Conditions: Carcinoma, Hepatocellular Metastatic Colorectal Cancer
Keywords: mCRC, HCC, radiopaque beads, vandetanib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
This is a pilot, open label single arm phase 0 window of opportunity study of vandetanib-eluting radiopaque beads in patients with resectable liver malignancies.

Detailed description:
A pilot open-label single arm multicenter phase 0 window of opportunity study of BTG-002814 given up to 3 weeks prior to surgery in up to 12 patients with resectable Hepatocellular carcinoma (HCC) or Colorectal cancer (CRC) with liver metastases.

Arms:
arm 1: Single arm: BTG-002814 (vandetanib-eluting radiopaque beads)

Interventions: intervention 1: BTG-002814
Intervention descriptions: intervention 1: BTG-002814 containing 100 mg vandetanib

Protocol document:
Prot_001.pdf: 
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Page 1 of 68  
Biocompatibles UK Ltd  
  
Protocol Number:  
BTG-002814-01  
Protocol Short Title:  
VEROnA: A window of opportunity study of vandetanib-eluting 
radiopaque beads (BTG-002814) in patients with resectable liver 
malignancies  
Protocol Name:  
A pilot, open label, single-arm, phase 0, window of opportunity 
study 
of 
vandetanib-eluting 
radiopaque 
embolic 
beads 
(BTG002814) in patients with resectable liver malignancies  
Global Sponsor:  
Biocompatibles UK Ltd, a BTG International group company  
Lakeview  
Riverside Way  
Watchmoor Park  
Camberley  
Surrey GU15 3YL, UK  
Chief Investigator:  
Professor Ricky Sharma  
Chair of Radiation Oncology  
University College London  
Cancer Institute, Paul O’Gorman Building   
72 Huntley Street  
London  
WC1E 6DD  
Protocol Medical Monitor:  
Dr Eveline Boucher  
Biocompatibles UK Ltd, a BTG International group company  
Lakeview  
Riverside Way  
Watchmoor Park  
Camberley  
Surrey GU15 3YL, UK  
Investigational Product  
BTG-002814, vandetanib-eluting radiopaque embolic beads   
EudraCT Number  
2016-004164-19  
Protocol ver.6.0 Approval 
Date:  
03 December 2018  
This document is the confidential property of the Sponsor. No part of it may be transmitted, reproduced, published, or 
used by other persons without prior written permission.    


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Table 1. Protocol Revision History  
VERSION 
NUMBER  
AMENDMENT  
APPROVAL  
DATE  
BRIEF DESCRIPTION OF CHANGES  
1.0  
  
Original protocol  
2.0  
24 Nov 2016  
Correction of Hb value in Inclusion Criterion 5  
3.0  
18 Jan 2017  
Amendment of serum bilirubin Inclusion Criterion 6  
Specification of laboratory tests in Exclusion Criterion 10  
Defining abstinence in Section 5.3 Reproductive Potential  
Addition of advice to minimize exposure to Ultra Violet light 
in Section 6.12 Safety Criteria for Adjusting or Stopping 
Treatment  
Addition of Thyroid Stimulating Hormone (TSH) to Section 
7.3.8 Clinical Laboratory Evaluations  
Addition of reference to MHRA guidance for regulatory 
reporting of Urgent Safety Issues to Section 11.9  
  
4.0  
03 Mar 2017  
Schema, schedule of events and section 7.2.5 updated 
stating all visit 4 assessments to be repeated if surgery is 
delayed > 7 days  
Biochemistry and Haematology analysis moved V2 to V3.   
Term “blood urea nitrogen” changed to “urea” throughout  
Term “glucose” changed to “random glucose” throughout  
Term “uric acid” changed to “urate” throughout  
“Peak” HR and BP to be collected post treatment at visit 2  
Visit 2 note stating treatment not to take place on Fridays  
7.3.14 Vandetanib plasma analysis changed blood sample 
volume from 2mL to 4mL  
7.3.8. Biochemistry added calculated GFR  
8.1.3 Recording of “time” for Adverse Events removed from 
onset and resolution  
8.1.6 BTG responsible for sponsor causality assessment 
and section re-ordered  
8.1.7 BTG responsible for preparing DSURs and CTC for 
submitting these to the CA and EC  


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5.0  
26 Mar 2018  
The Study Physician role has been transferred from Dr 
Nermeen Varawalla (Biocompatibles UK Ltd) to Dr Eveline 
Boucher (Biocompatibles UK Ltd)).  
 
 
Study Summary – Study Design - Changed “total” to 
“target” sample size to be consistent with the intention of 
the sample size, as outlined in Section 9.1 - Study Design 
and Determination of Sample Size  
5.3  All references to Females Of Child-bearing Potential 
(FOCP) have now been updated to Women Of Child-bearing 
Potential (WOCBP) and a definition of WOCBP has been 
included for clarity).  
5.6  Rephrased sentence to better define “Lost-to-Follow 
Up”  
7.3.5  FOCP has been changed to WOCBP for consistency  
7.3.8 Removed “Reticulocyte count” as a required 
investigation for Haematology  
7.3.14 Added a window of ± 15 mins for the Vandetanib 
plasma samples taken at 2 hours and 4 hours, and a window 
of ± 1 hour for the Vandetanib plasma sample taken at 24 
hours post administration of BTG-002814  
8.2.7 Extended the window for Visit 6 End of Study 
assessments to from 30-32 to 28-32 days  
10.3 Removed specified timelines for CRF return   
11.5 Removed the requirement to collect date of birth for 
patient registration   
11.9.2  Added section to define “Serious Breaches” of 
ICHGCP  
11.14 Added notification that BTG Clinical Quality may audit 
sites as anytime during the study  
Minor formatting updates throughout the document  
  


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6.0  
03 Dec 2018  
Change on BTG Senior Member of Clinical Development 
protocol signatory  
Change of BTG Biostatistical protocol signatory  
4.2.3 & 4.5.3 Additional exploratory Objective/endpoint to 
explore key immune, inflammatory and drug related 
mechanism on resected tumour tissue  
5.2.1 Amendment of required platelet count Inclusion 
Criterion 5  
7.2.5 Window added for Visit 4  
7.2.6 Liver biomarker analysis added to Visit procedures  
7.3.16 Clarification of the biomarker analysis on the resected 
liver tissue   
  
  
PROTOCOL APPROVAL & RELEASE 
SIGNATURE PAGE  
Protocol Number:  
BTG-002814-01  
Protocol Short Title:  
VEROnA: A window of opportunity study of vandetanib-eluting radiopaque beads (BTG-
002814) in patients with resectable liver malignancies  
Protocol Name:  
A pilot, open label, single-arm, phase 0, window of opportunity study of 
vandetanibeluting radiopaque embolic beads (BTG-002814) in patients with resectable 
liver malignancies  
Protocol Version:  
Version 6.0  
Protocol Approval Date:  
03 December 2018  
The above-referenced protocol was reviewed and approved for release by the following:  
  
Approver  
Signature and Date  
Chief Investigator  
  
Prof Ricky Sharma  
  
 
Sponsor: Manager, Clinical Development  
  
Sarah Cooper  
  
 
  
  
  
  
  
  


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Biocompatibles UK Ltd  
Sponsor: Project Physician  
  
Dr Eveline Boucher  
  
 
Sponsor: VP, IO Clinical Development  
  
Henk Tissing  
  
 
Sponsor: Statistician  
  
Sam Ryan  
  
 
  
INVESTIGATOR PROTOCOL REVIEW 
STATEMENT  
Protocol Number:  
BTG-002814-01  
Protocol Short Title:  
VEROnA: A window of opportunity study of vandetanib-eluting radiopaque beads (BTG-
002814) in patients with resectable liver malignancies  
Protocol Name:  
A pilot, open label, single-arm, phase 0, window of opportunity study of 
vandetanibeluting radiopaque embolic beads (BTG-002814) in patients with resectable 
liver malignancies  
Protocol Version:  
Version 6.0  
Protocol Approval Date:  
03 December 2018       
  
The site Principal Investigator (undersigned) hereby declares that he/she has read this protocol 
and agrees to its contents.  
The undersigned confirms that the trial will be conducted and documented in accordance with the 
Declaration of Helsinki, the protocol, standards of Good Clinical Practice, applicable laws and 
regulatory requirements specified in the protocol, and the stipulations of the clinical trial 
agreement.  
By written consent to this protocol, the investigator agrees to the above and to fully co-operate 
with all monitoring and audits in relation to this trial by allowing direct access to all documentation, 


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including source data, by authorised individuals representing Biocompatibles UK Ltd, REC and/or 
by competent authorities.  
  
Investigator Name (please print): ___________________________________________  
  
Investigator Signature:    
  
___________________________________________  
  
Date (DD/MMM/YYYY):  
  
___________________________________________  
  
  
  
  
TABLE OF CONTENTS, LISTS OF 
TABLES   
1.  SCHEMA ............................................................................................................................................... 19 
2.  SCHEDULE OF VISITS ........................................................................................................................ 19 
3.  BACKGROUND .................................................................................................................................... 22 
3.1.  DISEASE BACKGROUND ..................................................................................................................... 22 
3.2.  GENERAL DESCRIPTION OF INVESTIGATIVE AGENT(S)/DEVICE ............................................................. 24 
3.3.  PRE-CLINICAL BACKGROUND OF INVESTIGATIVE AGENT(S)/DEVICE ..................................................... 26 
4.  STUDY RATIONALE, OBJECTIVES AND DESIGN ............................................................................ 28 
4.1.  STUDY RATIONALE ............................................................................................................................ 28 
4.2.  STUDY OBJECTIVES .......................................................................................................................... 28 
4.2.1.  Primary Objectives................................................................................................................... 28 
4.2.2.  Secondary Objectives .............................................................................................................. 28 
4.2.3.  Exploratory Objective............................................................................................................... 28 
4.3.  STUDY DESIGN ................................................................................................................................. 29 
4.3.1.  Study Design Flow Chart ......................................................................................................... 29 
4.3.2.  Summary of Study Design ....................................................................................................... 29 
4.4.  RANDOMISATION ............................................................................................................................... 29 
4.5.  STUDY ENDPOINTS ........................................................................................................................... 30 
4.5.1.  Co-Primary Endpoints ............................................................................................................. 30 
4.5.2.  Secondary Endpoints .............................................................................................................. 30 
4.5.3.  Exploratory Endpoints ............................................................................................................. 30 
5.  PATIENT SELECTION .......................................................................................................................... 31 
5.1.  PATIENT POPULATION ....................................................................................................................... 31 
5.2.  SUBJECT SELECTION......................................................................................................................... 31 
5.2.1.  Inclusion Criteria ...................................................................................................................... 31 
5.2.2.  Exclusion Criteria ..................................................................................................................... 31 
5.3.  REPRODUCTIVE POTENTIAL ............................................................................................................... 32 
5.4.  PATIENT COMPLETION ....................................................................................................................... 32 
5.5.  PATIENT WITHDRAWAL ...................................................................................................................... 32 
5.6.  PATIENTS “LOST TO FOLLOW-UP” PRIOR TO LAST SCHEDULED VISIT ................................................... 33 
6.  TREATMENT OF PATIENTS ................................................................................................................ 34 


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6.1.  VANDETANIB-ELUTING RADIOPAQUE BEAD (BTG-002814) .................................................................. 34 
6.1.1.  Dosage & Administration ......................................................................................................... 34 
6.1.2. Safety Criteria for Adjusting or Stopping Treatment ................................................................. 35 
6.1.3. Post-study Management ........................................................................................................... 35 
6.1.4.  Duration of Treatment and Follow up ...................................................................................... 35 
6.1.5.  Concomitant Medications ........................................................................................................ 35 
6.2.  INVESTIGATIONAL PRODUCT/LABELING/PACKAGING/STORAGE/ HANDLING ........................................... 36 
6.2.1. Investigational Product ............................................................................................................. 36 
6.2.2. Labeling and Packaging ........................................................................................................... 36 
6.2.3. Storage and Handling ............................................................................................................... 36 
6.2.4.  Accountability ........................................................................................................................... 36 
7.  STUDY PROCEDURES ........................................................................................................................ 38 
7.1.  STUDY SCHEDULE............................................................................................................................. 38 
7.2.  SCHEDULE OF VISITS, PROCEDURES, AND EVALUATIONS .................................................................... 38 
7.2.1.  Visit 0: Screening (up to 7 days before registration) ............................................................... 38 
7.2.2.  Visit 1: Baseline Visit (up to 7 days before treatment) ............................................................. 38 
7.2.3.  Visit 2: Treatment Day ............................................................................................................. 39 
7.2.4.  Visit 3 (Day 1 after treatment) .................................................................................................. 39 
7.2.5.  Visit 4 (Up to and including 3 days prior to surgical resection) ............................................... 40 
7.2.6.  Visit 5 Surgical Resection (7 to 21 days following treatment with BTG-002814) .................... 40 
7.2.7.  Visit 6 End of Study/Early Withdrawal (28-32 days post-surgery) ........................................... 40 
7.3.  STUDY EVALUATIONS AND PROCEDURES ........................................................................................... 41 
7.3.1.  Informed Consent Process ...................................................................................................... 41 
7.3.2.  Demographics .......................................................................................................................... 43 
7.3.3.  Medical History ........................................................................................................................ 43 
7.3.4.  Physical Examination............................................................................................................... 43 
7.3.5.  Vital Signs ................................................................................................................................ 43 
7.3.6.  Performance Status ................................................................................................................. 43 
7.3.7. Medication and Prior Treatment History ................................................................................... 44 
7.3.8. Clinical Laboratory Evaluations – Biochemistry, Coagulation Parameters, Haematology ....... 44 
7.3.9. Pregnancy Test ......................................................................................................................... 45 
7.3.10. Serum Tumour Markers .......................................................................................................... 45 
7.3.11.  Imaging including Dynamic Imaging ...................................................................................... 45 
7.3.12.  ECG Assessment .................................................................................................................. 46 
7.3.13.  Blood Biomarkers .................................................................................................................. 46 
7.3.14.  Vandetanib and N-desmethyl metabolite Plasma Sampling and Analysis ............................ 47 
7.3.15.  Vandetanib and N-desmethyl metabolite Liver Sampling and Analysis ................................ 47 
7.3.16.  Surgical Resection and Local Histopathological Assessment and Procedures .................... 47 
7.3.17.  Eligibility Review .................................................................................................................... 48 
7.3.18.  Patient Registration ............................................................................................................... 48 
7.3.19.  Study Medication Treatment Record ..................................................................................... 48 
7.3.20.  Concomitant Medication Record ........................................................................................... 49 
7.3.21.  Observation and Recording of Adverse Events .................................................................... 49 
8.  ADVERSE EVENTS .............................................................................................................................. 50 
8.1.  ADVERSE EVENT DEFINITIONS ........................................................................................................... 50 
8.1.1.  Adverse Event (AE) ................................................................................................................. 50 
8.1.2.  Serious Adverse Event (SAE) ................................................................................................. 50 
8.1.3.  Recording Adverse Events ...................................................................................................... 50 
8.1.4.  Causality (Relationship to Drug) Assessment ......................................................................... 51 
8.1.5.  Reporting Serious Adverse Events .......................................................................................... 51 
8.1.6.  SAE Processing at UCL CTC .................................................................................................. 51 


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8.1.7.  Adverse Event Reporting ......................................................................................................... 52 
8.1.8.  Safety Profile of BTG-002814 .................................................................................................. 52 
9.  STATISTICAL CONSIDERATIONS ...................................................................................................... 52 
9.1.  STUDY DESIGN AND DETERMINATION OF SAMPLE SIZE ....................................................................... 52 
9.2.  STATISTICAL ANALYSIS ...................................................................................................................... 53 
9.2.1.  Analysis Populations and Sub-Groups .................................................................................... 53 
9.3.  BASELINE AND DEMOGRAPHIC CHARACTERISTICS .............................................................................. 53 
9.4.  EFFICACY ANALYSES......................................................................................................................... 53 
9.4.1.  Vandetanib concentration ........................................................................................................ 53 
9.4.2.  Distribution of BTG-002814 ..................................................................................................... 53 
9.4.3. Histopathology of resected liver ............................................................................................... 54 
9.4.4. 3D modelling ............................................................................................................................. 54 
9.4.5.  Blood flow following embolisation ............................................................................................ 54 
9.4.6.  Biomarker analysis .................................................................................................................. 54 
9.5.  SAFETY ANALYSES ............................................................................................................................ 54 
9.5.1.  Adverse Events ........................................................................................................................ 54 
9.5.2.  Laboratory Parameters ............................................................................................................ 54 
9.5.3.  Other Safety Parameters ......................................................................................................... 54 
9.6.  INTERIM SAFETY ANALYSIS ................................................................................................................ 55 
10.  DATA MANAGEMENT ....................................................................................................................... 56 
10.1. COMPLETING CASE REPORT FORMS ................................................................................................. 56 
10.2. MISSING DATA ................................................................................................................................. 56 
10.3. TIMELINES FOR DATA RETURN .......................................................................................................... 56 
10.4. DATA QUERIES ................................................................................................................................ 56 
11.  LEGAL/ETHICS AND ADMINISTRATIVE PROCEDURES ............................................................... 58 
11.1. GOOD CLINICAL PRACTICE/REGULATORY COMPLIANCE ..................................................................... 58 
11.2. STUDY SITE AND INVESTIGATOR QUALIFICATION ................................................................................ 58 
11.2.1.  Investigator Curriculum Vitae (CV) ........................................................................................ 58 
11.2.2.  Site qualifications and study-specific procedural training ...................................................... 58 
11.2.3.  Laboratory Certification and Normal Values .......................................................................... 59 
11.3. INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT ETHICS COMMITTEES (IEC) ................................ 59 
11.3.1.  Institutional Approval of the Protocol ..................................................................................... 59 
11.3.2.  IRB/Ethics Committee Membership Roster ........................................................................... 59 
11.4. INFORMED CONSENT ........................................................................................................................ 59 
11.5. PATIENT PRIVACY AND CONFIDENTIALITY .......................................................................................... 60 
11.6. STUDY MONITORING ........................................................................................................................ 60 
11.7. MODIFICATION OF THE PROTOCOL .................................................................................................... 61 
11.8. SUSPENSION OR TERMINATION OF STUDY ......................................................................................... 61 
11.9. DEPARTURE FROM PROTOCOL .......................................................................................................... 61 
11.9.1.  Protocol Deviations ................................................................................................................ 61 
11.9.2.  Serious Breaches .................................................................................................................. 62 
11.10.  RECORDING, ACCESS TO AND RETENTION OF SOURCE DATA .......................................................... 62 
11.11.  SOURCE DOCUMENTS AND CASE REPORT FORMS .......................................................................... 63 
11.12. END OF STUDY .............................................................................................................................. 63 
11.13. PUBLICATIONS ............................................................................................................................... 63 
11.14.  AUDIT/INSPECTIONS ...................................................................................................................... 63 
12.  BIBLIOGRAPHY ................................................................................................................................. 63 
APPENDIX 1. MEDICATIONS KNOWN TO PROLONG QT INTERVAL AND/OR INDUCE TORSADES 
DE POINTES .............................................................................................................................................. 66 


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LIST OF TABLES  
Table 1. Protocol Revision History ............................................................................................. 2  
Table 2. Terms, acronyms, abbreviations. .................................................................................10  
Table 3. Drugs that are generally accepted by authorities to have a risk of causing Torsades de  
Pointes (TDP) ...........................................................................................................................65  
Table 4. Drugs that in some reports may be associated with Torsades de Pointes but at this time 
lack substantial evidence of causing Torsades de Pointes ................................................66  
  
  
  


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Table 2. Terms, acronyms, abbreviations.  
The following abbreviations and specialist terms are used in this protocol.  
AASLD  
American Association of the study of Liver Diseases  
AE  
Adverse Event  
AFP  
Alpha Feto Protein  
ALT  
Alanine Aminotransferase  
ALP  
Alkaline Phosphatase  
ANC  
Absolute neutrophil count  
AST  
Aspartate Aminotransferase  
ATC  
Anatomical-Therapeutic-Chemical  
BP  
Blood Pressure  
Cmax  
Maximum Concentration  
CRC  
Colorectal Cancer  
CRF  
Case Report Form  
CT  
Computerised Tomography  
cTACE  
Conventional Transarterial Chemoembolisation  
CTCAE  
Common Terminology Criteria for Adverse Events  
CV  
Curriculum Vitae  
DCE-MRI  
Dynamic Contrast-Enhanced Magnetic Resonance Imaging  
DEB-TACE  
Drug Eluting Bead Transarterial Chemoembolisation  
DLT  
Dose-Limiting Toxicity  
DMP  
Data Management Plan  
DSUR  
Development Safety Update Report  
EASL  
European Association for the Study of the Liver  
ECG  
Electrocardiogram  
EGFR  
Endothelial Growth Factor Receptor  
FOLFIRI  
FOLinic acid, Fluorouracil, Irinotecan  


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FOLFOX  
FOLinic acid, Fluorouracil, OXaliplatin  
GCP  
Good Clinical Practice  
GFR  
Glomerular Filtration Rate  
GGT  
Gamma Glutamyl Transferase  
GLP  
Good Laboratory Practice  
GMP  
Good Manufacturing Practice  
Hb  
Haemoglobin  
HCC   
Hepatocellular Carcinoma  
hCG  
Human Chorionic Gonadotropin  
HGF  
Hepatocyte Growth Factor  
HR  
Heart Rate  
IB  
Investigator’s Brochure  
ICF  
Informed Consent Form  
ICH  
International Council for Harmonisation  
INR  
International Normalised Ratio  
IP  
Investigational Product  
kg  
Kilogram  
LDH  
Lactate dehydrogenase  
mCRC  
Metastatic colorectal cancer  
MCV  
Mean Corpuscular Volume  
MedDRA  
Medical Dictionary for Regulatory Activities  
mg  
Milligram  
MHRA  
Medicines and Healthcare products Regulatory Agency  
mL  
Millilitre  
MRI  
Magnetic Resonance Imaging  
MTD  
Maximum Tolerated Dose  


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NCI  
National Cancer Institute  
NSCLC  
Non-Small-Cell Lung Cancer  
OS  
Overall Survival  
PDGFR  
Platelet-Derived Growth Factor Receptor  
PFS  
Progression Free Survival  
PI  
Principal Investigator  
Plt  
Platelets  
PS  
Performance Status  
PT  
Prothrombin Time  
PTT  
Partial Thromboplastin Time  
PV  
Pharmacovigilance  
RBC  
Red Blood Cells  
REC  
Research Ethics Committee  
RET  
Rearranged during Transfection  
RO  
Radiopaque  
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SC  
Safety Committee  
SoDA  
Summary of Drug Arrangements  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
TACE  
Transarterial chemoembolisation  
TDP  
Torsades de Pointes  
UAE  
Unexpected Adverse Event  
UCL CTC  
University College London Cancer Trials Centre  
ULN  
Upper Limit of Normal  
ver.  
Version  
VEGF  
Vascular Endothelial Growth Factor  


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VEGFR  
Vascular Endothelial Growth Factor Receptor  
WBC  
White Blood Cell  
WHO  
World Health Organisation  
WOCBP  
Women Of Child-bearing Potential  
YBS  
York Bioanalytical Solutions  
  
  
  
PROTOCOL SYNOPSIS  
Protocol Number  
BTG-002814-01  
Protocol Short Title  
VEROnA: A window of opportunity study of vandetanib-eluting 
radiopaque beads (BTG-002814) in patients with resectable liver 
malignancies  
Protocol Title  
A pilot, open label, single arm, phase 0, window of opportunity study 
of vandetanib-eluting radiopaque embolic beads (BTG-002814) in 
patients with resectable liver malignancies  
Investigational Product  BTG-002814 (vandetanib-eluting radiopaque embolic beads)  
Type of Study  
Phase 0, Window of Opportunity  


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Study Rationale  
Transarterial chemoembolisation (TACE) is the current standard of 
care for patients with intermediate-stage hepatocellular carcinoma 
(HCC) and is also a treatment option for patients with metastatic 
colorectal cancer (mCRC). Despite advances and technical 
refinements of TACE, including the introduction of drug-eluting beads 
(DEB)-TACE, the long term survival of patients managed with TACE 
has not been optimised, and tumour recurrence occurs in more than 
half of patients treated. Improving the DEB-TACE administration 
technique and investigating the ability to deliver new anti-cancer 
drugs locally to the tumour via TACE are important research 
approaches to improve the outlook for patients with primary and 
secondary liver cancer.  
The combination of a new radiopaque bead , that can be visualised 
on CT scans, pre-loaded with vandetanib, a tyrosine kinase inhibitor, 
that targets both VEGFR and EGFR signaling pathways, is a “dual” 
innovation that could enhance DEB-TACE significantly compared to 
current liver-directed therapies.  
This first-in-human study of this new technology will study safety and 
tolerability in patients with resectable HCC or mCRC. TACE is 
currently used in the pre-surgical setting to downstage cancers prior 
to resection or to stop cancers from growing while patients are on the 
waiting list for surgery. Studying this new drug for DEB-TACE prior 
to surgery provides an opportunity to confirm the levels of vandetanib 
in the cancer and in liver tissue.  
Study Objectives  
Primary objectives:  
• 
To assess the safety and tolerability of treatment with BTG002814 
• 
Measure the plasma and resected liver tissue concentrations of 
vandetanib and the N-desmethyl metabolite following treatment 
with BTG-002814  
Secondary objectives:  
• 
Evaluate the anatomical distribution of BTG-002814 on 
noncontrast enhanced imaging using 4D CT  
• 
Evaluate histopathological features in the surgical specimen 
following treatment with BTG-002814  
 
• 
Assess changes in blood flow on dynamic contrast-enhanced 
magnetic resonance imaging (DCE-MRI) following treatment with 
BTG-002814  
Exploratory Objectives:  
• 
Study blood biomarkers with the potential to identify patients likely 
to respond to treatment with BTG-002814   
• 
Study tissue biomarkers to explore key immune, inflammatory and 
drug related mechanisms  
• 
Correlate the distribution of BTG-002814 on imaging with 
pathology by 3D modelling  


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Co-Primary Endpoints  • 
Adverse events (AEs) related to treatment with BTG-002814 
using the standardised grading criteria (National Cancer Institute- 
Common Terminology Criteria for Adverse Events- Version 4.0 
(NCI-CTCAE v4.0))  
• 
Concentration of vandetanib and N-desmethyl vandetanib in 
plasma and in resected liver tissue following treatment with 
BTG002814.  
Secondary Endpoints  
• 
Distribution of BTG-002814 on non-contrast enhanced imaging 
of tumour vasculature and regions of interest using 4D CT  
• 
Evaluation of histopathological features in the surgical specimen 
(malignant and non-malignant liver tissue): tumour necrosis, 
viable tumour, vascular changes  
• 
Assessment of changes in blood flow on DCE-MRI following 
treatment with BTG-002814.  The following parameters will be 
derived from DCE-MRI images:  Ktrans, Kep and Ve  
Exploratory Endpoints  • 
Study blood biomarkers with the potential to identify patients likely 
to respond to treatment with BTG-002814   
• 
Study tissue biomarkers to explore key immune, inflammatory and 
drug related mechanisms  
• 
Correlate the distribution of BTG-002814 on imaging with 
pathology by 3D modelling  
Study Duration  
The study duration is up to 9 weeks per patient (up to 1 week 
screening, up to 1 week baseline prior to treatment plus up to 3 
weeks for surgery, followed by 4 weeks follow-up)  
A Baseline period of up to 7 days is followed by treatment with 
BTG002814 at Visit 2.  
Surgical resection will occur 7 to 21 days following treatment with 
BTG-002814.  
The End of Study visit (Visit 6), will occur 28-32 days after surgery.  
Study Design  
• 
Open-label, single arm, multicentre, phase 0, window of 
opportunity study of BTG-002814 up to 3 weeks prior to surgical 
resection  
• 
Three patients with HCC and/or liver metastases from CRC who 
are candidates for surgery will initially be enrolled to receive one 
treatment of BTG-002814   
 
• 
An interim analysis conducted by a safety committee (SC) is 
planned when the first three patients complete the last follow-up 
visit scheduled at 4 weeks after surgery.   
• 
If the SC deems that there is no significant toxicity related to 
BTG002814, a further 9 patients will be enrolled in order to have 
a target sample size in the study of 6 patients with liver 
metastases from CRC and 6 patients with HCC.  


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Study Population  
Patients with radiologically and/or histologically confirmed diagnosis 
of HCC or histologically confirmed diagnosis of CRC with liver 
metastases deemed suitable for liver surgery  
Total Number of 
Patients  
12 patients (replacement of up to 2 patients is permitted if patients do 
not complete the study investigations and follow-up)  
Number & Location of 
Sites  
University College London Hospitals NHS Trust and Royal Free 
London Hospital NHS Trust  
Study Treatment   
Single treatment arm   
Patients will receive one treatment of BTG-002814 (1 mL BTG002814 
containing 100 mg vandetanib)  
Inclusion/Exclusion 
Criteria  
Inclusion Criteria  
1. Male or female adults (≥ 18 years old)  
2. Patient with resectable HCC (Child Pugh A, INR ≤1.5) or 
resectable liver metastases from CRC and a candidate for 
liver surgery    
3. Patients with low risk for surgical morbidity and mortality from 
liver surgery according to the investigators judgement  
4. WHO performance status 0, 1 or 2   
5. Adequate haematological function with Hb >90 g/L, absolute 
neutrophil count >1.5 x 109/L, Plt >75 x 109/L  
6. Adequate liver function with serum bilirubin <1.5 x ULN, ALT 
(or AST if ALT not available) ≤5 x ULN, ALP <5 x ULN  
7. Adequate renal function with serum creatinine ≤1.5 x ULN and 
calculated creatinine clearance (GFR) ≥50 mL/min estimated 
using a validated creatinine clearance calculation (e.g. 
Cockroft-Gault or Wright formula).  
8. Patient is willing to provide blood samples, and tissue samples 
at surgical resection, for research purposes   
9. Patient is willing and able to provide written informed consent 
Exclusion Criteria  
1. 
Any systemic chemotherapy within 3 months of the 
screening visit or any plan to administer systemic 
chemotherapy prior to surgery  
2. 
Previous treatment with transarterial embolisation (with or 
without chemotherapy) of the liver, prior radiotherapy or 
ablation therapy to the liver or prior yttrium-90 microsphere 
therapy  
3. 
Any contraindication to vandetanib according to its local label 
including:  
o  Hypersensitivity to the active substance  


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o Congenital long QTc syndrome  
o Patients known to have a QTc interval over 480 milliseconds 
o Concomitant use of medicinal products known to also prolong 
the QTc interval and/or induce Torsades de pointes (see 
Appendix 1)  
4. Any contraindication to hepatic artery catheterisation or 
hepatic 
embolisation 
procedures 
(e.g. 
portal 
venous 
thrombosis, severely reduced portal venous flow or 
hepatofugal blood flow, untreated varices at high risk of 
bleeding)  
5. Women of child-bearing potential not using effective 
contraception or women who are breast feeding  
6. Confirmed allergy to iodine-based intravenous contrast media 
7. Patients who cannot have CT, MRI or DCE-MRI Imaging  
(according to site policy)  
8. Active uncontrolled cardiovascular disease  
9. Any co-morbid disease or condition or event that, in the 
investigator’s judgment, would place the patient at undue risk 
and would preclude the safe use of BTG-002814  
10. Levels of potassium, calcium, magnesium or thyroid 
stimulating hormone (TSH) outside the normal ranges, and 
that in the investigator’s judgement are clinically significant, or 
other laboratory findings that in the view of the investigator 
makes it undesirable for the patient to participate in the study  
11. Patients who have participated in another clinical trial with an 
investigational product within 4 weeks prior to the screening 
visit   
Imaging Requirements  • 
CT scan chest, abdomen, liver, pelvis, incorporating perfusion CT 
of liver at baseline, within a day prior to treatment, and the day 
before surgery. If surgery is delayed more than 7 days, the CT 
scan should be repeated the day before the re-scheduled 
surgery.  
• 
4D CT scan of liver on the day after treatment.  
• 
Liver MRI, incorporating DCE-MRI at baseline, within a day prior 
to treatment, and the day before surgery. If surgery is delayed 
more than 7 days, the MRI scan should be repeated the day 
before the re-scheduled surgery.  
Plasma sampling and 
analysis - vandetanib 
and N-desmethyl 
metabolite  
Plasma sampling will be performed in all patients immediately before 
treatment and at 2 hours (± 15 mins), 4 hours (± 15 mins), and 24 
hours (± 1 hour) after treatment. Samples also to be taken within 24 
hours prior to surgery and at End of Study visit.  
If patients require a longer hospital stay, an optional additional sample 
can be taken after 36 hours and up to the time of discharge.   


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Liver tissue sampling 
and analysis - 
vandetanib and 
Ndesmethyl metabolite  
Samples of liver tissue (both malignant and non-malignant) will be 
collected for analysis.  
Blood and tissue 
biomarker analysis  
Blood biomarkers will be measured to indicate the activity of the 
investigational treatment on the target cancer, specifically cytokines, 
chemokines and growth factors relevant to cancer and inflammation. 
Blood samples will be taken for the measurement of serum 
alphafetoprotein (AFP) in patients with HCC, and serum CEA, CA19-
9 and CA125 in patients with mCRC.  
Resected liver tumour tissue will be analysed to explore key immune, 
inflammatory and drug related mechanisms.  
Safety Committee  
A safety committee (SC) will review study data as detailed in the 
charter. The SC will review all AEs and SAEs.   
An Interim analysis is planned when the first three patients complete 
the last follow-up visit scheduled at 4 weeks after surgery.  
If the SC deem that there is no significant toxicity related to 
BTG002814 to prevent additional recruitment, a further 9 patients will 
be enrolled.  
Sample Size  
Justification  
A target sample size of 6 patients with each primary diagnosis is 
deemed to be sufficient to assess the safety and drug concentrations 
in plasma and resected specimens following treatment.  
Statistical Methods  
The number (n) and percentages (%) of patients with adverse events 
(AEs), and with AEs related to the study treatment, will be summarised 
overall and by system/organ class and preferred term (MedDRA). AEs 
will also be tabulated by intensity, treatment, outcome and causality. 
Deaths, serious adverse events (SAEs), AEs leading to withdrawal 
and Unexpected Adverse Events (UAE) will be listed separately.   
For all other endpoints, categorical results will be reported as numbers 
and percentages, and continuous results will be summarised 
descriptively with mean, standard deviation, median and range 
(minimum and maximum).   
Procedures in  
Screening/Baseline 
Period  
See Schedule of Visits  
Study Visits and Follow-
up  
See Schedule of Visits  
Visits extra to standard care for the clinical study:  Screening and 
Baseline visits, BTG-002814 treatment visit (1 to 2 nights as an 
inpatient procedure) and end of study visit, 4 weeks post-surgery   
The trial will be conducted and documented in accordance with the Declaration of Helsinki, the 
protocol, standards of Good Clinical Practice, applicable laws and regulatory requirements 
specified in the protocol, and the stipulations of the clinical trial agreement.  


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1. 
SCHEMA  
 
   
  
2. 
SCHEDULE OF VISITS  
Study Visit  
Visit 0  
Visit 1  
Visit 2  
Visit 3  
Visit 45  
Visit 5  
Visit 6  
  
Screening  
Baseline  
Treatment Day  
  
  
  
End of 
Study  


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Assessment  
Up to 7 
days  
before 
registration  
Up to 7 days 
before  
treatment 
and  
following 
registration  
Pre-treatment  
Posttreatment  
Day 1 after 
treatment  
Up to 3 days 
prior to  
surgical 
resection    
Surgical 
resection (7  
to 21 days 
after 
treatment)  
28-32 days 
postsurgery  
Informed Consent  
X  
  
  
  
  
  
  
  
Patient Demographics  
X  
  
  
  
  
  
  
  
Medical and Prior Treatment History  
X  
  
  
  
  
  
  
  
Eligibility Assessment  
(Inclusion/Exclusion Criteria)  
X  
  
  
  
  
  
  
  
Child Pugh Assessment (HCC patients 
only)  
X  
  
  
  
  
  
  
  
Physical Examination  
X  
X2  
  
  
  
X  
  
X  
Vital Signs  
X  
X2  
X  
X  
X  
X  
X  
X  
WHO Performance Status  
X  
X2  
  
  
  
X  
  
X  
Concomitant Medications  
X  
X  
X  
X  
X  
X  
X  
X  
Assessment of Adverse Events  
X  
X  
X  
X  
X  
X  
X  
X  
Biochemistry  
X  
X2  
  
  
X  
X  
  
X  
Haematology  
X  
X2  
  
  
X  
X  
  
X  
Coagulation Tests  
X  
X2  
  
  
  
X  
  
X  
12-Lead ECG  
X  
X2  
X  
X  
  
X  
  
X  
Serum Pregnancy Test1  
X  
X2  
  
  
  
  
  
  
Liver MRI, Incorporating DCE-MRI  
  
X  
X3  
  
  
X  
  
  
CT scan chest, abdomen, liver, pelvis, 
incorporating perfusion CT of liver  
  
X  
X3  
  
  
X  
  
  
4D CT scan liver  
  
  
  
  
X  
  
  
  
Blood Biomarker Analysis  
  
X  
X  
  
X  
X  
  
X  
Serum Tumour Markers (AFP for HCC 
patients; CEA, CA19-9, CA125 for 
mCRC patients)  
  
X  
X  
  
  
X  
  
  


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Study Visit  
Visit 0  
Visit 1  
Visit 2  
Visit 3  
Visit 45  
Visit 5  
Visit 6  
  
Screening  
Baseline  
Treatment Day  
  
  
  
End of 
Study  
Assessment  
Up to 7 
days  
before 
registration  
Up to 7 days 
before  
treatment 
and  
following 
registration  
Pre-treatment  
Posttreatment  
Day 1 after 
treatment  
Up to 3 days 
prior to  
surgical 
resection    
Surgical 
resection (7  
to 21 days 
after 
treatment)  
28-32 days 
postsurgery  
Vandetanib and N-desmethyl 
metabolite plasma sampling (0 min, 2hr 
(± 15 mins), 4hr (± 15 mins), 24h (± 1 
hour), and up to hospital discharge4) in 
addition to Visits 4 and 6  
  
  
X  
X  
X  
X  
  
X  
Vandetanib and N-desmethyl 
metabolite tissue sampling,  
histopathological and biomarker 
analysis  
  
  
  
  
  
  
X  
  
1. 
For women of child-bearing potential. A negative pregnancy test must be obtained prior to treatment  
2. 
Do not need to be repeated if screening assessments performed within 7 days prior to treatment  
3. 
May be performed the day before treatment  
4. 
Optional one additional plasma sample can be taken after 36 hours and up to time of hospital discharge  
5. 
If surgery is delayed > 7 days, then all visit 4 assessments should be repeated the day before the rescheduled surgery  
  


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3. 
BACKGROUND  
3.1. 
Disease background  
Treatment of primary and secondary liver cancer  
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most 
common cause of cancer-related death, estimated to have been responsible for nearly 746 000 
deaths in 2012 (World Health Organisation, 2012). The incidence varies from 3 out of 100 000 in 
Western countries to more than 15 out of 100 000 in certain areas of the world, mapping the 
geographical distribution of viral hepatitis B and hepatitis C which are the most important causes 
of chronic liver disease and HCC (Parkin, Bray, Ferlay & Pisani, 2005). In developed countries, 
increasing prevalence of obesity in the general population and alcoholic liver disease account for 
the rising incidence of HCC.  
The prognosis of HCC remains poor because of the high recurrence rate (Lencioni, Petruzzi & 
Crocetti, 2013). Treatment options such as surgical resection, liver transplantation, and ablative 
therapies can provide a chance of cure; however, these modalities are limited and often not 
feasible because HCC is usually diagnosed at an advanced stage. Palliative therapies such as 
transcatheter arterial embolic therapies, radiation therapy, and systemic therapies provide 
potential therapeutic solutions for patients not suitable for surgery or ablation.  
Secondary liver tumours (i.e., metastatic to the liver from a primary site outside the liver) are the 
most common form of hepatic malignancy and are even more common than HCC (Lewandowski 
et al., 2005). The most common sites of primary tumours which spread to the liver are colorectal 
cancer (CRC), breast cancer and lung cancer. In patients with metastatic colorectal cancer 
(mCRC), the liver is the most common site of metastatic disease. Approximately 50% of CRC 
patients will develop liver metastases during the course of the disease (Adam et al., 2012). 
Progressive hepatic metastases cause liver failure, especially once all chemotherapeutic and/or 
surgical options have been exhausted. Although surgical resection of liver metastases for curative 
intent is the treatment of choice, most patients present with unresectable liver-predominant mCRC 
and are therefore not suitable for surgery. In these cases, locoregional therapies including 
transarterial chemoembolisation (TACE) are treatment options, either alone or in combination with 
systemic chemotherapy (De Groote & Prenen, 2015).   
Conventional TACE (cTACE) involves the administration of an anticancer agent followed by an 
embolic agent into the tumour feeding arteries to block its major nutrient source resulting in 
ischemic necrosis of the targeted tumour. The most common anticancer cytotoxic drugs for local 
delivery via TACE are doxorubicin, cisplatin, epirubicin, mitoxantrone and mitomycin C.  However, 
the systemic release of chemotherapy agents following cTACE is high and many patients suffer 
from systemic side effects. These factors led to innovative research to develop a different method 
of local drug delivery with less of the systemic toxicity associated with cTACE. One of these 
methods is the use of drug-eluting microspheres for TACE, henceforth referred to as drug-eluting 
bead TACE (DEB-TACE) (Lewis et al., 2006; Poon et al., 2007; Varela et al., 2007).  
DEB-TACE ensures slow and sustained release of the drug locally ensuring high intra-tumoural 
drug concentrations in addition to the ischaemic effects of the embolic agent. In vitro data have 
confirmed the slow, sustained release of the drug (Lewis et al., 2006) and it has been shown in 
HCC patients that TACE with drug-eluting microspheres (DC Bead™) achieves higher 
intratumoural concentrations and lower systemic concentrations of cytotoxic agent than cTACE, 
thereby reducing the potential liver toxicity of treatment (Poon et al., 2007; Varela et al., 2007).   


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TACE using drug-eluting beads loaded with doxorubicin (DEBDOX) has been widely performed 
in patients with HCC and has become the standard therapy for patients not suitable for surgical 
resection or transplantation (Lencioni, Petruzzi & Crocetti, 2013). Current international guidelines 
from the American Association for the Study of Liver Disease (AASLD) and the European 
Association for the Study of the Liver (EASL) recommend TACE as first-line, non-curative therapy 
for non-surgical patients with large/multifocal HCC who do not have vascular invasion or 
extrahepatic spread (Bruix, Sherman & American Association for the Study of Liver, 2011; EASL 
& EORTC, 2012).  
Based on extensive experience with TACE in patients with HCC, this treatment has also been 
developed for patients with liver-dominant metastatic disease, particularly CRC metastases within 
the liver.  It has been shown to be effective in the treatment of patients with mCRC using 
drugeluting beads loaded with irinotecan (DEBIRI) (Wang, De Baere, Idee & Ballet, 2015). This 
treatment has been shown to be safe and well tolerated, offering patients with mCRC a potential 
improvement in quality of life and potentially in overall survival (Fiorentini et al., 2007; Narayanan, 
Barbery, Suthar, Guerrero & Arora, 2013). According to the recent European ESMO consensus 
guideline for the management of patients with mCRC, TACE is considered as a treatment that 
could be offered along with other local ablation therapies to mCRC patients with a limited number 
of lesions and involved sites (i.e., termed “oligometastatic disease”) (Van Cutsem et al., 2016).  
TACE is a treatment that can be repeated several times, but primary and secondary liver cancer 
can become resistant to the treatment.  The mechanisms of post-TACE and DEB-TACE tumour 
recurrence have not been elucidated. Improving the DEB-TACE administration technique and 
investigating the ability to deliver new anticancer drugs locally to the tumour via the beads are 
important research approaches to potentially improving the efficacy of TACE for patients with 
cancer.  
In addition to the use of conventional chemotherapy regimens, biological agents including 
bevacizumab, a humanised monoclonal antibody that targets vascular endothelial growth factor 
(VEGF), a central regulator of angiogenesis, and cetuximab/panitumumab, monoclonal 
antibodies directed against endothelial growth factor receptors (EGFR) have contributed to the 
improvement of survival for patients with mCRC. Unlike mCRC, HCC is highly refractory to 
conventional cytotoxic chemotherapy. In the last decade, no effective conventional systemic 
cytotoxic therapy has been available and no single regimen has emerged as superior to any other 
(Lopez, Villanueva & Llovet, 2006). Systemic chemotherapy with doxorubicin or cisplatin yields 
low objective response rates (<10%).  To date, only sorafenib, an oral multi-kinase inhibitor and 
anti-angiogenic agent has been approved in patients with advanced HCC.  Sorafenib inhibits 
abnormal growth of multiple cell surfaces and intra-cellular kinases which are involved in 
angiogenesis, cell proliferations and cellular differentiation. The different kinases include various 
VEGF receptors (VEGFR-1,2,3), platelet-derived growth factor receptor (PDGFR-B), c-KIT and 
RET (Wilhelm S et al, 2006).  Sorafenib also inhibits the RAF/MEK/ERK pathway that is important 
in tumour cell proliferation and survival (Liu et al., 2006).  
In order to improve treatment for HCC, new agents targeting the genetic alterations and/or 
signaling pathways involved in hepatocarcinogenesis are being investigated. These pathways 
include various growth factors such as EGF, VEGF, hepatocyte growth factor (HGF), insulin-like 
growth factor and regulating specific intracellular pathways such as RAF/MEK/ERK and 
P13K/PTEN/Akt/mTOR and Wnt/B-catenin pathways (Kudo, 2012; Raza & Sood, 2014).  


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3.2. 
General Description of Investigative Agent(s)/Device  
Radiopaque Beads  
A current limitation in improving the accuracy of embolic administration during TACE and in 
understanding how well the treatment is reaching its target is the inability to visualise the beads 
used to deliver the drug locally within the liver.  BTG has recently developed a radiopaque (RO) 
bead that can be visualised with CT or fluoroscopic imaging and have the advantage of providing 
intra and post-procedural visible confirmation of bead location during the embolisation procedure, 
enabling real-time adjustments to optimise patient treatment (Johnson et al., 2016). The 
radiopaque bead builds on existing DC Bead™ technology used to embolise the blood vessels 
and deliver drugs at high concentrations to tumours. The lasting radio-opacity of RO beads means 
that they are visible on X-ray based follow-up scans, allowing precise evaluation of the 
completeness of tumour treatment.   
RO beads are commercially available in the US (as LC Bead LUMI™) for the treatment of 
hypervascularised tumours and arteriovenous malformations. In Canada, DC Bead LUMI™ is 
approved for the treatment of HCC in combination with doxorubicin and for the treatment of mCRC 
in combination with irinotecan.  BTG-002814 is an imageable product based on the BTG RO bead 
platform. It is a pre-loaded, RO bead with a size range of 60–160 µm and is provided in a 20 mL 
glass vial. In addition, the 60-160 µm size range in the BTG-002814 formulation was chosen to 
ensure tumour penetration by the embolic agent and to maximise drug exposure to the tumour 
tissue.    
Vandetanib  
Vandetanib is a potent inhibitor of the tyrosine kinase activity of VEGFR-2, an endothelial cell 
receptor for vascular endothelial growth factor (VEGF). It also possesses activity against EGFR 
and REarranged during Transfection (RET) tyrosine kinases.  VEGF is a potent stimulator of new 
blood vessel growth (angiogenesis) and plays an essential role in the formation and maintenance 
of the vasculature by activating protease expression, endothelial cell proliferation and migration, 
and capillary vessel formation. Pathological angiogenesis is necessary for the progression of 
solid, malignant tumours and inhibition of VEGF-dependent signaling has been identified as a key 
anti-angiogenic strategy (Ferrara, 2004).  
EGFR-dependent signaling is an important pathway contributing to the growth and metastasis of 
tumour cells, and aberrant EGFR tyrosine kinase activity has been reported in a number of human 
solid tumours. EGFR tyrosine kinase activity plays a key role in numerous processes that affect 
tumour growth and progression, including proliferation, dedifferentiation, inhibition of apoptosis, 
metastasis and angiogenesis (Vlahovic & Crawford, 2003).  
By targeting both angiogenesis and EGFR- and RET-dependent tumour cell growth, it is 
hypothesised that the growth of tumours will be controlled, with relative sparing of normal tissues.  
The oral version of vandetanib, branded as Caprelsa®, is approved for the treatment of patients 
with advanced medullary thyroid cancer.    
Phase 1 dose-escalation studies performed in Western and Japanese patients, with solid tumours 
refractory to standard therapy, showed that vandetanib was generally well tolerated at daily doses 
up to 300 mg (Holden et al., 2005; Tamura et al., 2006). Vandetanib can significantly prolong 
progression-free survival (PFS) of patients with advanced medullary thyroid cancer (Wells et al., 
2010) and is not inferior to erlotinib as a second-line therapy for patients with advanced non-
smallcell lung cancer (NSCLC) (Natale et al., 2011). Vandetanib plus docetaxel can significantly 


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prolong PFS, compared with docetaxel alone, in patients with advanced NSCLC after progression 
following first-line chemotherapy (Herbst et al., 2010).  
Systemic therapy with oral vandetanib has been investigated in a clinical setting in a broad range 
of human malignancies, including HCC and mCRC. Some of these clinical studies are reviewed 
below.  
Systemic vandetanib treatment of HCC  
Sixty-seven HCC patients were randomised to oral vandetanib 300 mg (n=19), oral vandetanib 
100 mg (n=25) or placebo (n=23). Twenty nine patients subsequently entered open-label 
treatment. Vandetanib induced a significant increase in circulating VEGF and decrease in 
circulating VEGFR levels. In both vandetanib arms, tumour stabilisation rate was not significantly 
different from placebo. Although trends towards improved PFS and Overall Survival (OS) after 
vandetanib treatment were found, they were not statistically significant. The most common 
adverse events were diarrhoea and rash in both treatment groups (Hsu et al., 2012).  
Systemic vandetanib treatment of colorectal cancer  
A number of phase 1 dose escalation studies were conducted to determine the maximum tolerated 
dose (MTD) of vandetanib in combination with different therapeutic agents and regimens, 
predominantly in mCRC patients.  In a study of 21 patients with vandetanib 100 mg (n=11) and 
vandetanib 300 mg (n=10) combined with standard 14-day treatment cycles of FOLFIRI, the most 
commonly reported AEs were diarrhoea, fatigue and nausea. In one study of vandetanib 
combined with cetuximab and irinotecan, 27 patients were enrolled at 4 dose levels. Two dose-
limiting toxicities (DLTs) (grade 3 QTc prolongation and diarrhoea) were detected at 300 mg 
vandetanib with cetuximab and irinotecan resulting in 200 mg being the MTD (Meyerhardt et al., 
2012).  In another study, 13 patients received vandetanib at doses of 100 mg and 300 mg daily 
in combination with capecitabine and oxaliplatin, which was well tolerated. However, the addition 
of bevacizumab resulted in severe diarrhoea in three out of four patients. Bevacizumab was not 
well tolerated with vandetanib and XELOX in combination (Cabebe, Fisher & Sikic, 2012).  In 17 
patients with advanced mCRC, vandetanib 100 mg (n=9) or 300 mg (n=8) was combined with 
mFOLFOX6 chemotherapy. The most commonly reported AEs were diarrhoea, lethargy and 
nausea. The CTCAE Grade 3/4 events that were considered to be related to vandetanib was 
Grade 3 diarrhoea in 3 patients (1 patient in the 100 mg cohort and 2 patients in the 300 mg 
cohort) and Grade 3 thrombocytopenia in 1 patients (300 mg cohort) (Michael, Gibbs, Smith, 
Godwood, Oliver & Tebbutt, 2009). In another study to assess the effect of vandetanib on vascular 
permeability in patients with advanced CRC and liver metastases, 22 patients received the study 
drug; 10 received 100 mg and 12 received 300 mg. The most commonly reported AEs were 
diarrhoea, dry mouth, fatigue and nausea (Mross et al., 2009).   
Two phase II, double-blind, placebo-controlled, randomised studies were conducted to assess the 
efficacy and safety of 2 doses of vandetanib (100 mg and 300 mg) in combination with FOLFOX 
or FOLFIRI in patients who had failed with FOLFIRI (109 patients) or FOLFOX (121 patients) 
regimens respectively.  The addition of vandetanib to FOLFOX regimen did not show any 
additional benefit in terms of number of patients with disease progression and the time to 
progression. A lower risk of disease progression was reported with 100 mg vandetanib combined 
with FOLFIRI regimen compared to the FOLFIRI regimen with placebo (57% vs 69%). The 
percentages of patients who had a disease progression event in the vandetanib 300 mg group 
and placebo group were similar (67% vs 69%). The estimated median times to progression were 
114 days for the vandetanib 100 mg group, 151 days for the vandetanib 300 mg group, and 103 
days for the placebo group.  The safety profile of vandetanib (100 mg and 300 mg) in combination 


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with both regimens, FOLFOX and FOLFIRI, was acceptable. The most commonly reported AEs 
were diarrhoea and nausea; thrombocytopenia was reported with FOLFOX-vandetanib and 
neutropenia with FOLFIRI-vandetanib.  
3.3. 
Pre-Clinical Background of Investigative 
Agent(s)/Device  
In vitro pharmacology  
Vandetanib is a potent inhibitor of VEGFR-2 tyrosine kinase activity with an IC50 value of 40 nM. 
In isolated enzyme assays, vandetanib was also found to be a sub-micromolar inhibitor of fmslike 
tyrosine kinase (Flt)-4 (VEGFR-3, the VEGF-C and –D receptor: IC50 =110 nM) and EGFR 
tyrosine kinases (IC50 = 500 nM). Additional vandetanib activity has been demonstrated against 
oncogenic RET kinase (IC50 = 100 nM) which is activated in certain thyroid carcinomas.   
Further details are provided in the BTG-002814 Investigator Brochure.  
In vivo pharmacology  
Vandetanib has demonstrated broad spectrum anti-tumour angiogenesis activity in several 
histologically diverse tumour xenograft models (lungs, prostate, breast, ovarian, colon). Chronic 
once daily oral administration (12.5-100 mg/kg/day) produced significant dose dependent 
inhibition of tumour growth. Vandetanib has also been shown to inhibit growth of tumours 
implanted orthotopically e.g. orthotopic models of gastric and pancreatic cancer.  In mouse 
models of human prostate and colon cancer, DCE-MRI analysis showed a dose dependent 
reduction in contrast agent uptake by tumour 24 hours after initiating therapy with vandetanib, 
consistent with vandetanib inhibition of VEGF induced permeability in tumour vasculature (Ryan 
& Wedge, 2005). Vandetanib inhibited tumour growth of hepatoma cells in subcutaneous mouse 
tumour model. In addition, vandetanib suppressed phosphorylation of VEGFR-2 and EGFR in 
tumour tissues, significantly reduced tumour vessel density, enhanced tumour cell apoptosis,  
improved survival, reduced number of intra-hepatic metastases and upregulated VEGF, TGF-α 
and EGF in tumour tissues (Inoue et al., 2012).   
Further details are provided in the BTG-002814 Investigator Brochure.  
Pre-clinical background of BTG-002814  
The safety of the vandetanib-eluting bead has been evaluated in a GLP swine liver embolisation 
model. In this model, vandetanib-loaded RO beads (100 mg vandetanib per 1 mL bead) were 
delivered to healthy liver by hepatic intra-arterial administration. Up to 1 mL of vandetanib-loaded 
bead was administered, which equates to delivery of 100 mg vandetanib to the targeted liver lobe. 
The animals were maintained for either 30 or 90 days. There were no treatment-related effects 
evident in parameters evaluated, namely, clinical observations, body weight, ophthalmoscopy, 
ECG, and organ weights. Transient changes in coagulation and clinical chemistry parameters 
were observed, likely to be related to the hepatic embolisation procedure.   
There were expected microscopic findings associated with hepatic embolisation following 
intrahepatic administration of vandetanib-loaded bead. The study indicated that intrahepatic 
administration of up to 1 mL vandetanib-loaded RO bead containing 100 mg of vandetanib was 
well tolerated, did not produce any obvious systemic toxicity and resulted in nothing more than 
expected microscopic findings associated with hepatic embolisation and subsequent healing.    


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In an efficacy study conducted in a rabbit model, VX-2 carcinoma tumours were implanted in the 
liver, followed by hepatic intra-arterial administration of DC Bead loaded with vandetanib up to  
135 mg/mL (DCV). DCV showed equivalent anti-tumoural activity to doxorubicin-loaded bead and 
superior anti-tumoural activity compared to bland (unloaded) bead.  Single hepatic administration 
of DCV showed equivalent anti-tumoural efficacy to repeat dose of oral vandetanib, at the doses 
administered (~5.4 mg per animal with DCV vs 1470 mg oral vandetanib, respectively). Compared 
to oral dosing, it is notable that DCV showed a lower plasma concentration and a higher tumour 
concentration of vandetanib relative to the total dose administered.  
 


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4. 
STUDY RATIONALE, OBJECTIVES and DESIGN  
4.1. 
Study Rationale  
TACE is the current standard of care for patients with intermediate-stage HCC and is also a 
treatment option for patients with mCRC. Despite advances and technical refinements of TACE, 
including the introduction of drug-eluting beads (DEB)-TACE, the long term survival of patients 
managed with TACE is generally poor, mainly as a result of the high rates of tumour recurrence. 
Improving the technique used for DEB-TACE, by being able to visualise the beads on CT scans, 
and by developing the ability to load new anti-cancer molecularly targeted drugs on to the beads, 
specifically vandetanib, are two important approaches to potentially improving the efficacy of 
TACE for patients with HCC or mCRC.   
This clinical trial will study the feasibility of administering radiopaque beads loaded with 
vandetanib, a tyrosine kinase inhibitor that targets both VEGFR and EGFR signaling pathways, 
as two novel approaches combined in to one new therapy, BTG-002814, to enhance anti-tumour 
efficacy compared to current liver-directed therapies. It will be the first time that BTG-002814 has 
been administered to humans. Since cTACE can be safely used in the pre-operative setting to 
treat cancers prior to liver surgery, this study will be performed in resectable patients with HCC 
and mCRC, therefore providing a ‘window of opportunity” to measure the levels of vandetanib in 
the resected liver sample, as well as assessing the safety and tolerability of BTG-002814 in 
patients with cancer.  Tumour recurrence rates for HCC and mCRC after liver surgery are 
currently up to 50% of patients, so the development of any pre-operative therapy with the potential 
to improve the chances of long-term disease control following surgery is an important research 
goal.  
4.2. 
Study Objectives  
4.2.1. Primary Objectives  
• 
To assess the safety and tolerability of treatment with BTG-002814  
• 
Measure the plasma and resected liver tissue concentrations of vandetanib and the 
Ndesmethyl metabolite following treatment with BTG-002814  
4.2.2. Secondary Objectives  
• 
Evaluate the anatomical distribution of BTG-002814 on non-contrast enhanced imaging using 
4D CT  
• 
Evaluate histopathological features in the surgical specimen following treatment with 
BTG002814  
• 
Assess changes in blood flow on dynamic contrast-enhanced magnetic resonance imaging 
(DCE-MRI) following treatment with BTG-002814  
  
4.2.3. Exploratory Objective  
• 
Study blood biomarkers with the potential to identify patients likely to respond to treatment 
with BTG-002814  
• 
Study tissue biomarkers to explore key immune, inflammatory and drug related mechanisms  
• 
Correlate the distribution of BTG-002814 on imaging with pathology by 3D modelling  


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4.3. 
Study Design  
4.3.1. Study Design Flow Chart  
  
9 patients treated with 
BTG-002814  
 
4.3.2. Summary of Study Design  
A pilot, open-label, single arm, multicentre, phase 0, window of opportunity study with DEB-TACE 
treatment with BTG-002814 given between 1 and 3 weeks prior to surgery in up to 12 patients 
with resectable HCC or mCRC.  
Three patients who have either HCC or liver metastases from CRC and who are candidates to 
receive surgery will initially be enrolled.  
An interim analysis conducted by a Safety Committee (SC) is planned when the first three patients 
complete the last follow-up visit scheduled at 4 weeks after surgery.  
If the SC deems that there is no significant toxicity related to BTG-002814, a further 9 patients will 
be enrolled in order to have a target sample size of 6 patients with HCC and 6 patients with liver 
metastases from CRC.  
A final analysis will be performed when 12 patients complete the last follow-up visit, or once 14 
patients have been enrolled and are no longer on study All patients will receive one treatment of 
BTG-002814.  
4.4. 
Randomisation  
This is a single arm study; so randomisation is not applicable.  3
   patients
 TreatedwithBTG
 - 
  002814 (
 
  100 mgvandetanibin
 
  1 mLRObeads
 ) (
 
  100 mgvandetanibin
 
  1
   mLRObeads
 ) SafetyCommittee
 (
 SC  )   Assessment
 STOP
 SC“go”
 SC“no
 - go”basedonany
 toxicitydeemed
 unacceptablebytheSC
 
  


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4.5. 
Study Endpoints  
4.5.1. Co-Primary Endpoints  
• 
Adverse events (AEs) related to treatment with BTG-002814 using the standardised grading 
criteria (National Cancer Institute Common Terminology Criteria for Adverse Events Version 
4.0 (NCI-CTCAE v4.0))  
• 
Concentration of vandetanib and N-desmethyl vandetanib in plasma and in resected liver 
tissue following treatment with BTG-002814.  
4.5.2. Secondary Endpoints  
• 
Distribution of BTG-002814 on non-contrast enhanced imaging of tumour vasculature and 
regions of interest using 4D CT  
• 
Evaluation of histopathological features in the surgical specimen (malignant and nonmalignant 
liver tissue): tumour necrosis, viable tumour, vascular changes  
• 
Assessment of changes in blood flow on DCE-MRI following treatment with BTG-002814.  The 
following parameters will be derived from DCE-MRI images: Ktrans, Kep and Ve  
4.5.3. Exploratory Endpoints  
• 
Study blood biomarkers with the potential to identify patients likely to respond to treatment 
with BTG-002814  
• 
Study tissue biomarkers to explore key immune, inflammatory and drug related mechanisms  
• 
Correlate the distribution of BTG-002814 on imaging and pathology by 3D modelling  


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5. 
PATIENT SELECTION   
5.1. 
Patient Population  
The study population will consist of patients with HCC or liver metastases from CRC who are 
deemed suitable for liver surgery.  
5.2. 
Subject Selection  
5.2.1. Inclusion Criteria  
1. 
Male or female adults (≥ 18 years old)  
2. 
Patient with resectable HCC (Child Pugh A, INR ≤1.5) or resectable liver metastases from 
CRC and a candidate for liver surgery    
3. 
Patients with low risk for surgical morbidity and mortality from liver surgery according to 
the investigator’s judgement    
4. 
WHO performance status 0, 1 or 2   
5. 
Adequate haematological function with Hb >90 g/L, absolute neutrophil count >1.5 x 
109/L, Plt >75 x 109/L  
6. 
Adequate liver function with serum bilirubin <1.5 x ULN, ALT (or AST if ALT not available) 
≤5 x ULN, ALP <5 x ULN  
7. 
Adequate renal function with serum creatinine ≤1.5 x ULN and calculated creatinine 
clearance (GFR) ≥50 mL/min estimated using a validated creatinine clearance calculation 
(e.g. Cockroft-Gault or Wright formula).  
8. 
Patient is willing to provide blood samples, and tissue samples at surgical resection, for 
research purposes   
9. 
Patient is willing and able to provide written informed consent  
5.2.2. Exclusion Criteria  
1. 
Any systemic chemotherapy within 3 months of the screening visit or any plan to 
administer systemic chemotherapy prior to surgery  
2. 
Previous treatment with transarterial embolisation (with or without chemotherapy) of the 
liver, prior radiotherapy or ablation therapy to the liver or prior yttrium-90 microsphere 
therapy  
3. 
Any contraindication to vandetanib according to its local label including:  
o 
Hypersensitivity to the active substance o  Congenital long QTc syndrome  
o 
Patients known to have a QTc interval over 480 milliseconds  
o 
Concomitant use of medicinal products known to also prolong the QTc interval and/or 
induce Torsades de pointes (see Appendix 1)  
4. Any contraindication to hepatic artery catheterisation or hepatic embolisation procedures 
(e.g. portal venous thrombosis, severely reduced portal venous flow or hepatofugal blood 
flow, untreated varices at high risk of bleeding)  
5. Women of child-bearing potential not using effective contraception or women who are 
breast feeding  
6. Confirmed allergy to iodine-based intravenous contrast media  
7. Patients who cannot have CT, MRI or DCE-MRI Imaging (according to site policy)  
8. Active uncontrolled cardiovascular disease  


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9. Any co-morbid disease or condition or event that, in the investigator’s judgement, would 
place the patient at undue risk and would preclude the safe use of DEB-TACE with 
BTG002814  
10. Levels of potassium, calcium, magnesium or thyroid stimulating hormone (TSH) outside 
of the normal ranges, and that in the investigator’s judgment are clinically significant, or 
other laboratory findings that in the view of the investigator makes it undesirable for the 
patient to participate in the study  
11. Patients who have received treatment in another clinical trial with an investigational 
medicinal product within 4 weeks prior to the screening visit  
5.3. 
Reproductive Potential  
All women of child-bearing potential (WOCBP) enrolled into this study will have a serum 
pregnancy test at Screening (Visit 0) to assess their suitability for entry into the study. Women 
who are pregnant or who are breast feeding are excluded from this study.  
Definition of WOCBP  
A WOCBP is a sexually mature woman (i.e. any woman who has experienced menstrual bleeding) 
who has not:  
• undergone a hysterectomy or bilateral oophorectomy/salpingectomy  
• been postmenopausal for 12 consecutive months (i.e. who has had menses at any time in 
the preceding 12 consecutive months without an alternative medical cause)  
• had premature ovarian failure confirmed by a specialist gynaecologist   
• XY genotype, Turner syndrome, uterine agenesis  
  
WOCBP, or any male patient enrolled in the study who has a WOCBP partner, must use effective 
contraception during the study and for four months after treatment.  
Acceptable methods of contraception include established use of oral, injected or implanted 
hormonal birth control, intrauterine device, or barrier method in conjunction with spermicidal 
foam/cream/jelly/suppository, female/male sterilisation or abstinence where this is the patient’s 
preferred and usual lifestyle.  
5.4. 
Patient Completion  
Patient enrolment is planned to continue until the target number of 12 patients have been included.    
Patients will complete the study 28-32 days following the surgical resection.  
5.5. 
Patient Withdrawal  
Patients may withdraw from the study at any time for any reason without prejudice to their future 
medical care by the physician or at the institution. The Investigator or Sponsor may withdraw the 
patient at any time (e.g., in the interest of patient safety). The withdrawal of a patient from the 
study by the Investigator should be discussed where possible with UCL CTC and the Sponsor.  
For patients who withdraw before the end of the study, all Visit 6 (End of Study) assessments 
should be completed, if possible, prior to withdrawal. All AEs must be documented in the patient 
medical notes and case report forms (CRF).  


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If a patient withdraws from the study for any reason, all efforts should be made to follow AEs as 
described in section 8, unless the patient withdraws consent.  
A maximum of 2 patients who withdraw from the study early will be replaced.  
5.6. 
Patients “Lost to Follow-up” Prior to Last Scheduled 
Visit  
At least 3 documented attempts must be made to contact any patients Lost to Follow-up at any 
time point prior to the last scheduled visit.  
 


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6. 
TREATMENT OF PATIENTS  
6.1. 
Vandetanib-eluting radiopaque bead (BTG-002814)  
6.1.1. Dosage & Administration   
All patients will receive one treatment of BTG-002814. One vial of BTG-002814 will be used for 
each patient.  
To hydrate BTG-002814, 1 mL of Water For Injection followed by 9 mL of Omnipaque 350 contrast 
agent will be added to the vial. The full contents of the vial will be delivered slowly (approximately 
1 min per mL) under fluoroscopic visualisation while observing the contrast flow rate, through an 
intra-arterially placed microcatheter and must be used within 4 hours of reconstitution.  Full 
instructions for use will be provided in the Summary of Drug Arrangements (SoDA).  
Embolisation procedure  
Using a unilateral femoral approach, selective catheterisation of the hepatic artery will be 
performed. Diagnostic visceral arteriography will be performed to delineate the arterial supply to 
the tumour, determine the presence of variant arterial anatomy and to confirm patency of the 
portal vein. Once the patient’s arterial anatomy is understood, a catheter is advanced into the 
right or left hepatic artery distal to the cystic artery (if visualised). The treatment plan is based on 
the fluoroscopic appearances during arteriography. For the purposes of this clinical trial, since all 
eligible patients have resectable disease, it is not a requirement of the protocol that all lesions 
visible on CT are treated with BTG-002814. This decision will be at the discretion of the treating 
investigator. For example, if a right hemihepatectomy is the operation planned, it is not necessary 
to treat all the lesions in the anterior and posterior sector; the lesions to be treated may be those 
deemed to be at highest risk of a positive surgical resection margin and therefore at highest risk 
of tumour recurrence following surgery. It is important to confirm the location of delivered beads 
on 4D CT at the end of the procedure relative to the treatment plan based on fluoroscopic 
appearances.  
Once the catheter is in place within the artery feeding the tumour, the re-constituted BTG-002814 
suspension will be slowly infused into the artery (approximately 1 mL per minute). Catheter 
selection will be by operator preference. There will not be any issues with a 4- or 5-Fr catheter, 
but the choice of a microcatheter, in case of tortuous, narrow or spastic vessels must be consistent 
with the size of embolic agent used (see IFU). The end point of the procedure is either full delivery 
of the reconstituted bead volume (i.e. 1 mL beads + vandetanib + contrast) or stasis in the 
tumoural vessel over 2-5 cardiac cycles. Undelivered volume of reconstituted embolic solution 
must be recorded.  
For HCC patients, a super selective (segmental/subsegmental) approach should be taken with 
the catheter placed as selectively as possible whilst maintaining sufficient flow to the tumour. For 
mCRC patients, it is generally a lobar approach, by placing the catheter tip beyond the origin of 
the cystic artery (or any other arteries supplying extrahepatic organs) and maintaining forward 
flow.  
The catheter will then be removed and haemostasis achieved by manual compression or with a 
percutaneous closure device. Each patient will be admitted for overnight care.   


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The amount of contrast agent delivered to the patient during the procedure and skin dose of xrays 
from fluoroscopy will be recorded as well as the time exposed to fluoroscopic imaging. The 
vessels embolised will be noted and the amount of embolic agent used will be recorded. All 
medications used during the procedure will be recorded, including pain management regime.  
6.1.2. Safety Criteria for Adjusting or Stopping Treatment  
Hypersensitivity reactions may occur to the active substance of vandetanib. Such hypersensitivity 
is a contraindication for BTG-002814 administration and is covered by this protocol’s exclusion 
criterion 3.   
Allergy to contrast media that cannot be managed with standard care may also cause 
hypersensitivity reactions. Such hypersensitivity is a contraindication for treatment with 
BTG002814 and is covered by this protocol’s exclusion criterion 6.  
Should any previously unknown hypersensitivity become apparent at any stage during treatment, 
administration of BTG-002814 will stop immediately and standard care indicated for 
hypersensitivity reactions will be initiated and completed.  
Rash and other skin reactions including photosensitivity reactions and palmar-plantar 
erythrodysaesthesia syndrome have been observed in patients who have received vandetanib. 
Patients will be advised to minimise exposure to the sun by wearing protective clothing and/or 
sunscreen due to the potential risk of phototoxicity reactions associated with vandetanib for UV 
light for at least four weeks following treatment (visit 2).  
6.1.3. Post-study Management  
Management of patients after they have completed or been withdrawn from the study should be 
as per the investigational site’s standard procedures  
6.1.4. Duration of Treatment and Follow up  
All patients will receive one treatment of BTG-002814 between 7 and 21 days prior to surgery. All 
patients will be followed up for 28-32 days following surgery.  
6.1.5. Concomitant Medications   
Concomitant medications are defined as those taken from the date of Informed Consent to the 
date of the final visit (Visit 6, End of Study).  
Patients previously treated with other loco-regional therapies including transarterial embolisation 
(with or without chemotherapy), prior external beam radiation or prior yttrium-90 microsphere 
therapy are excluded from this study (see exclusion criterion 2).  
Medicinal products known to also prolong the QTc interval and/or induce Torsades de pointes 
should not be used in combination with BTG-002814, and should not be administered during the 
study (see exclusion criterion 3). Refer to Appendix 1.  
With the exception of the above, there are no concomitant medications specifically prohibited 
during the study, however, there are multiple known drug interactions that are relevant for the 
vandetanib active drug, including:   
• 
Strong CYP3A4 inducers (e.g., rifampicin, rifabutin, St John’s Wort, carbamazepine, 
phenytoin, barbiturates)  


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• 
Vandetanib can increase the Cmax of metformin, therefore metformin dosage monitoring is 
recommended.  
• 
Vandetanib can increase the Cmax of P-gp substrates such as digoxin, therefore digoxin 
dosage monitoring is recommended.  
• 
If the patient’s concomitant medication includes vitamin K antagonists (e.g., warfarin, 
phenindione, acenocoumarol), increased frequency of INR monitoring is recommended.  
Documentation of all concomitant medication, including any sedative medication used during 
treatment and surgery, and any over the counter medications, should continue until the final visit 
and must be recorded in the patient’s medical notes and CRFs.  
6.2. 
Investigational Product/Labeling/Packaging/Storage/ 
Handling  
6.2.1. Investigational Product  
BTG-002814 is a radiopaque embolic bead pre-loaded with vandetanib. It is light brown/golden in 
colour and is provided lyophilized, in glass vials.   
Each vial contains 1 mL of BTG-002814 containing 100 mg vandetanib when hydrated as per 
protocol.  
BTG-002814 will be provided free of charge to the site by BTG and must not be used outside 
the context of this study.  
6.2.2. Labeling and Packaging  
BTG-002814 will be labelled and packaged by BTG International Germany GmbH.   
BTG-002814 vials will be sealed in an aluminium foil pouch and placed within a carton.  The vial, 
pouch and carton will be labelled with a single panel, local language label, in accordance with 
good manufacturing practice (GMP) and in compliance with local law(s) and legislation. Supplies 
will be labelled in accordance with Annex 13 guidelines on labelling of Investigational Medicinal 
Products and in line with local legislation. They will contain the following at a minimum; protocol 
identifier, contents, directions for use, expiry date, storage, batch number, unique medication 
identification number i.e., vial number.  
6.2.3. Storage and Handling  
Prior to use, BTG-002814 must be stored in a secured access, locked area, accessible only to 
authorised site personnel.   
BTG-002814 should be stored above 8ºC and must not be refrigerated or frozen.  
In the event of a product complaint, the Sponsor and UCL CTC must be informed within 24 hours, 
including a brief description of the incident seen.  The Sponsor will then investigate and inform 
the site on any actions that need to be taken. Refer to the SoDA for reporting instructions.  
6.2.4. Accountability  
Ordering and Receipt of Investigational Product  
Procedures for ordering and receipt of BTG-002814 will be provided in the SoDA.  


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Compliance and Accountability Procedures  
Biocompatibles UK Ltd will supply BTG-002814 for use within this study only to approved 
investigational sites with an authorised investigational pharmacist as designated by the 
Investigator. The investigational pharmacist is responsible for accurate documentation of receipt, 
inventory, storage, preparation, and dispensing of BTG-002814.  
Additional instructions on BTG-002814 accountability will be provided in the SoDA.  
Unused Supplies  
At the end of the study, or as instructed by the Sponsor or designee, all unused BTG-002814 
provided for use in this study must be returned to Biocompatibles UK Ltd/designee or destroyed 
according to instruction detailed within the SoDA once full accountability has been completed.   
Destruction must not occur at site without prior approval from the Sponsor.  
 


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7. 
STUDY PROCEDURES  
7.1. 
Study Schedule  
See Section 2, Schedule of Visits for the study schedule and the sequence of study procedures.   
7.2. 
Schedule of Visits, Procedures, and Evaluations  
7.2.1. Visit 0: Screening (up to 7 days before registration)  
The following assessments and procedures are required to evaluate the eligibility of patients prior 
to entry. Results from assessments or procedures carried out as part of routine practice may be 
used to assess eligibility, as long as they were carried out according to the timeframe and 
specification in the protocol. Patients must give written informed consent before any trial specific 
screening investigations may be carried out.  
• 
Written Informed consent will be obtained, as described in section 7.3.1  
• 
All patients who have signed the Informed Consent form will be included on the Screening 
and Enrolment Log. If the patient fails to fulfil the eligibility criteria, the Screening and 
Enrolment Log must be completed with the reason for the failure.  
• 
Patient demographic information will be collected, as described in section 7.3.2  
• 
Eligibility to participate in the study will be assessed, as described in section 7.3.17  
• 
Child Pugh assessment (HCC patients only), as described in section 7.3.17  
• 
Medical history information will be collected, as described in section 7.3.3  
• 
Physical examination will be conducted, as described in section 7.3.4  
• 
Vital signs will be taken, as described in section 7.3.5  
• 
Performance status will be assessed, as described in section 7.3.6  
• 
Medications and prior treatments will be recorded, as described in section 7.3.7  
• 
Adverse events will be recorded and assessed as described in section 7.3.21  
• 
Blood samples for biochemistry, haematology and coagulation, as described in section 7.3.8  
• 
A 12-lead ECG will be taken as described in section 7.3.12  
• 
Blood sample for serum pregnancy test for all patients of child-bearing potential, as described 
in section 7.3.9  
7.2.2. Visit 1: Baseline Visit (up to 7 days before treatment)  
Following fulfilment of the inclusion and exclusion criteria and registration of the patient, the 
following assessments and procedures are required to be done within 7 days prior to treatment 
with BTG-002814:  
• 
Liver MRI, incorporating Dynamic Contrast Enhanced MRI (DCE-MRI), as described in 
section 7.3.11  
• 
CT scan of chest, abdomen & pelvis, incorporating perfusion CT of liver, as described in 
section 7.3.11  
• 
Blood sample for biomarkers, as described in section 7.3.13  
• 
Blood sample for serum tumour markers, as described in section 7.3.10  
• 
Record any concomitant medications, as described in section 7.3.20  
• 
Adverse events will be recorded and assessed as described in section 7.3.21  
The following tests and procedures do not need to be repeated if carried out within 7 days prior 
to treatment with BTG-002814 as part of screening work up:  


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Physical examination will be conducted, as described in section 7.3.4  
Vital signs will be taken, as described in section 7.3.5  
• 
Performance status will be assessed, as described in section 7.3.6  
• 
Blood samples for biochemistry, haematology and coagulation, as described in section 7.3.8  
• 
A 12-lead ECG will be done as described in section 7.3.12  
• 
Blood sample for serum pregnancy test for all patients of child-bearing potential, as described 
in section 7.3.9  
7.2.3. Visit 2: Treatment Day  
NB: Treatment should NOT be scheduled to take place on a Friday, due to the assessments 
required to be performed the day after treatment (Visit 3).  
Pre-treatment Assessments  
The following scans will be performed within a day prior to administration of BTG-002814:  
• 
Liver MRI, incorporating DCE-MRI, as described in section 7.3.11  
• 
CT scan of chest, abdomen & pelvis, incorporating perfusion CT of liver, as described in 
section 7.3.11  
The following assessments and procedures will be performed on the day of treatment prior to 
administration of BTG-002814:  
• 
Vital signs will be taken, as described in section 7.3.5  
• 
Record any concomitant medications, as described in section 7.3.20  
• 
Record any adverse events, as described in section 7.3.21  
• 
A 12-lead ECG will be taken, as described in section 7.3.12  
• 
Blood sample for biomarkers, as described in section 7.3.13  
• 
Blood sample for serum tumour markers, as described in section 7.3.10  
• 
Blood sample for vandetanib and metabolite analysis, as described in section 7.3.14  
Post-treatment Assessments  
The following assessments and procedures will be performed on the day of treatment after 
administration of BTG-002814:  
• 
Vital signs will be taken, as described in section 7.3.5. Peak heart rate (HR) and peak blood 
pressure (BP) should be recorded in the CRF  
• 
Record any concomitant medications, as described in section 7.3.20  
• 
Record any adverse events, as described in section 7.3.21  
• 
A 12-lead ECG will be taken, as described in section 7.3.12  
• 
Blood samples for vandetanib and metabolite analysis at 2 and 4 hours after treatment, as 
described in section 7.3.14  
7.2.4. Visit 3 (Day 1 after treatment)  
The following assessments and procedures will be performed:  
• 
Vital signs will be taken, as described in section 7.3.5  
• 
Record any concomitant medications, as described in section 7.3.20  
• 
Record any adverse events, as described in section 7.3.21  


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• 
Blood samples for biochemistry and haematology, as described in section 7.3.8  
• 
4D CT scan of liver will be performed, as described in section 7.3.11  
Blood sample for biomarkers, as described in section 7.3.13  
Blood sample for vandetanib and metabolite analysis, as described in section 7.3.14  
7.2.5. Visit 4 (Up to and including 3 days prior to surgical resection)  
The following assessments and procedures will be performed:  
NB: if surgery is delayed by > 7 days, all visit 4 assessments should be repeated up to and 
including 3 days before the rescheduled surgery.  
• 
Physical examination will be conducted, as described in section 7.3.4  
• 
Vital signs will be taken, as described in section 7.3.5  
• 
Performance status will be assessed, as described in section 7.3.6  
• 
Record any concomitant medications, as described in section 7.3.20  
• 
Record any adverse events, as described in section 7.3.21  
• 
Blood samples for biochemistry, haematology and coagulation, as described in section 7.3.8  
• 
A 12-lead ECG will be taken, as described in section 7.3.12  
• 
Liver MRI, incorporating DCE-MRI, as described in section 7.3.11  
• 
CT scan of chest, abdomen & pelvis, incorporating perfusion CT of liver, as described in 
section 7.3.11.  
• 
Blood sample for biomarkers, as described in section 7.3.13  
• 
Blood sample for serum tumour markers, as described in section 7.3.10  
• 
Blood sample for vandetanib and metabolite analysis, as described in section 7.3.14  
7.2.6. Visit 5 Surgical Resection (7 to 21 days following treatment 
with BTG-002814)  
The following assessments and procedures will be performed:  
• 
Vital signs will be taken before surgery, as described in section 7.3.5  
• 
Record any concomitant medications, as described in section 7.3.20  
• 
Record any adverse events, as described in section 7.3.21  
• 
Samples of resected liver will be taken for vandetanib and metabolite analysis, as described 
in section 7.3.15 and for histopathological and biomarker analysis as described in section 
7.3.16  
7.2.7. Visit 6 End of Study/Early Withdrawal (28-32 days 
postsurgery)  
Patients complete the study 28-32 days following the day of surgical resection. The following 
assessments and procedures will be performed for those patients who complete the study or 
those who withdraw early.  
• 
Physical examination will be conducted, as described in section 7.3.4  
• 
Vital signs will be taken, as described in section 7.3.5  
• 
Performance status will be assessed, as described in section 7.3.6  
• 
Record any concomitant medications, as described in section 7.3.20  


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• 
Record any adverse events, as described in section 7.3.21. Any AEs related to BTG-002814 
continuing at this visit should be recorded as ‘ongoing’ in the patient’s medical notes and 
CRFs.  
• 
Blood samples for biochemistry, haematology and coagulation, as described in section 7.3.8 
  A 12-lead ECG will be taken, as described in section 7.3.12  
Blood sample for biomarkers, as described in section 7.3.13  
Blood sample for vandetanib and metabolite analysis, as described in section 7.3.14  
• 
As appropriate, record the date and reason for study completion as listed in section 5.4  
 
As appropriate, record the date and reason for study withdrawal as listed in section 5.5  
7.3. 
Study Evaluations and Procedures  
7.3.1. Informed Consent Process  
Sites are responsible for assessing a patient’s capacity to give informed consent.  
Sites must assess a patient’s ability to understand verbal and written information in English and 
whether or not an interpreter would be required to ensure fully informed consent. If a patient 
requires an interpreter and none is available, the patient should not be considered for the study.  
Patients with the potential to meet eligibility criteria may be offered the opportunity to be evaluated 
for participation in this clinical study. All such patients must sign the current REC approved 
informed consent form (ICF) before any study-related evaluations can be performed.  
The Investigator or delegate will review the study and the treatment plan with the patients and the 
patients will have an opportunity to ask questions about study procedures, the required visit 
schedule, risks and benefits of the study treatment and alternative treatment options prior to 
signature of the ICF. The patient will receive a copy of the signed ICF to keep for their records.   
A minimum of twenty four (24) hours must be allowed for the patient to consider and discuss 
participation in the study.  
The discussion and consent process must be documented in the patient notes.  
Site staff are responsible for:  
• 
checking that the current REC-approved version of the patient information sheet and consent 
form are used  
• 
checking that information on the consent form is complete and legible  
• 
checking that the patient has completed/initialled all relevant sections and signed and dated 
the form  
• 
checking that an appropriate member of staff has countersigned and dated the consent form 
to confirm that they provided information to the patient  
• 
checking that an appropriate member of staff has made dated entries in the patient’s medical 
notes relating to the informed consent process (i.e., information given, consent signed etc.)  
• 
following registration, adding the patients’ study number to all copies of the consent form, 
which should be filed in the patient’s medical notes and Investigator Site File  
• 
giving the patient a copy of their signed consent form, patient information sheet and patient 
contact card  


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Patients will be informed of any revisions to the ICF and any revisions must be signed and kept 
in the patient study file.   
Each time an ICF is administered (original and subsequent revisions as appropriate), the process 
of obtaining the patient’s informed consent should be documented in the patient’s medical record 
and the ICF signed and dated by the individual who conducted the informed consent discussion.  
The right of the patient to refuse to participate in the study without giving reasons must be 
respected. All patients are free to withdraw at any time.   


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7.3.2. Demographics  
The following demographic data will be obtained: date of birth/age, gender, child-bearing potential, 
race and ethnicity.  
7.3.3. Medical History  
Medical history deemed clinically significant by the Investigator will be collected per body system.  
Diagnosis and medical history for HCC and mCRC will be recorded separately from other medical 
history.   
All ongoing medical conditions and AEs arising from treatment of those conditions present for 30 
days or more prior to entering the study are generally considered a part of the patient’s medical 
history and must be recorded at Screening.  
7.3.4. Physical Examination  
A full physical examination, including height (required at Screening only) and weight, will be 
performed by a qualified licensed individual. A review of body systems will include the following:  
• 
General appearance  
• 
Skin  
• 
Head, Ears, Eyes, Nose, Throat   
• 
Respiratory  
• 
Cardiovascular  
• 
Abdomen (including liver and kidneys)  
• 
Musculoskeletal   
Neurological   
Any abnormalities or changes in intensity noted during the initial review of body systems should 
be documented in the patient’s medical notes and CRFs. If a new clinically significant finding (i.e., 
not noted at Screening) or change in intensity occurs at subsequent visits, this must be 
documented as an AE. Resolution of any abnormal findings during the study will be noted in the 
patient’s medical notes and CRFs.  
7.3.5. Vital Signs  
Assessments of vital signs (i.e., BP and HR) will be performed at all study visits. When possible, 
BP and HR will be determined after the patient has been in the sitting position for 5 minutes.  
Any clinically significant changes from Screening will be recorded as an AE.  
7.3.6. Performance Status  
WHO performance status will be assessed according to the following categories:  
Grade  
WHO Description  
0  
Fully active, able to carry on all pre-disease performance without restriction  
1  
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work  


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2  
Ambulatory and capable of all selfcare but unable to carry out any work activities. 
Up and about more than 50% of waking hours  
3  
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours  
4  
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair  
5  
Dead  
7.3.7. Medication and Prior Treatment History  
The use of concurrent medications (medications taken within 30 days of Screening and during the 
conduct of the study) will be obtained and documented in the patient’s medical notes and CRFs.  
Prior treatment history for HCC and mCRC will also be recorded.  
7.3.8. Clinical Laboratory Evaluations – Biochemistry, Coagulation 
Parameters, Haematology   
All clinical laboratory tests will be performed at the local laboratory according to the laboratory’s 
normal procedures. Reference ranges will be supplied by the laboratory and used to assess the 
laboratory data for clinical significance and out-of-range pathological changes. The Investigator 
should assess out-of-range laboratory values for clinical significance, indicating if the value(s) 
is/are not clinically significant or clinically significant. Abnormal laboratory values, which are 
unexpected or not explained by the patient’s clinical condition, should be repeated until confirmed, 
explained or resolved. Repeat evaluations should be performed as soon as possible after the 
original evaluation.  
Changes from Screening will be recorded as an AE if assessed as clinically significant by the 
Investigator.  
The following clinical laboratory assessments will be completed as per the Schedule of Visits:  
Biochemistry  
Blood samples for biochemistry will be taken.  
• 
Sodium  
• 
Potassium  
• 
Calcium  
• 
Magnesium  
• 
Urea  
• 
Creatinine  
• 
Albumin  
• 
Total Protein  
• 
Alanine transaminase (ALT)  
• 
Aspartate transaminase (AST), if ALT not available  
• 
Alkaline phosphatase (ALP)  
• 
Gamma glutamyl transferase (GGT)  


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• 
Total bilirubin  
• 
Random glucose  
• 
Lactate Dehydrogenase (LDH)  
• 
Urate  
• 
Thyroid Stimulating Hormone (TSH)  
• 
Calculated GFR (using a validated creatinine clearance calculation)  
Coagulation Parameters  
Blood samples for coagulation parameters will be taken.  
• 
Prothrombin Time (PT)  
• 
Partial Thromboplastin Time (PTT)  
• 
International Normalised Ratio (INR)  
Haematology  
Blood samples for haematology will be taken.  
• 
Haemoglobin  
• 
Haematocrit  
• 
White Blood Cell (WBC) Count   
• 
Platelet Count  
• 
WBC- differential and Absolute Neutrophil Count (ANC)  
• 
Red Blood Cell (RBC) Count    Mean corpuscular volume (MCV)  
7.3.9. Pregnancy Test  
All WOCBP will have a serum beta hCG pregnancy test at the Screening Visit to assess their 
suitability for entry into the study.  
7.3.10. Serum Tumour Markers  
The following clinical laboratory tests will be performed at the local laboratory according to the 
laboratory’s normal procedures. Reference ranges will be supplied by the laboratory and used to 
assess the laboratory data for clinical significance and out-of-range pathological changes.    
The following clinical laboratory assessments will be completed as per the Schedule of Visits:  
Patients with HCC:  
• 
serum alpha-fetoprotein (AFP) Patients with mCRC:  
• 
serum CEA  
• 
serum CA19-9  
• 
serum CA125  
7.3.11. Imaging including Dynamic Imaging  
Since measurement of perfusion characteristics may improve understanding of liver tumour 
biology and behaviour, patients in this study will undergo dynamic contrast enhanced (DCE) 
magnetic resonance imaging (MRI) and perfusion Computed Tomography (pCT) at timepoints 
stated in the Schema. pCT and DCE-MRI will be combined with routine scans and study visits 
where possible, although additional visits to the Radiology Department may be required.  


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DCE-MRI  
For DCE-MRI, patients will lie supine on the scanner table and an intravenous cannula placed in 
the antecubital fossa. No oral contrast is required. After acquisition of standard clinical MRI liver 
sequences, T1 mapping will be performed using three-dimensional volumetric gradient echo 
imaging with varying flip angles.  A series of T1–weighted three-dimensional volumetric images 
will be acquired at baseline and at short intervals during administration of a bolus of intravenous 
paramagnetic MR contrast agent at a rate of 3-5 mL/s. Each acquisition takes approximately 5 
seconds during which time patients are asked to hold their breath in full expiration or if necessary 
to breathe in a shallow fashion. The entire post contrast DCE series takes approximately 3-5 
minutes.  
Liver parenchyma and tumour signal intensity curves will be used to calculate semiquantitative 
and quantitative tissue parameters describing tumour perfusion, blood flow and vascularity, using 
a compartment model with an arterial and portal venous input function.  
Assessment of changes in blood flow on DCE-MRI following treatment with BTG-002814. Ktrans, 
Kep and Ve will be derived from DCE-MRI images.  
CT  
CT will incorporate dual energy (DECT) and perfusion imaging (pCT) of the liver, in addition to 
standard clinical contrast enhanced imaging of the chest, abdomen and pelvis. CT should be 
performed before or at least 90 minutes after the MRI scan. Images will be acquired in a supine 
position using a cannula placed in the antecubital fossa, and no oral contrast is required. A 
combined CT protocol will be carried out as follows, with each volume acquired in inspiration:  
1. 
dual energy (80+135 kV) acquisition of the liver prior to contrast administration  
2. 
bolus of 0.5 mL/kg of iodinated contrast (300 mgI/mL) injected at a rate of no less than 5 mL/s 
(total <8 seconds).  
3. 
volume perfusion acquisition of the liver, with intermittent scanning over 90 seconds   
4. 
interval of at least 3 minutes to allow contrast washout  
5. 
bolus of 1 mL/kg of iodinated contrast (300 mgI/mL) injected at a rate of 3-5 mL/s  
6. 
late arterial phase (35 seconds post contrast bolus) volume of the chest and liver  
7. 
portal venous phase (60 seconds post contrast bolus) volume of the abdomen and pelvis 
Data from CT and DCE-MRI will be used in developing the 3D modelling of the distribution of 
BTG-002814.  
Following treatment with BTG-002814 a 4D CT scan will be performed to check and track the 
positioning of the beads in ‘real time’. This scan should be performed without contrast.  
7.3.12. ECG Assessment  
A 12-lead ECG reading will be taken as per the Investigator’s standard practice.  
7.3.13. Blood Biomarkers  
Approximately 4 mL of blood will be collected at the timepoints shown in the schedule of visits for 
the measurement of blood biomarkers. The analysis will be performed by the ECMC GCLP 
Laboratory at UCL Cancer Institute.   
Blood biomarkers will be measured to indicate the activity of the investigational treatment on the 
target cancer, specifically cytokines, chemokines and growth factors relevant to cancer and 
inflammation.  


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Detailed information on sample handling, storage and shipping are provided in the Laboratory 
Manual.  
7.3.14. Vandetanib and N-desmethyl metabolite Plasma Sampling 
and Analysis  
Blood samples (approximately 4 mL) will be taken from an indwelling venous catheter in the 
antecubital fossa or another such suitably positioned catheter for obtaining blood samples. 
Sampling times will be pre-dose (0 min) and at 2 hours (± 15 mins), 4 hours (± 15 min) and 24 
hours (± 1 hour) following the initial administration of BTG-002814. If patients require a longer 
hospital stay, an optional additional sample can be taken after 36 hours and up to the time of 
hospital discharge. Samples also to be taken within 24 hours prior to surgery (Visit 4) and at End 
of Study visit (Visit 6).  
Plasma samples will be analysed by York Bioanalytical Solutions Ltd (YBS) (York, UK) using a 
validated assay.  
Following the completion of the analysis, YBS will store plasma samples for up to 5 years; after 
which, upon written confirmation from the Sponsor, samples will be destroyed by YBS.  
Detailed information on sample handling, storage and shipping are provided in the Laboratory 
Manual.  
7.3.15. Vandetanib and N-desmethyl metabolite Liver Sampling and 
Analysis  
Samples of resected liver tissue (both malignant and non-malignant) will be collected, processed 
and analysed by YBS using a validated assay.  
Following the completion of the analysis, YBS will store the liver samples for up to 5 years; after 
which, upon written confirmation from the Sponsor, samples will be destroyed by YBS.  
Detailed information on sample handling, storage and shipping are provided in the Laboratory 
Manual.  
7.3.16. Surgical Resection and Local Histopathological Assessment 
and Procedures  
Surgical resection is to be carried out as per standard care.   
Participants will be asked for consent to access any stored pathology material from previous 
surgery or biopsy for HCC or colorectal cancer, so that histology pre-BTG-002814 treatment can 
be compared with histology post-treatment.  
The date and type of liver surgery occurring during the protocol period must be recorded in the 
CRF.  Surgical complications occurring within 30 days after surgical resection must be recorded 
in detail.  
The histopathological stage and grade must be recorded (ypTN classification).  The histological 
status of the resection margins must also be recorded (distance to nearest margin) and whether 
the resection was R0, R1 or R2.  
Histopathological assessment of samples of resected liver tissue (both malignant and 
nonmalignant) will include microscopic examination to correlate radiologic extent of tumour cell 


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necrosis to microscopic extent of tumour cell necrosis. Sections of resected liver tissue will be 
paraffin-embedded.  
H&E slides will be produced, which will be scanned to produce 3D pathology models of tumour 
volume. Additional slides will be stained to explore key immune, inflammatory and drug related 
mechanisms. These models can be used to investigate the tumour environment, such as extent 
of necrosis and neoangiogenesis.   
These 3D models will be compared to the 3D models generated from clinical imaging.  
7.3.17. Eligibility Review  
Data documenting demographic information, medical history, physical examination, medication 
and prior treatment history, clinical laboratory tests, Child Pugh assessment (HCC patients only) 
and pregnancy test (for FOCP) will be reviewed against the eligibility criteria to determine 
eligibility. The determination will be recorded in the patient’s medical notes and CRFs.  
7.3.18. Patient Registration   
Patient registration will be undertaken centrally at UCL CTC and this must be performed prior to 
commencement of any study treatment. Pre-registration evaluations should be carried out as 
detailed in section 7.2.1.  
Following consent of the patient, pre-treatment evaluations and confirmation of eligibility, the 
registration form must be fully completed and faxed to UCL CTC who will review the form to 
confirm patient eligibility. If further information is required UCL CTC will contact the person 
requesting registration to discuss the patient and request updated forms to be faxed.  
Once eligibility has been confirmed a unique numeric patient identity code will be assigned for the 
patient and should be added to the form by the site.  
UCL CTC will fax/e-mail confirmation of the patient’s inclusion in the study, their patient code to 
the Principal Investigator (PI), study staff and pharmacy.   
REGISTRATION CONTACT DETAILS  
VEROnA Trial Coordinator  
Cancer Research UK & UCL Cancer Trials Centre  
General Queries: 020 7679 9887  
Randomisation Fax Number: 020 7679 9871  
Office hours: 9am to 5pm, Monday to Friday  
  
7.3.19. Study Medication Treatment Record  
The details of treatment administered at Visit 2 (Treatment day), including the volume 
administered and start/stop times will be recorded in the patient’s medical notes and CRFs.  


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7.3.20. Concomitant Medication Record  
At every study visit, new medications or changes in concomitant medications will be recorded in 
the patient’s medical notes and CRFs. Documentation will include medication dosage and 
start/stop dates.  
7.3.21. Observation and Recording of Adverse Events  
All AEs will be documented from the date of signature of Informed Consent until the patient’s last 
visit.  
Refer to section 8.1.7 for information regarding the procedure for recording AEs.  
The Investigator will assess all AEs for severity grading according to CTCAE v4.0, and relationship 
to BTG-002814 (relationship to vandetanib and the drug eluting beads/TACE procedure will be 
assessed separately). Definitions and procedures for assessment can be found in Section 8.  
Pregnancy: any report of pregnancy or complications of pregnancy such as miscarriage or 
congenital abnormality recorded for any female trial participant or female partner of trial 
participant, should be reported within the same time-frame as required for an SAE (24 hours) to 
UCL CTC using the study specific Pregnancy Report. Every effort should be made to gather 
information regarding the pregnancy outcome until 8 weeks post-partum. It is the responsibility of 
the Investigator to obtain all pregnancy information.  
 


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8. 
ADVERSE EVENTS  
8.1. 
Adverse Event Definitions  
Adverse experience will be considered synonymous with the term adverse event and vice versa.  
8.1.1. Adverse Event (AE)  
An AE is any untoward medical occurrence or undesirable event(s) experienced by a patient that 
begins or worsens following administration of the study drug, whether or not considered related 
to the treatment by the Investigator.   
An undesirable event(s) can be, but is not limited to, symptoms experienced by a patient or 
objective findings, such as significant clinical laboratory abnormalities.  
For the purpose of this study, the occurrence of a pregnancy is not considered to be an AE but 
should be reported within 24 hours to UCL CTC using the study specific Pregnancy Report. 
Reports of exposure during pregnancy will be followed up and the outcome of the pregnancy 
should be reported to UCL CTC by submitting a follow up Pregnancy Report. If the pregnancy 
results in an AE to the mother, foetus or neonate, then the SAE process should be followed and 
the event reported in accordance with Section 8.1.5.  
8.1.2. Serious Adverse Event (SAE)  
Any untoward medical occurrence that at any dose:  
• 
results in death;  
• 
is life-threatening (“life-threatening” refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe);  
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation;  
• 
results in a persistent or significant disability/incapacity; or  
• 
is a congenital anomaly/birth defect   
important medical event, see below  
Medical and scientific judgment should be exercised in deciding whether medical events that may 
not be immediately life-threatening or result in death or hospitalisation but may jeopardise the 
patient or may require intervention to prevent one of the other outcomes listed in the definition 
above, should also be considered serious.  
8.1.3. Recording Adverse Events  
All AEs will be documented from the date of signature of Informed Consent until the patient’s last 
visit.  
Patients should be encouraged to report AEs spontaneously or in response to general, 
nondirected questions.  At any time during the study, the patient may volunteer information that 
resembles an AE. Once it is determined that an AE has occurred, the Investigator should obtain 
all the information required to complete the AE form. Where possible, a diagnosis, rather than a 
list of signs or symptoms, should will be recorded. Any medical management of an event and the 
date of resolution of the event must be recorded in the patient’s medical notes and on the 
appropriate CRF using medical terminology according to Sponsor instructions.  
For each AE, the following information will be recorded:   
• 
AE term  


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• 
Serious/non-serious   
• 
Severity  
• 
Action taken  
• 
Relationship to study treatment  
• 
Date of onset  
• 
Date of resolution  
If there are any AEs related to BTG-002814 continuing at the End of Study Visit, these should be 
recorded as ‘ongoing’ in the patient’s medical notes and CRFs. These events should be managed 
according to sites local practice.  
SAEs should be managed as discussed in Section 8.1.5.  
Once the patient has been discharged from the study, the Investigator has no obligation to seek 
further follow-up with the patient in order to identify new AEs. However, if the Investigator 
becomes aware of an SAE that has occurred following the patient’s discharge from the study and 
the Investigator considers the SAE to be related to BTG-002814, then the Investigator should 
report the SAE as described in Section 8.1.5.  
8.1.4. Causality (Relationship to Drug) Assessment  
The Investigator or physician sub-investigator must indicate whether he/she believes the AE is 
related (reasonable possibility that the investigational drug caused the AE), or not related (no 
reasonable possibility).   
Relationship to vandetanib and the drug eluting beads/TACE procedure will be assessed 
separately.  
8.1.5. Reporting Serious Adverse Events   
All SAEs that occur between the signing of informed consent and Visit 6/End of Study visit (or 
after this date if the site Investigator feels the event is related to study treatment) must be 
submitted to UCL CTC by fax within 24 hours of observing or learning of the event, using the 
study specific SAE Report form. All sections of the SAE Report form must be completed. If the 
event is not being reported within 24 hours to UCL CTC, the circumstances that led to this 
must be detailed in the SAE Report.  
Patients experiencing an SAE should be followed clinically and with laboratory and/or 
diagnostic procedures, if appropriate, until medical treatment and/or medical monitoring 
of the event is no longer required because the event resolves or stabilises, returns to 
baseline if a baseline value is available, can be attributed to agents other than the study 
treatments or a referral for appropriate follow-up care has been made.  
8.1.6. SAE Processing at UCL CTC  
On receipt of an SAE Report, UCL CTC will check for legibility, completeness, accuracy and 
consistency. Expectedness will be evaluated, to determine whether or not the case qualifies for 
expedited reporting, using information provided in the Investigator Brochure (IB).  
UCL CTC will submit all SAE Reports concerning patients who have received BTG-002814 to 
BTG according to the timelines outlined in the agreement between UCL CTC and BTG. BTG will 
perform the Sponsor causality assessment. If UCL CTC has considered expectedness difficult to 
determine BTG will be consulted for their opinion at this time.  


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The Chief Investigator, or their delegate, may be contacted to review the SAE and to perform an 
evaluation of causality on behalf of the Sponsor.   
If the event is a Suspected Unexpected Serious Adverse Reaction (SUSAR), UCL CTC will submit 
a report to the MHRA within the required timelines.  
UCL CTC will fulfil the reporting requirements of the REC in relation to SAEs and SUSARs.  
Each AE reported on an SAE form must also be reported on the AE section of the CRF.  
8.1.7. Adverse Event Reporting  
AEs will be recorded on the AE form and the severity grade using NCI CTCAE Version 4.0.  The 
Investigator or physician sub-investigator will judge the severity of each AE and whether or not it 
is thought to be related to study treatment.  All AEs that occur after signing the informed consent, 
including events likely to be related to the underlying disease or likely to represent concurrent 
illness, will be recorded, including events present at the Screening visit which worsen during the 
study  
Development Safety Update Reports (DSURs) will be prepared by BTG and submitted to the 
competent authority and REC by UCL CTC.  
8.1.8. Safety Profile of BTG-002814  
There have been no patients treated with BTG-002814. This will be the first study of BTG-002814 
in humans. The first patient recruited to the study will be observed until the completion of surgery 
before subsequent patients are recruited.  
Safety data with the use of oral vandetanib to treat medullary thyroid cancer  
Oral vandetanib is a standard therapy used to treat medullary thyroid cancer. Vandetanib 
produces repolarisation abnormalities in human myocardium that are consistent with blockade of 
the IKR (potassium) channel. The most consistent electrophysiologic effects are a change in Twave 
morphology (flattening, broadening or notching) and prolongation of the QT interval, both of which 
occur more commonly as the dose is increased. Vandetanib can cause rash, diarrhoea and 
hypertension, all of which appear to be dose-related and are likely to be related to the 
pharmacologic activity of vandetanib.  
For the full list of known Adverse Reactions and safety warnings, refer to the current version of 
the BTG-002814 IB.  
Safety data with the use of radiopaque embolic beads  
The clinical risks of the RO bead are mainly due to the embolisation procedure (e.g. non-target 
embolisation, post embolisation syndrome) itself and are the same as known for other similar 
products on the market. These risks can be minimised by following the warnings and precautions 
in the IB and the requirement that BTG-002814 is used only by well-trained physicians.   
9. 
STATISTICAL CONSIDERATIONS  
9.1. 
Study Design and Determination of Sample Size  
The statistical analysis in this study will be primarily descriptive, to assess the safety and 
tolerability of the study treatment, as well as the distribution of the product following delivery. The 
study is not statistically powered. A staged enrollment will be performed, allowing for a safety 


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review after three patients have completed study treatment and follow up. Provided the safety 
committee deems that there is no significant toxicity related to BTG-002814, a further 9 patients 
will be enrolled in order to have a target sample size in the study of 6 patients with HCC and 6 
patients with liver metastases from CRC. If up to two patients fail to complete study treatment and 
follow up, they will be replaced, giving a maximum total sample size of 14.  
9.2. 
Statistical Analysis   
The statistical analysis plan will be a separate document and will be updated as required prior to 
the analysis, in association with any protocol amendments. The plan will include descriptions of 
tables, listings and figures and will describe statistical programming considerations.  
9.2.1. Analysis Populations and Sub-Groups  
The Analysis Population will consist of all patients who received treatment with BTG-002814. 
The safety and efficacy analyses will be performed on the Analysis Population. Results will be 
presented separately for HCC and mCRC patients.  
9.3. 
Baseline and Demographic Characteristics  
The following demographic and baseline characteristics will be summarised descriptively, overall 
and by disease (HCC or mCRC):  
• 
Gender, age, race and ethnicity.  
• 
WHO Performance Status.  
• 
Location and characteristics of tumour.  
• 
Other characteristics (e.g. baseline laboratory profiles, vital signs, physical examination, child-
bearing potential, ECG, blood biomarkers and serum tumour markers).  
Medical history will be coded using MedDRA, and summarised by primary system organ class 
and preferred term.  
The previous and concomitant medications will be summarised by ATC class and preferred term 
(WHO Drug Dictionary).  
9.4. 
Efficacy Analyses  
The following assessments are exploratory indicators of efficacy. Each will be summarised for all 
patients and by disease (HCC or mCRC):  
9.4.1. Vandetanib concentration  
Concentration of vandetanib and N-desmethyl vandetanib in plasma and in resected liver tissue 
following treatment with BTG-002814. Concentration profiles over time will be reported.  
9.4.2. Distribution of BTG-002814  
The distribution of BTG-002814 within the tumour vasculature and regions of interest will be 
assessed on non-contrast enhanced imaging. The findings will be summarised descriptively.  


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9.4.3. Histopathology of resected liver  
An evaluation of histopathological features in both malignant and non-malignant liver tissue from 
the surgical specimen will be performed. The extent of tumour necrosis, viable tumour and any 
vascular changes observed will be summarised descriptively.  
9.4.4. 3D modelling  
The correlation between the distribution of BTG-002814 on imaging and within the pathological 
specimen will be explored using 3D modelling.  
9.4.5. Blood flow following embolisation  
Assessment of changes in blood flow will be assessed using DCE-MRI following treatment with 
BTG-002814.  The parameters Ktrans, Kep and Ve will be derived from the DCE-MRI images and 
will be summarised descriptively.  
9.4.6. Biomarker analysis  
Levels of blood biomarkers (cytokines, chemokines and growth factors relevant to cancer and 
inflammation) will be measured following treatment with BTG-002814. The levels and changes in 
levels across the study will be summarised descriptively.  
Levels of serum alpha-fetoprotein (AFP) in patients with HCC, and serum CEA, CA19-9 and 
CA125 in patients with mCRC will be measured following treatment with BTG-002814. The levels 
and changes in levels across the study will be summarised descriptively.  
9.5. 
Safety Analyses  
All safety results will be presented overall and by disease (HCC or mCRC):  
9.5.1. Adverse Events  
Adverse events will be graded by the Investigators using the NCI CTCAE v4.0 scale, and coded 
using MedDRA (the current version at the time of coding).  
The number (n) and percentages (%) of patients affected by at least one AE, as well as the number 
of patients affected by at least one AE with causal relationship to the study treatment, will be 
summarised firstly overall, then by system/organ class and preferred term (MedDRA). Adverse 
events will also be tabulated by intensity, treatment for the AE, outcome and causality.  
Deaths, SAEs, treatment-related complications, AEs leading to withdrawal and Unexpected 
Adverse Events (UAE) will be listed separately.   
9.5.2. Laboratory Parameters  
Observed values, changes from baseline, shifts in CTC grade and normal values/above and 
below normal values will be summarised with descriptive statistics. A listing of individual laboratory 
data will be provided with values outside normal ranges flagged.  
9.5.3. Other Safety Parameters  
Other safety parameters such as ECG, vital signs and physical examinations will be summarised.  


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9.6. 
Interim Safety Analysis  
The interim safety analysis will incorporate a review of the following data for the first three patients 
who have completed study treatment and follow up:  
• 
Baseline characteristics and demography  
• 
Details of treatment   
• 
All AEs, graded according to NCI CTCAE and coded using MedDRA.  
 


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10. 
DATA MANAGEMENT  
All data management processes up to and including database lock will be detailed in the Data 
Management Plan (DMP), including the processes for import of external data (e.g. laboratory 
data).  
Data will be collected from sites on version controlled CRFs designed for the study and supplied 
by UCL CTC. Data must be accurately transcribed onto the CRFs and must be verifiable from 
source data at site. Examples of source documents are hospital records which include patient’s 
notes, laboratory and other clinical reports etc.  
Where copies of supporting source documentation (e.g. CT/MRI scan images etc.) are being 
submitted for the study, the patient’s study number must be clearly indicated on all material and 
any patient identifiers removed/redacted prior to sending to maintain confidentiality.  
10.1. Completing Case Report Forms  
All CRFs must be completed and signed by staff who are listed on the site staff delegation log 
and authorised by the PI to perform this duty. The PI is responsible for the accuracy of all data 
reported in the CRF.  
All entries must be clear, legible and written in ball point pen. Any corrections made to a CRF at 
site must be made by drawing a single line through the incorrect item ensuring that the previous 
entry is not obscured. Each correction must be dated and initialed. Correction fluid must not be 
used.  
The use of abbreviations and acronyms should be avoided.  
Once completed the original CRFs must be sent to UCL CTC and a copy kept at site.  
10.2. Missing Data  
To avoid the need for unnecessary data queries CRFs must be checked at site to ensure there 
are no blank fields before sending to UCL CTC (unless it is specifically stated that a field may be 
left blank). When data are unavailable because a measure has not been taken or test not 
performed, enter “ND” for not done. If an item was not required at the particular time the form 
relates to, enter “NA” for not applicable. When data are unknown enter the value “NK” (only use 
if every effort has been made to obtain the data).  
10.3. Timelines for Data Return  
CRFs must be completed at site and returned to UCL CTC as soon as possible after the relevant 
visit.    
Sites that persistently do not return data within the agreed timelines may be suspended from 
recruiting further patients into the study by UCL CTC and subjected to a ‘for cause’ monitoring 
visit.   
10.4. Data Queries  
Data arriving at UCL CTC will be checked for legibility, completeness, accuracy and consistency, 
including checks for missing or unusual values. Data Clarification Requests will be sent to the 
data contact at site. Further guidance on how data contacts should respond to data queries can 
be found on the Data Clarification Request forms.  


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Raw data collected by third party vendors i.e., YBS will be electronically transferred to UCL CTC 
for inclusion in the UCL CTC Data Management study database. The transfer of derived data to 
UCL CTC will be described in the DMP.  
Data verification and data validation checks will be performed by UCL CTC Data Management 
utilising electronic edit checks comprised of validated computer programs and manual data 
review. Any data discrepancies will be referred back to the Investigator via the site monitor. A 
clean database will be declared by UCL CTC after consistency checks have been run, all SAE 
reconciliations have been resolved, all data in a clean data transfer have been received including 
third party vendor data, all the data in the database has been accounted for, all edit checks have 
been run and data discrepancies have been resolved or accepted and a Quality Check on a 
sample of the data has been performed. After the database has been declared clean it will be 
locked and editing in the database will only be allowed with the proper documentation.   
After database lock, data will be extracted to SAS® datasets (SAS Institute, Inc., Cary, NC, USA) 
for analysis as defined in the Statistical Analysis Plan (SAP). SAEs will be entered into the UCL 
CTC study safety database.  
AEs and prior concomitant diseases will be coded according to the version of MedDRA agreed 
with the Sponsor. Concomitant medications will be coded using the version of the WHO Drug 
dictionary agreed with the Sponsor.  
 


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11. 
LEGAL/ETHICS and ADMINISTRATIVE 
PROCEDURES  
11.1. Good Clinical Practice/Regulatory Compliance  
The procedures set out in this study protocol, pertaining the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
the Declaration of Helsinki, Good Clinical Practice (GCP) and International Council for 
Harmonisation (ICH).  
It is the Investigator’s responsibility to ensure that adequate time and appropriate resources are 
available at the study site prior to commitment to participate in this study. The Investigator should 
also be able to estimate or demonstrate the potential for recruiting the required number of suitable 
patients within the agreed recruitment period. The Investigator will maintain a list of appropriately 
qualified person to whom the Investigator has delegated significant study-related tasks.  
11.2. Study Site and Investigator Qualification  
This study will be performed by appropriately qualified and licensed Investigators at two sites in 
the UK. All site staff must be appropriately qualified by education, training and experience to 
perform the study related duties allocated to them, which must be recorded on the site delegation 
log.  
GCP training is required for all staff responsible for study activities. The frequency of repeat 
training may be dictated by the requirements of their employing institution, or 2 yearly where the 
institution has no policy, and more frequently when there have been updates to the legal or 
regulatory requirements for the conduct of clinical trials.  
The study sites will be reviewed by UCL CTC (on behalf of the Sponsor) to verify that they are 
able to conduct the study.   
11.2.1. Investigator Curriculum Vitae (CV)  
The Investigator will provide the Sponsor or designee with his/her current curriculum vitae (CV), 
and any revisions/updates, as well as those of any sub-investigator or staff personnel with 
significant study responsibilities.    
11.2.2. Site qualifications and study-specific procedural training  
The Institution must have appropriately qualified Investigators, and clinical and administrative 
support staff in place to adequately conduct the study according to GCP in general and must have 
the adequate expertise and staff to conduct this study in compliance with the relevant guidelines 
and regulations and to treat patients with HCC and mCRC.  
The physicians who will perform the treatment with BTG-002814 will be qualified Interventional 
Radiologists who are experienced with DEB-TACE treatments and will be accustomed to DC 
Bead® and its comparator products as spherical microsphere embolisation devices. However, 
prior to performing the first study-related treatment, the Interventional Radiologists who will be 
performing the treatment will undergo documented training in the use of RO bead.   


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11.2.3. Laboratory Certification and Normal Values  
The Investigator will provide the Sponsor with the name and location of the clinical laboratory to 
be used for determination of laboratory assays, copy of certification, and a list of the normal range 
of values of all laboratory tests. Any changes in laboratory, certification or normal ranges will be 
communicated promptly to the Sponsor or UCL CTC.  
11.3. Institutional Review Board (IRB)/Independent Ethics 
Committees (IEC)  
11.3.1. Institutional Approval of the Protocol  
It is the responsibility of UCL CTC to submit this protocol, the informed consent document 
(approved by the Sponsor or designee), relevant supporting information and all types of patient 
recruitment information to the Research Ethics Committee (REC) for review and approval prior to 
site initiation.  A copy of the written approval of the protocol and ICF must be received by the 
Sponsor or designee prior to shipment of investigational product or recruitment of patients. Prior 
to implementing changes in the study, the Sponsor and REC must also approve any revised 
informed consent documents and amendments to the protocol with documentation of the 
approvals submitted to the Sponsor or designee. The approval document should clearly state the 
study reference, date of review and actions taken.  
The Sponsor or designee will be responsible for keeping the REC apprised of the progress of the 
study, any changes to the protocol, deviations from the protocol and SAEs as required by the 
REC.  
11.3.2. IRB/Ethics Committee Membership Roster  
A complete and current membership roster of the REC should be provided to the Sponsor or 
designee.   
11.4. Informed Consent  
It is the responsibility of the Investigator to obtain written Informed Consent from patients prior to 
the conduct of any study procedures. All Informed Consent documentation must be in accordance 
with applicable regulations and GCP. Each patient is requested to sign the ICF after the patient 
has received and read the written information and received an explanation of the study, including 
but not limited to: the objectives, treatment plan, potential benefits and risk, inconveniences, 
alternative treatment options and the patient’s rights and responsibilities. A copy of the Informed 
Consent documentation (Informed Consent Form or Patient Information and Informed Consent  
Form, as applicable) must be given to the patient or the patient’s legally authorised representative.   
Acquisition of the Informed Consent should be documented in the patient’s medical record and 
the ICF should be personally signed and dated by the patient and the individual who conducted 
the Informed Consent discussion. Signed Informed Consent forms must remain in each patient’s 
study file and must be available for verification by Study Monitors at any time.  
The Sponsor must receive a copy of the REC- approved Informed Consent form and a copy of 
the REC written approval, prior to the start of the study. Additionally, if the REC required 
modification of the sample Patient Information and Informed Consent document provided by the 
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The Sponsor reserves the right to delay initiation of the study at a site where the Informed Consent 
forms do not meet the standards of applicable regulations and international GCP 
standards/guidelines.  
11.5. Patient Privacy and Confidentiality  
The Sponsor and Investigator affirm and uphold the principle for the patient’s right to protection 
against invasion of privacy. Throughout this trial, all data collected and analysed by the Sponsor 
or designee will be treated confidentially and identified by an identification number.   
To verify compliance with the protocol, the Sponsor will require the Investigator to permit its 
designee access to the patient’s primary medical record to review those portions that directly 
concern this study (including but not limited to laboratory test results, radiology images, and 
hospital and outpatient records).  
As part of required content of the Informed Consent, the patient must be informed that his/her 
records will be reviewed by the Sponsor, Sponsor representative and/or a representative of the 
appropriate competent authority and Safety Committee. The Informed Consent or related 
document will also state that patient privacy will be maintained pursuant to local regulations. 
Should access to such medical records require a waiver or authorisation separate from the 
statement of Informed Consent, the Investigator will obtain such permission in writing from the 
patient before the patient is entered in the study.  
Patient identifiable data, including initials, gender and age, will be required for the registration 
process and will be provided to UCL CTC. UCL CTC and the Sponsor will preserve patient 
confidentiality and will not disclose or reproduce any information by which patients could be 
identified. Data will be stored in a secure manner and studies conducted by UCL CTC are 
registered in accordance with the Data Protection Act 1998 with the Data Protection Officer at 
UCL.  
Data collected during this study may be used to support the development, registration or 
marketing of BTG-002814.  Collected data may be reviewed by the Sponsor and/or its 
representatives, independent auditors who validate the data on behalf of the Sponsor, third parties 
with whom the Sponsor may develop, register or market BTG-002814, national or local competent 
authorities and the REC which granted approval for this study to proceed.  
11.6. Study Monitoring  
Monitoring of the study will be detailed in the Study Monitoring Plan and will be performed by 
qualified personnel from the Sponsor or Sponsor designee. At the monitoring visits, the progress 
of the study will be discussed with the Investigator or his/her representative. The ICFs will be 
reviewed for signatures and the CRFs checked for completeness and accuracy. Patient source 
data must be available for review. The Investigator and his/her staff are expected to cooperate 
with the Study Monitor and be available during at least a portion of the monitoring visit to review 
the CRFs and any queries/resolutions, answer questions, and provide any missing information.  
The Study Monitor will record the date of each visit together with a summary of the status and 
progress of the study. Proposed actions will be confirmed with the Investigator in writing. 
Telephone and electronic mail contact will be made with the Investigator and study staff as 
necessary during the data collection and report writing periods.   


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11.7. Modification of the Protocol  
UCL CTC (on behalf of the Sponsor) will be responsible for gaining ethical and regulatory 
approval(s), as appropriate, for amendments made to the protocol and other study-related 
documents. Once approved, UCL CTC will ensure that all amended documents are distributed to 
sites as appropriate.  
Site staff will be responsible for acknowledging receipt of documents and for implementing all 
amendments promptly.  
All amendments to the protocol must be documented in writing, reviewed and approved by the 
Chief Investigator and Sponsor and submitted to the REC and/or competent authority for approval 
prior to initiation. If the protocol amendment substantially alters the study design or potential risk 
to the patient, new written Informed Consent must be obtained from each patient for continued 
participation in the study.   
11.8. Suspension or Termination of Study  
If conditions arise requiring further clarification before the decision can be reached to proceed 
with or terminate the study, the study will be suspended until the situation has been resolved.   
The Sponsor has the right to terminate this study and remove all study material from the site at 
any time. Examples of situations where this might occur include:  
• 
It becomes apparent that patient enrollment is unsatisfactory with respect to quality and/or 
quantity or data recording is chronically inaccurate and/or incomplete.  
• 
The incidence and/or severity of adverse events in the study indicate a potential health hazard 
caused by the trial treatment.  
11.9. Departure from Protocol  
No deviation may be made from the protocol unless an amendment has been agreed to in writing 
by both the Investigator and the Sponsor and approved by the REC and competent authority, if 
applicable.  When an emergency occurs that requires a departure from the protocol for an 
individual, the Investigator or other physician in attendance will, if circumstances and time permit, 
contact UCL CTC or their representatives, immediately by telephone. Urgency is important to 
permit a decision as to whether or not the patient (for whom the departure from protocol effects) 
is to continue in the study. The source documents will completely describe the departure from the 
protocol and state the reasons for such departure. As appropriate, the REC will be notified in 
writing.   
Urgent Safety Measures will be reported to the MHRA in accordance with the MHRA guidance on 
Reporting Urgent Safety Issues  
11.9.1. Protocol Deviations  
All protocol deviations will be documented and will be reviewed periodically by the Sponsor as 
detailed in the study Protocol Deviation Plan.  
Protocol deviations will be tracked according to the following categories:  
• 
Informed consent process not followed  
• 
Screening tests or procedures out of window or not done  
• 
Imaging tests not performed as required  


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• 
Dose delivery outside specified range   Use of prohibited medications  
Major protocol deviations are defined as:  
• 
Enrollment violations: eligibility criteria deviations, informed consent issues,  
• 
Data violations: those affecting primary study endpoints  All others will be classified as minor 
protocol deviations  
11.9.2. Serious Breaches  
A “serious breach” is defined as a breach of the protocol or of the conditions or principles of Good 
Clinical Practice  which is likely to affect to a significant degree the safety or physical or mental 
integrity of the trial subjects, or the scientific value of the research.  
Systematic or persistent non-compliance by a site with GCP and/or the protocol, including failure 
to report SAEs occurring on trial within the specified timeframe, may be deemed a serious breach.  
In cases where a serious breach has been identified, BTG will inform the MHRA and REC within 
7 calendar days of becoming aware of the breach.  
11.10. Recording, Access to and Retention of Source Data  
Investigators are required to prepare and maintain adequate source documentation which 
includes:  
• 
Documents relative to the patient medical history that verify Eligibility criteria  
• 
Records covering patient participation in the study including basic identification information, 
results of physical examinations and diagnostic tests, original laboratory results (initialled 
and dated by the Investigator), study treatment administration, concurrent medication 
information, and visit notes.  
Data must be recorded in the patient’s source documents including the date of Informed Consent.  
The Investigator must permit authorised representatives of the Sponsor, the competent authority, 
the REC, and auditors to inspect facilities and records relevant to the study.  
The monitor, auditors, REC or regulatory inspectors  may check the CRF entries against the 
source documents. The Informed Consent form will include a statement by which the patients 
allow the above-named access to source data that substantiate information recorded in the CRFs. 
These personnel, bound by professional secrecy, will not disclose any personal information or 
personal medical information.   
As described in the ICH GCP Guidelines, ‘essential documents’, including CRFs, source 
documents, Informed Consent forms, laboratory test results, IP inventory records, should be 
retained by the Investigator until at least two years after the last approval of a marketing 
application in an ICH region or at least two years have elapsed since the formal discontinuation 
of a clinical development of the IP. These documents should be retained for a longer period 
however if required by the applicable regulatory requirements or by an agreement with the 
Sponsor. The Investigator must obtain written permission from the Sponsor prior to destruction of 
any study document.  
These records must be made available at reasonable times for inspection and duplication, if 
required.  


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11.11. Source Documents and Case Report Forms  
The Investigator is responsible for maintaining adequate and accurate source documents from 
which accurate information will be transcribed into CRFs that have been designed to capture all 
observations and other data pertinent to the clinical investigation. CRFs should be completed by 
the Investigator or delegate as stated on the Delegation of Authority Log.   
Overwriting of information or use of liquid correcting fluid is not allowed in source documentation.   
Once the Study Monitor has verified the contents of the completed CRF against the source data, 
queries may be raised if the data are unclear or contradictory.  
11.12. End of Study  
For regulatory purposes the end of the study will be the last visit of the last subject (LVLS), at 
which point the ‘declaration of end of trial’ form will be submitted to the MHRA and Ethics 
Committee, as required.  
Following this, UCL CTC will advise sites on the procedure for closing the study at the site.  
Once the end of study has been declared, no more prospective patient data will be collected but 
sites must co-operate with any data queries regarding existing data to allow for analysis and 
publication of results.  
11.13. Publications  
All manuscripts, abstracts or other modes of presentation arising from the results of the study will 
be prepared by the Chief Investigator and must be reviewed and approved in writing by the 
Sponsor, in advance of submission. The review is intended to protect Sponsor proprietary 
information existing either at the date of commencement of the study or generated during the 
study. No individual Investigator may publish results from his/her site until after publication of the 
primary manuscript describing the full study population.  
The detailed obligations regarding the publication of any data, material results or other information 
that is generated or created in relation to the study shall be set out in the agreement between the 
Investigator and Sponsor.  
In accordance with recommendations from the International Committee of Medical Journal 
Editors, the study will be listed in a publicly accessible registry of clinical trials such as 
clinicaltrials.gov.  
11.14. Audit/Inspections  
BTG Clinical Quality Assurance may audit the study sites at any time during the study. To ensure 
compliance with relevant regulations, data generated by this trial must be available for inspection 
upon request by representatives of the REC, competent authorities, the Sponsor and its 
representatives.   
12. 
BIBLIOGRAPHY  
Adam R, De Gramont A, Figueras J, Guthrie A, Kokudo N, Kunstlinger F, et al. (2012). The 
oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary 
international consensus. Oncologist 17: 1225-1239.  
  


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Bruix J, Sherman M, & American Association for the Study of Liver D (2011). Management of 
hepatocellular carcinoma: an update. Hepatology 53: 1020-1022.  
  
Cabebe EC, Fisher GA, & Sikic BI (2012). A phase I trial of vandetanib combined with 
capecitabine, oxaliplatin and bevacizumab for the first-line treatment of metastatic colorectal 
cancer. Invest New Drugs 30: 1082-1087.  
  
De Groote K, & Prenen H (2015). Intrahepatic therapy for liver-dominant metastatic colorectal 
cancer. World J Gastrointest Oncol 7: 148-152.  
  
EASL, & EORTC (2012). EASL-EORTC clinical practice guidelines: management of 
hepatocellular carcinoma. J Hepatol 56: 908-943.  
  
Ferrara N (2004). Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 
9 Suppl 1: 2-10.  
  
Fiorentini G, Aliberti C, Turrisi G, Del Conte A, Rossi S, Benea G, et al. (2007). Intraarterial hepatic 
chemoembolization of liver metastases from colorectal cancer adopting irinotecan-eluting beads: 
results of a phase II clinical study. In Vivo 21: 1085-1091.  
  
Herbst RS, Sun Y, Eberhardt WE, Germonpre P, Saijo N, Zhou C, et al. (2010). Vandetanib plus 
docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell 
lung cancer (ZODIAC): a double-blind, randomised, phase 3 trial. Lancet Oncol 11: 619-626.  
  
Holden SN, Eckhardt SG, Basser R, de Boer R, Rischin D, Green M, et al. (2005). Clinical 
evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients 
with solid, malignant tumors. Ann Oncol 16: 1391-1397.  
  
Hsu C, Yang TS, Huo TI, Hsieh RK, Yu CW, Hwang WS, et al. (2012). Vandetanib in patients with 
inoperable hepatocellular carcinoma: a phase II, randomized, double-blind, placebo-controlled 
study. J Hepatol 56: 1097-1103.  
  
Inoue K, Torimura T, Nakamura T, Iwamoto H, Masuda H, Abe M, et al. (2012). Vandetanib, an 
inhibitor of VEGF receptor-2 and EGF receptor, suppresses tumor development and improves 
prognosis of liver cancer in mice. Clin Cancer Res 18: 3924-3933.  
  
Johnson CG, Tang Y, Beck A, Dreher MR, Woods DL, Negussie AH, et al. (2016). Preparation 
of Radiopaque Drug-Eluting Beads for Transcatheter Chemoembolization. J Vasc Interv Radiol 
27: 117-126 e113.  
  
Kudo M (2012). Signaling pathway/molecular targets and new targeted agents under development 
in hepatocellular carcinoma. World J Gastroenterol 18: 6005-6017.  
  
Lencioni R, Petruzzi P, & Crocetti L (2013). Chemoembolization of hepatocellular carcinoma. 
Semin Intervent Radiol 30: 3-11.  
  
Lewandowski RJ, Thurston KG, Goin JE, Wong CY, Gates VL, Van Buskirk M, et al. (2005). 90Y 
microsphere (TheraSphere) treatment for unresectable colorectal cancer metastases of the liver: 


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response to treatment at targeted doses of 135-150 Gy as measured by [18F]fluorodeoxyglucose 
positron emission tomography and computed tomographic imaging. J Vasc Interv Radiol 16: 
1641-1651.  
  
Lewis AL, Gonzalez MV, Lloyd AW, Hall B, Tang Y, Willis SL, et al. (2006). DC bead: in vitro 
characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv 
Radiol 17: 335-342.  
  
Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. (2006). Sorafenib blocks the 
RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in 
hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66: 11851-11858.  
  
Lopez PM, Villanueva A, & Llovet JM (2006). Systematic review: evidence-based management 
of hepatocellular carcinoma--an updated analysis of randomized controlled trials. Aliment 
Pharmacol Ther 23: 1535-1547.  
  
Meyerhardt JA, Ancukiewicz M, Abrams TA, Schrag D, Enzinger PC, Chan JA, et al. (2012). 
Phase I study of cetuximab, irinotecan, and vandetanib (ZD6474) as therapy for patients with 
previously treated metastastic colorectal cancer. PLoS One 7: e38231.  
  
Michael M, Gibbs P, Smith R, Godwood A, Oliver S, & Tebbutt N (2009). Open-label phase I trial 
of vandetanib in combination with mFOLFOX6 in patients with advanced colorectal cancer. Invest 
New Drugs 27: 253-261.  
  
Mross K, Fasol U, Frost A, Benkelmann R, Kuhlmann J, Buchert M, et al. (2009). DCE-MRI 
assessment of the effect of vandetanib on tumor vasculature in patients with advanced colorectal 
cancer and liver metastases: a randomized phase I study. J Angiogenes Res 1: 5.  
  
Narayanan G, Barbery K, Suthar R, Guerrero G, & Arora G (2013). Transarterial 
chemoembolization using DEBIRI for treatment of hepatic metastases from colorectal cancer. 
Anticancer Res 33: 2077-2083.  
  
Natale RB, Thongprasert S, Greco FA, Thomas M, Tsai CM, Sunpaweravong P, et al. (2011). 
Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced 
non-small-cell lung cancer. J Clin Oncol 29: 1059-1066.  
  
Parkin DM, Bray F, Ferlay J, & Pisani P (2005). Global cancer statistics, 2002. CA Cancer J Clin 
55: 74-108.  
  
Poon RT, Tso WK, Pang RW, Ng KK, Woo R, Tai KS, et al. (2007). A phase I/II trial of 
chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. 
Clin Gastroenterol Hepatol 5: 1100-1108.  
  
Raza A, & Sood GK (2014). Hepatocellular carcinoma review: current treatment, and 
evidencebased medicine. World J Gastroenterol 20: 4115-4127.  
  
Ryan AJ, & Wedge SR (2005). ZD6474--a novel inhibitor of VEGFR and EGFR tyrosine kinase 
activity. Br J Cancer 92 Suppl 1: S6-13.  


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Tamura T, Minami H, Yamada Y, Yamamoto N, Shimoyama T, Murakami H, et al. (2006). A phase 
I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors. J Thorac 
Oncol 1: 1002-1009.  
  
Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, et al. (2016). ESMO 
consensus guidelines for the management of patients with metastatic colorectal cancer. Ann 
Oncol 27: 1386-1422.  
  
Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. (2007). Chemoembolization of 
hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J 
Hepatol 46: 474-481.  
  
Vlahovic G, & Crawford J (2003). Activation of tyrosine kinases in cancer. Oncologist 8: 531-538.  
  
Wang YX, De Baere T, Idee JM, & Ballet S (2015). Transcatheter embolization therapy in liver 
cancer: an update of clinical evidences. Chin J Cancer Res 27: 96-121.  
  
Wells SA, Jr., Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, et al. (2010). Vandetanib for 
the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. 
J Clin Oncol 28: 767-772.  
  
GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide. [Online] 
Available 
from 
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. 
[Accessed: 
29th 
September 2016].  
  
  
Appendix 1. Medications Known to Prolong QT 
Interval and/or Induce Torsades de Pointes  
Table 3. Drugs that are generally accepted by authorities to have a risk of causing Torsades 
de Pointes (TDP)  
Drug (Generic Names) Drug Class (Clinical Usage)  
Comments  
Amiodarone  
Anti-arrhythmic/abnormal heart rhythm  
TDP risk regarded as low  
Arsenic trioxide  
Anti-cancer/Leukaemia  
 
Astemizole  
Antihistamine/Allergic rhinitis  
 
Azithromycin  
Antibiotic/bacterial infection  
 
Bepridil  
Anti-anginal/heart pain  
 
Chloroquine  
Anti-malarial/malaria infection  
 


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Chlorpromazine  
Anti-
psychotic/Antiemetic/schizophrenia/nausea  
 
Cisapride  
GI stimulant/heartburn  
 
Citalopram  
Anti-depressant/depression  
 
Clarithromycin  
Antibiotic/bacterial infection  
 
Disopyramide  
Anti-arrhythmic/abnormal heart rhythm  
 
Dofetilide  
Anti-arrhythmic/abnormal heart rhythm  
 
Domperidone  
Anti-nausea/nausea  
 
Droperidol  
Sedative; Anti-nausea/anesthesia adjunct, 
nausea  
 
Erythromycin  
Antibiotic; GI stimulant/bacterial infection; 
increase GI motility  
 
Escitalopram  
Anti-depressant/Major depression/Anxiety 
disorders  
 
Flecainide  
Anti-arrhythmic/abnormal heart rhythm  
 
Halofantrine  
Anti-malarial/malaria infection  
 
Haloperidol  
Anti-psychotic/schizophrenia, agitation  
TDS risk with IV or excess 
dosage  
Ibutilide  
Anti-arrhythmic/abnormal heart rhythm  
 
Levomethadyl  
Opiate agonist/pain control, narcotic 
dependence  
 
Mesoridazine  
Anti-psychotic/schizophrenia  
 
Drug (Generic Names) Drug Class (Clinical Usage)  
Comments  
Methadone  
Opiate agonist/pain control, narcotic 
dependence  
 
Moxifloxacin  
Antibiotic/bacterial infection  
 
Pentamidine  
Anti-infective/pneumocystis pneumonia  
 
Pimozide  
Anti-psychotic/Tourette's tics  
 
Probucol  
Antilipemic/Hypercholesterolemia  
 
Procainamide  
Anti-arrhythmic/abnormal heart rhythm  
 


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Quinidine  
Anti-arrhythmic/abnormal heart rhythm  
 
Sevoflurane   
Anesthetic, general/anaesthesia  
Label warning for patients 
with congenital long QT or 
patients taking QT prolonging 
drugs  
Sotalol  
Anti-arrhythmic/abnormal heart rhythm  
 
Sparfloxacin  
Antibiotic/bacterial infection  
 
Terfenadine  
Antihistamine/Allergic rhinitis  
 
Thioridazine  
Anti-psychotic/schizophrenia  
 
Vandetanib*  
Anti-cancer/Thyroid cancer  
*Does not apply to this study  
  
Table 4. Drugs that in some reports may be associated with Torsades de Pointes but at this 
time lack substantial evidence of causing Torsades de Pointes  
Drug (Generic Names) Drug Class (Clinical Usage)  
Comments  
Alfuzosin  
Alpha1-blocker/Benign prostatic hyperplasia  
 
Dopaminergic/Anti-viral/Anti-infective/Parkinson's  
Amantadine  
Disease  
 
Artenimol + Piperaquine Anti-malarial  
 
Atazanavir  
Protease inhibitor/HIV  
 
Bedaquiline  
Anti-infective/Drug-resistant Tuberculosis  
 
Chloral hydrate  
Sedative/sedation/insomnia  
 
Clozapine  
Anti-psychotic/schizophrenia  
 
Dolasetron  
Anti-nausea/nausea, vomiting  
 
Dronedarone  
Anti-arrhythmic/Atrial Fibrillation  
 
Eribulin  
Anti-cancer/metastatic breast neoplasias  
 
Famotidine  
H2-receptor antagonist/Peptic ulcer/GERD  
 
Felbamate  
Anti-convulsant/seizure  
 
Drug (Generic Names) Drug Class (Clinical Usage)  
Comments  
Fingolimod  
Immunosuppressant/Multiple Sclerosis  
 


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Foscarnet  
Anti-viral/HIV infection  
 
Fosphenytoin  
Anti-convulsant/seizure  
 
Gatifloxacin  
Antibiotic/bacterial infection  
 
Gemifloxacin  
Antibiotic/bacterial infection  
 
Granisetron  
Anti-nausea/nausea and vomiting  
 
Iloperidone  
Antipsychotic, atypical/Schizophrenia  
 
Indapamide  
Diuretic/stimulate urine & salt loss  
 
Isradipine  
Anti-hypertensive/high blood pressure  
 
Lapatinib  
Anti-cancer/breast cancer, metastatic  
 
Levofloxacin  
Antibiotic/bacterial infection  
 
Lithium  
Anti-mania/bipolar disorder  
 
Mirtazapine  
Anti-depressant  
 
Moexipril/HCTZ  
Anti-hypertensive/high blood pressure  
 
Nicardipine  
Anti-hypertensive/high blood pressure  
 
Nilotinib  
Anti-cancer/Leukemia  
 
Octreotide  
Endocrine/acromegaly, carcinoid diarrhea  
 
Ofloxacin  
Antibiotic/bacterial infection  
 
Olanzapine   
Anti-psychotic, atypical/Schizophrenia, bipolar  
Combo with fluoxetine: 
Symbyax  
Ondansetron  
Anti-emetic/nausea and vomiting  
 
Oxytocin  
Oxytocic/Labor stimulation  
 
Paliperidone  
Antipsychotic, atypical/Schizophrenia  
 
Perflutren lipid 
microspheres  
Imaging contrast agent/Echocardiography  
 
Quetiapine  
Anti-psychotic/schizophrenia  
 
Ranolazine  
Anti-anginal/chronic angina  
 
Risperidone  
Anti-psychotic/schizophrenia  
 


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Roxithromycin  
Antibiotic/bacterial infection  
 
Sertindole  
Antipsychotic, atypical/Anxiety, Schizophrenia  
 
Sunitinib  
Anti-cancer/RCC, GIST  
 
Drug (Generic Names) Drug Class (Clinical Usage)  
Comments  
Tacrolimus  
Immunosuppressant/Immune suppression  
 
Tamoxifen  
Anti-cancer/breast cancer  
 
Telithromycin  
Antibiotic/bacterial infection  
 
Tizanidine  
Muscle relaxant  
 
Vardenafil  
Phosphodiesterase inhibitor/vasodilator  
 
Venlafaxine  
Anti-depressant/depression  
 
Voriconazole  
Anti-fungal/anti-fungal  
 
Ziprasidone  
Anti-psychotic/schizophrenia  
 
Source: www.QTdrugs.org/   
  


 
 
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SAP_000.pdf: 
 
 
Statistical Analysis Plan: 16 May 2019 
Page 1 of 14 
Sponsor protocol number: BTG-002814-01 
 
CANCER RESEARCH UK & UCL CANCER TRIALS CENTRE 
UCL Cancer Institute 
 
 
VEROnA 
 
 
 
A window of opportunity study of vandetanib-eluting radiopaque beads 
(BTG-002814) in patients with resectable liver malignancies 
 
 
 
Protocol Number: 
BTG-002814-01 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
Date finalised 
16 May 2019 
Version number 
1.0 
Prepared by  
Allan Hackshaw, Ricky Sharma, 
Laura Beaton 
 
 
 
Signed: Allan Hackshaw 
 
 
 
 
Contents 
1. Summary description of the trial 
2. Baseline characteristics  
3. Administration of BTG-002814 
4. Primary endpoints (adverse events and plasma/tissue drug concentrations) 
     5. Secondary endpoints 
     6. Tumour pathology of the surgical resection 
     7. Additional treatments 
     8. Follow up and deaths 
 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 2 of 14 
Sponsor protocol number: BTG-002814-01 
 
 
1. Summary description of the trial 
 
 
Sample size 
A target of 12 patients 
Intervention arms (what treatments 
were given) 
BTG-002814 (vandetanib-eluting radiopaque embolic 
beads), given 7-21 days before surgery. 
Primary trial objectives 
Primary objectives: 
 
To assess the safety and tolerability of treatment 
with BTG-002814  
 
Measure the plasma and resected liver tissue 
concentrations of vandetanib and the N-desmethyl 
metabolite following treatment with BTG-002814 
Primary outcome measures 
 
Adverse events (AEs) related to treatment with 
BTG-002814 using the standardised grading 
criteria 
(National 
Cancer 
Institute- 
Common 
Terminology Criteria for Adverse Events- Version 
4.0 (NCI-CTCAE v4.0)) 
 
Concentration of vandetanib and N-desmethyl 
vandetanib in plasma and in resected liver tissue 
following treatment with BTG-002814. 
 
 
SAP developed according to protocol version 6, 03 December 2018 
 
 
The analyses will be performed using SAS (likely version 9.4). 
Missing data in the analyses below will be indicated as such in tables (there will be no 
imputation). 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 3 of 14 
Sponsor protocol number: BTG-002814-01 
 
 
 
Secondary objectives 
 
Evaluate the anatomical distribution of BTG-002814 on non-contrast enhanced imaging using 
4D CT 
 
Evaluate histopathological features in the surgical specimen following treatment with BTG-
002814 
 
Assess changes in blood flow on dynamic contrast-enhanced magnetic resonance imaging 
(DCE-MRI) following treatment with BTG-002814 
 
Secondary outcomes measure 
 
Distribution of BTG-002814 on non-contrast enhanced imaging of tumour vasculature and 
regions of interest using 4D CT 
 
Evaluation of histopathological features in the surgical specimen (malignant and non-
malignant liver tissue): tumour necrosis, viable tumour, vascular changes 
 
Changes in blood flow on DCE-MRI following treatment with BTG-002814.  The following 
parameters will be derived from DCE-MRI images: Ktrans, Kep and Ve 
 
Exploratory Objectives and Outcomes 
 
Study blood biomarkers with the potential to identify patients likely to respond to treatment with 
BTG-002814 
 
Study tissue biomarkers to explore key immune, inflammatory and drug related mechanisms 
 
Correlate the distribution of BTG-002814 on imaging with pathology by 3D modelling 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 4 of 14 
Sponsor protocol number: BTG-002814-01 
Study Schema 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 5 of 14 
Sponsor protocol number: BTG-002814-01 
2. Baseline characteristics 
 
 
Table showing the number of patients (categorical variables) or the mean/median and range 
(for continuous variables), for: 
 
 Gender, age, ethnicity, ECOG performance status. 
 HCC or colorectal cancer 
 For HCC, state whether histological or radiological diagnosis 
 Location (liver segments) and characteristics of the tumour: number of liver lesions, sum 
of longest diameters (mm). 
 Vital signs: blood pressure, weight, height, heart rate, ECG results (including QTc 
interval) 
 Key baseline laboratory measures: Hemoglobin, absolute neutrophil count, platelets, 
serum bilirubin, serum creatinine, liver function tests, and others agreed by the 
investigators (from the screening case report form Visit 0). 
 Child-Pugh score and serum alpha-fetoprotein level (HCC patients only) 
 Tumour markers (colorectal cancer paitents only): CEA, CA19-9, CA125 
 Previous systemic treatments for cancer 
 
 
Provide in the text or CONSORT diagram: 
 The number of patients who were ineligible, and the reasons why they were ineligible 
 
 The number of patients who were recruited to the trial but withdrew later on, and the 
reasons (if available) 
 
 List any possible major protocol violations or ineligibility criteria that would lead to the 
patient not being included in the analysis. This information is not in the main database 
but would be summarised in a table. 
 
 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 6 of 14 
Sponsor protocol number: BTG-002814-01 
3. BTG-002814 treatment 
 
Assessments on treatment day 
 
Measurements  
Mean/median, and 
range, and 
standard deviation 
Before BTG-002814  treatment (absolute values) 
 
Blood pressure 
 
Heart rate 
 
ECG QTc interval (state method used for calculation) 
 
ECG results (descriptive) 
 
 
 
 
 
After BTG-002814  treatment (but use the change/difference 
from the pre-treatment levels) 
 
Blood pressure 
 
Heart rate 
 
ECG QTc interval 
 
ECG results (descriptive) 
 
 
 
 
Delivery of BTG-002814 
 
Measurements  
 
 
 
Volume of drug delivered (mL) 
Mean/median, and range 
Full volume of drug delivered: yes or no 
Percentage 
Full volume of drug not delivered- reasons 
Percentages 
 
Stasis reached 
 
 
Complication 
 
 
State other reasons 
 
 
 
Total time between start of 1st infusion and end of the 
last infusion (minutes) 
Mean/median, and range 
Number of infusions over all patients 
Mean/median, and range 
Radiation dose-length product (mGy-cm) 
Mean/median, and range 
 
 
Any TACE-related problems: yes or no 
Percentage 
Different TACE-related problems 
Percentages 
 
 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 7 of 14 
Sponsor protocol number: BTG-002814-01 
 
4. Primary endpoints 
 
4.1 Safety 
 
All adverse events will have severity graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
This will be based on combining all the AEs, SAEs and SUSARs, and any other source of 
adverse events (e.g. unscheduled bloods case report form). 
 
For each type of event, for each patient, the maximum grade will be obtained.  
 
4.1.1 Number of patients with each type of event (each patient only counted once on each 
row) 
 
Event Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Abdominal pain 
 
 
 
 
Anorexia 
 
 
 
 
Ascites 
 
 
 
 
Back pain 
 
 
 
 
Bronchospasm 
 
 
 
 
Cardiac disorders 
 
 
 
 
Constipation 
 
 
 
 
Cough 
 
 
 
 
Diarrhea 
 
 
 
 
Dry mouth 
 
 
 
 
Dyspepsia 
 
 
 
 
Dyspnea 
 
 
 
 
Electrocardiogram QT corrected interval 
prolonged 
 
 
 
 
Fatigue 
 
 
 
 
Flu like symptoms 
 
 
 
 
Gastritis 
 
 
 
 
etc 
 
 
 
 
 
 Several versions of the above table: 
 
AEs post-TACE: 
 AEs on the day after BTG-002814  treatment only 
 AEs after BTG treatment and up to (but not including) the day of surgery 
 AEs after BTG treatment and up to (but not including) the day of surgery, which are 
considered to be related to vandetanib 
 AEs after BTG treatment and up to (but not including) the day of surgery, which are 
considered to be related to TACE 
 
AEs post Surgery: 
 AEs only occurring after surgery (up to the end of the 32-day follow up) 
 All AEs occurring at any time from the delivery of BTG treatment 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 8 of 14 
Sponsor protocol number: BTG-002814-01 
 
4.1.2 Number of events with each type of event (a patient can be counted more than once 
on each row if they experienced the same event several times) 
 
Event Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Abdominal pain 
 
 
 
 
Anorexia 
 
 
 
 
Ascites 
 
 
 
 
Back pain 
 
 
 
 
Bronchospasm 
 
 
 
 
Cardiac disorders 
 
 
 
 
Constipation 
 
 
 
 
Cough 
 
 
 
 
Diarrhea 
 
 
 
 
Dry mouth 
 
 
 
 
Dyspepsia 
 
 
 
 
Dyspnea 
 
 
 
 
Electrocardiogram QT corrected interval 
prolonged 
 
 
 
 
Fatigue 
 
 
 
 
Flu like symptoms 
 
 
 
 
Gastritis 
 
 
 
 
etc 
 
 
 
 
 
 Several versions of the above table: 
AEs post-TACE: 
 AEs on the day after BTG treatment only 
 AEs after BTG-002814  treatment and up to (but not including) the day of surgery 
 AEs after BTG-002814  treatment and up to (but not including) the day of surgery, 
which are considered to be related to vandetanib 
 AEs after BTG-002814  treatment and up to (but not including) the day of surgery, 
which are considered to be related to TACE 
 
AEs post Surgery: 
 AEs only occurring after surgery (up to the end of the 32-day follow up) 
 All AEs occurring at any time from the delivery of BTG treatment 
 For any grade 3 or 4 event, look at time to the first occurrence of the grade 3/4 event 
(BTG treatment day is Day 0): do scatter plot of these 
 
4.1.3 Examine which grade 3 or 4 AEs that occur any time after BTG-002814 delivery were 
already present at baseline in the patient (i.e. pre-treatment). 
 
Descriptively, provide summary of which had got worse. 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 9 of 14 
Sponsor protocol number: BTG-002814-01 
 
 
4.2 Drug concentrations 
These analyses will be performed by BTG. 
 
4.2.1 Plasma 
For each patient, obtain the plasma time-concentration curve for: 
 vandetanib  
 N-desmethyl metabolite  
Each plot would be indicated as to whether the patient had HCC or mCRC. 
 
Time points are: 
o Day of BTG treatment but before administration (0 hours) 
o 2 hours post-BTG treatment  
o 4 hours post-BTG treatment 
o 24 hours post-BTG treatment 
o 3 days to1 day prior to surgery 
o 28-32 days post-surgery. 
 
PK parameters such as Tmax (time taken to reach the highest concentration) and Cmax 
(the maximum concentration) could be obtained, and use summary statistics to describe 
these. Other standard PK parameters can be included (e.g. AUC to 32 days, and AUC to 
the end of the observation time period), as determined by the investigators, such as T1/2, 
clearance CL/F, and volume of distribution (Vz/F). 
 
4.2.2 Resected tissue 
 
For each patient, provide a concentration-time plot for: 
 vandetanib  
 N-desmethyl metabolite  
(concentration as the y-axis and time as the x-axis). 
Each plot would be indicated as to whether the patient had HCC or mCRC. 
 
This will be for: 
 malignant tissue – three measurements for each patient: 
o Centre of tumour 
o Mid tumour 
o Edge of tumour 
 non-malignant tissue 
o 1 cm from the edge of the tumour  
 paired samples (difference, per patient, using malignant (based on the average of the 
3 locations/samples) minus non-malignant values). Can be analysed using a t-test or 
non-parametric test 
 Describe technical reasons for missing data points 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 10 of 14 
Sponsor protocol number: BTG-002814-01 
 
 
5. Secondary objectives/outcomes (other blood, tissue and imaging markers) 
 
5.1 Distribution of BTG-002814 
The distribution of BTG-002814 within the tumour vasculature and regions of interest will be 
assessed on non-contrast enhanced imaging. The findings will be summarised descriptively, and 
HCC or mCRC will be indicated. 
 
5.2 Histopathology of resected liver 
An evaluation of histopathological features in both malignant and non-malignant liver tissue from the 
surgical specimen will be performed. The extent of tumour necrosis, viable tumour and any vascular 
changes observed will be summarised descriptively. 
 
5.3 3D modelling 
Associations between the distribution of BTG-002814 on imaging and within the pathological 
specimen will be described using 3D modelling, and HCC or mCRC will be indicated. 
 
5.4 Blood flow following embolisation 
Assessment of changes in blood flow will be assessed using DCE-MRI following treatment with BTG-
002814.  For individual patients, the following parameters will be derived from DCE-MRI scans at 
visits 1 and 2 (pre-treatment) and visit 4 (post-treatmemt), and HCC or mCRC will be indicated. 
 
Dual-input single-compartment model 
o Arterial flow (ml/min/100g) 
o Portal venous flow (ml/min/100g) 
o Arterial fraction (%) 
o Mean transit time (seconds) 
o Distribution volume (%) 
 
Tofts model 
o Volume transfer constant between plasma and extravascular extracellular space - Ktrans (min-
1) 
o Volume transfer constant between extravascular extracellular space and plasma - Kep (min-
1) 
o Volume of extravascular extracellular space per unit volume of tissue - Ve (%) 
 
Semi-quantitative analysis 
o Time-to-peak – TTP (seconds) 
o Area under curve at 60 seconds (mmol/L.s) 
o Peak Gadolinium concentrations – Cpeak (mmol/L) 
o Upslope - Cpeak/TTP (mmol/L.s) 
 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 11 of 14 
Sponsor protocol number: BTG-002814-01 
For each patient, perfusion parameters for visit 1 and 2 will be used to estimate intra-patient 
reproducibility. Visit 4 parameters from each patient will be used to measure potential changes 
following treatment with BTG-002814, in the context of the baseline reproducibility for each patient, 
and HCC or mCRC will be indicated.  
 
The same principles will be applied to perfusion CT parameters shown below. 
 
Maximum slope method: 
o Arterial flow (mL/min/100ml) 
o Portal flow (mL/min/100ml) 
o Perfusion index 
 
 
Patlak model: 
o Blood volume  (ml/ml tissue) 
o Arterial perfusion (mL/min/100ml) 
o Flow extraction product (ml/min/100ml) 
 
For changes observed within each patient, data from DCE-MRI will be compared to changes 
observed in perfusion CT at the same timepoints to confirm the veracity of potential changes 
observed in blood flow. 
 
5.5 Blood/serum biomarker analysis 
 
The following serum biomarkers will be measured at baseline (before BTG treatment) and at several 
time points afterwards (i.e pre-treatment (visit 2), Day 1 after treatment (visit 3), pre-surgery (visit 4) 
and end of study (visit 6): 
 
Levels of blood biomarkers (cytokines, chemokines and growth factors relevant to cancer 
and inflammation).  
 
Levels of serum alpha-fetoprotein (AFP) in patients with HCC.  
 
Levels of serum CEA, CA19-9 and CA125 in patients with mCRC.  
Time-concentration plots for each biomarker will be obtained for each patient. Each plot would be 
indicated as to whether the patient had HCC or mCRC. 
 
Changes in levels (last recorded value minus the baseline value, for each patient) summarized as  
scatter plots, with mean/median and range of the change. 
Non-parametric tests to be used for biomarkers that appear to show large changes. 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 12 of 14 
Sponsor protocol number: BTG-002814-01 
 
 
6. Tumour pathology after surgery (of the resected tissue) 
 
6.1 Tumour characteristics 
 
Pathology outcome 
Number of patients (%) 
 
 
HCC patients 
 
T-stage 
 
N-stage 
 
M-stage 
 
Histologic grade (G1-4) 
 
Resection (R0, R1, R2) 
 
Distance to nearest resection margin  
Median (range) 
 
Tumour necrosis (%) 
Median (range) 
 
Viable tumour (%) 
Median (range) 
 
Vascular changes  
 
 
 
Colorectal cancer patients 
 
Resection margins (R0, R1, R2) 
 
Grade (G1, G2, G3, G4) 
 
Tumour necrosis (%) 
Median (range) 
 
Viable tumour (%) 
Median (range) 
 
Vascular changes  
 
 
 
 
6.2. Tumour size/measurement 
 
 The longest diameter of each lesion (mm) is measured at baseline and again on the day 
before surgical resection. 
 The sum of the diameters can be taken for each patient, using the same lesions. 
 Produce a waterfall plot showing the change in the sum from baseline to pre-surgery. 
 Change in tumour size can also be compared using a paired t-test or Mann-Whitney test, 
depending on whether Normally distributed or not. 
 Waterfall plot obtained for all patients, then separately for HCC and mCRC. 
 
 
 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 13 of 14 
Sponsor protocol number: BTG-002814-01 
7. Concomitant Medications 
 
Patient ID 
Drug name/type 
Time (days) from day of BTG treatment to 
start of non-trial drug 
 
 
 
1 
A 
 
1 
B 
 
1 
C 
 
 
 
 
2 
D 
 
2 
E 
 
2 
F 
 
 
 
 
 
 


 
 
Statistical Analysis Plan: 16 May 2019 
Page 14 of 14 
Sponsor protocol number: BTG-002814-01 
8. Follow up and deaths 
 
 
 
 
 
 
 
 
9. Other Safety Parameters 
Other safety parameters such as ECG, vital signs and physical examinations will be summarised 
 
For laboratory paramaters, observed values, changes from baseline, shifts in CTC grade and normal 
values/above and below normal values will be summarised with descriptive statistics. A listing of 
individual laboratory data will be provided with values outside normal ranges flagged. 
 
 
 
All patients 
HCC 
mCRC 
 
n (%) 
n (%) 
n (%) 
No. patients who died 
 
 
 
Cause of death 
 
 
 
 
 
 
 
 
 
 
 
No. patients who dropped out/withdrew 
from the trial 
 
 
 
 
Reasons for withdrawal 
 
 
 
 
Lost to follow up