
 Day  
 Week 
 Month 
 Year 
ITT Population/Efficacy 
Analysis Set 
Figure 2 
Overall Survival 
Timescale to be used on horizontal 
axis: 
 Day  
 Week 
 Month 
 Year 
ITT Population/Efficacy 
Analysis Set