Conditions: Neuroendocrine Tumors
Keywords: Positron Emission Tomography
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 56
Healthy volunteers: no

Brief summary:
Radiolabelled somatostatin analogs are invaluable in the diagnosis and treatment of neuroendocrine tumours (NET). The most common positron emission tomography (PET) radiotracers used for the visualisation of NET are radiolabelled somatostatin analogs (SSAs) labelled with \[68Ga\]Ga-DOTA-peptides. However, \[68Ga\]Ga-DOTA-peptide radiolabelled SSAs have significant limitations in terms of accessibility and low throughput. The team at Imperial College London developed a novel radiotracer, \[18F\]fluoroethyl triazole labelled \[Tyr3\]-Octreotate analogue (\[18F\]-FET-βAG-TOCA), in an attempt to overcome these limitations. The FETONET study was designed to have 3 parts. The FETONET study was designed to have 3 parts. Part A evaluated the biodistribution, dosimetry and safety of \[18F\]FET-βAG-TOCA. Uptake was assessed at multiple time points over a 4 hour period. The data was analysed and an optimal imaging time point determined. Part B of the FETONET study involved the performance of whole body static \[18F\]FET-βAG-TOCA PET-CT imaging, at the optimal time point previously established, within a larger cohort of patients. Part C comprised a prospective non-inferiority study that analysed the \[18F\]FET-βAG-TOCA PET/CT data collected within Part A \& Part B and compared this to standard of care \[Ga68\]Ga-DOTA-peptide PET-CT imaging.

Detailed description:
Neuroendocrine tumours (NET) are tumours derived from enterochromaffin cells, which are characterised by the expression of somatostatin receptors (SSTRs) on their surface. These tumours release substances into systemic circulation, resulting in episodic flushing, wheezing, diarrhoea, and eventual right-sided valvular heart disease. All of these symptoms negatively impact on patients' quality of life. The management of NET is primarily determined by the stage of disease. For patients with localised or limited disease the primary modality of therapy is surgery. Whilst patients with metastatic disease, undergo systemic therapy with palliative intent. Accurate imaging is therefore central to the management of this disease. Whilst computed tomography (CT) is useful in the localisation of NET, nuclear imaging using tumour-specific radiolabelled receptors are considerably more sensitive and specific methods for detecting NET and their metastases. The most commonly used positron emission tomography (PET) radiotracers used for the visualisation of NET are radiolabelled somatostatin analogs (SSAs) labelled with \[68Ga\]Ga-DOTA-peptides. The \[68Ga\]Ga-DOTA-peptide radiolabelled SSAs have significant limitations in terms of accessibility and low throughput. The team at Imperial College London developed a novel radiotracer, \[18F\]fluoroethyl triazole labelled \[Tyr3\]-Octreotate analogue (\[18F\]-FET-βAG-TOCA), in an attempt to overcome these limitations. The FETONET study was designed to have 3 parts. The FETONET study was designed to have 3 parts. Part A evaluated the biodistribution, dosimetry and safety of \[18F\]FET-βAG-TOCA. Uptake was assessed at multiple time points over a 4 hour period. The data was analysed and an optimal imaging time point determined. Part B of the FETONET study involved the performance of whole body static \[18F\]FET-βAG-TOCA PET-CT imaging, at the optimal time point previously established, within a larger cohort of patients. Part C comprised a prospective non-inferiority study that analysed the \[18F\]FET-βAG-TOCA PET/CT data collected within Part A \& Part B and compared this to standard of care \[Ga68\]Ga-DOTA-peptide PET-CT imaging.

Arms:
arm 1: Patients with histologically-confirmed neuroendocrine tumours (NET) enrolled into Part A of the FETONET study underwent whole-body dynamic \[18F\]FET-βAG-TOCA imaging at multiple time points over a 4 hour period, with sampling of venous bloods for radioactivity and radioactive metabolite quantification. arm 2: Patients with histologically confirmed neuroendocrine tumours (NET) underwent PET/CT imaging with both \[18F\]FET-βAG-TOCA and \[68Ga\]Ga-DOTA-peptide. The two PET/CT scans were performed within a 6-month time period. Whole-body static \[18F\]FET-βAG-TOCA PET/CT scan performed at 50 minutes post radiotracer injection.

Interventions: intervention 1: [18F]-FET-βAG-TOCA
Intervention descriptions: intervention 1: Single I.V. administration of a \[18F\]fluoroethyl triazole \[Tyr3\]Octreotate (\[18F\]-FET-βAG-TOCA). Patients will receive a maximum injected dose of 370MBq and will subsequently undergo PET/CT imaging.

Protocol document:
Prot_SAP_000.pdf: 
FETONET study      version 3.5      12th December 2016 
 
 
 
 
 
 
Evaluation of [18F]fluoroethyl triazole labelled [Tyr3]Octreotate 
analogues for the imaging of Neuroendocrine tumours 
 
 
 
Protocol Number: FETONET 
EudraCT Number: 2013-003152-20 
 
 
 
 
Principal Investigator: Dr Rohini Sharma 
Dept of Experimental Toxicology, and Dept Molecular 
Therapeutics and Imaging 
Imperial College London 
Hammersmith Hospital Campus 
Du Cane Road 
London W12 0HS 
United Kingdom 
 
Tel: +44 (0) 20 8383 3720 
Fax: +44 (0) 20 8383 1783 
 
 
Co-Investigators: 
 
Professor Eric Aboagye, 
 
 
Dept Molecular Therapeutics and Imaging, 
Imperial College London 
Hammersmith Hospital Campus 
Du Cane Road 
London W12 0HS 
United Kingdom 
Dr Suraiya Dubash 
 
 
Department of Surgery and Cancer 
Imperial College London 
Hammersmith Hospital Campus 
Du Cane Road 
London W12 0HS  
United Kingdom


FETONET study      version 3.5      12th December 2016 
 
Ms Kasia Kozlowski 
 
 
Clinical Research Practitioner 
Department of Surgery and Cancer 
Imperial College London 
Hammersmith Hospital Campus 
Du Cane Road 
London W12 0HS 
United Kingdom 
 
 
 
Professor Adil Al-Nahhas, 
Dept Nuclear Medicine Imperial 
College London Hammersmith 
Hospital Campus Du Cane 
Road 
London W12 0HS 
United Kingdom 
 
 
 
 
 
Dr Saleem Azeem 
 
 
Imanova Ltd, Centre for Imaging Sciences 
Burlington Danes Building 
Imperial College London 
Hammersmith Hospital 
Du Cane Road 
London, W12 0NN 
 
 
 
Professor Andrea Frilling 
Professor of Surgery, Chair in Endocrine Surgery 
Honorary Consultant Imperial College London 
Hammersmith Hospital Campus 
Du Cane Road 
London W12 0HS,  
United Kingdom 


FETONET study      version 3.5      12th December 2016 
 
Investigator Protocol Agreement Page 
 
 
 
 
I confirm agreement to conduct the study in compliance with the protocol. 
 
 
I acknowledge that I am responsible for overall study conduct. 
 
 
I agree to personally conduct or supervise the described clinical study in 
accordance with Good Clinical Practice requirements. 
 
 
I agree to ensure that all associates, colleagues and employees assisting 
in the conduct of the study are informed about their obligations. 
 
 
 
Chief Investigator Name: 
Dr Rohini Sharma 
Investigator Address: 
Imperial College London 
Hammersmith Campus 
Du Cane Road 
London 
W12 0HS 
Investigator Signature 
Date 
 
 
 
 
Principal 
Investigator 
Name: 
Dr Rohini Sharma 
Investigator Address: 
Imperial College London 
Hammersmith Campus 
Du Cane Road 
London 
W12 0HS 
Investigator Signature 
Date 


FETONET study      version 3.5      12th December 2016 
 
 
1.   SYNOPSIS 
Name of Sponsor/Company: Imperial College. 
Name of Finished Product:[18F]fluoroethyltriazole[Tyr3]Octreotate ([18F]-FET-βAG-TOCA) Injection 
Name of Active Ingredient: [18F]-FET-βAG-TOCA 
Title of Study: Evaluation of [18F]fluoroethyltriazole[Tyr3]Octreotate analogues for the imaging of 
neuroendocrine tumours. 
Investigators and Study Centre(s): Imanova. 
Phase of Development: Phase 1 
Primary Objective: 
To evaluate the utility of the [18F]fluoroethyl triazole labelled [Tyr3]Octreotate analogue, [18F]-FET-βAG-
TOCA, in the accurate localisation of tumours in patients with a histologic diagnosis of NETs of any site. 
Study Design: 
Primary Endpoint: 
To determine the biodistribution of [18F] following single i.v. administration of [18F]-FET-βAG-TOCA 
injection 
To assess tumoural uptake of [18F]-FET-βAG-TOCA 
Safety Endpoint: 
The occurrence of one or more treatment-emergent adverse events (AEs) from administration of [18F]-FET-
βAG-TOCA Injection throughout the study period, and changes in serum biochemistry, haematology, 
coagulation, immunology, 
urinalysis, vital signs, ECG, injection site, and physical examination findings. 
Selection of Subjects: 
Main Inclusion Criteria: 
 
1. Written informed consent 
2.  Age ≥ 18 years 
3.  Histological diagnosis of NET of any site, except where ENETS criteria does not mandate histology for 
confirmation of diagnosis or patients who have a positive 68Gallium-peptide scan in whom NET diagnosis is 
pre-operatively definitive. 
4.  Locally advanced or metastatic disease 
5.  Eastern Cooperative Oncology Group (ECOG) performance status of <2 (appendix A) 
6.  Life expectancy > 3 months 
7.  Measurable disease defined as a lesion that can be accurately measured in at least one dimension with the 
longest diameter ≥10mm using conventional techniques 
8.  Somatostatin receptor imaging within 6 months. (if patient does not have somatostatin receptor imaging 
they may also be included provided they have measurable disease (≥10mm) on conventional imaging. 
9.  Adequate organ system function as defined in Table 1 
 
 
Main Exclusion Criteria: 
 
Patients received chemotherapy within 3 weeks of study or radiotherapy within 4 weeks of study 
 
Active uncontrolled infections, gastrointestinal disease, haemolysis or any serious co-existing medical 
illness 
 
Psychological, familial, sociological or geographical condition potentially hampering compliance 
with the study protocol and follow-up schedule 
 
Pregnant or lactating women 
 
Females of childbearing potential who are unwilling to avoid pregnancy, for the duration of the study 
 
Presence of any underlying medical conditions which in the investigators opinion would make the 
patients unsuitable for treatment  
 
Satisfactory baseline haematologic and organ function Patient not expected to be able to tolerate the 
scanning sessions 
Number of Patients Planned: 56 patients with diagnosis of neuroendocrine tumours of any site 


FETONET study      version 3.5      12th December 2016 
 
Treatment of Subjects: 
Investigational Tracer: Subjects will receive a single i.v. bolus injection of 1-10 mL of [18F]-FET-
βAG-TOCA injection over a period of at least 30 seconds.   The tracer injection will be followed by a 
saline flush.   Patients will receive a maximum 18F activity of 165 MBq. 
Statistical Methods and Planned Analysis: 
Using results of dynamic scanning and metabolite analysis an appropriate protocol will be designed to analyse 
the diagnostic static scans.  The internal radiation dosimetry as well as biodistribution of the tracer will be 
calculated. Comparison between FET-βAG-TOCA PET and standard of care somatostatin receptor imaging 
will be made based on 
both a per-patient and per-lesion based analysis. Non-parametric McNemar test with Bonferroni correction for 
multiple comparison will be used.   The association between SSTR1-5 expression and imaging parameters 
obtained will be assessed. Data will be analysed using SPSS 16.0 for Windows. 
 
Bio-distribution and Radiation Dosimetry  
Bio-distribution  data  in  patients  will  consist  of  18F  activity  content  in  organs  and  tissues  of  interest,  
18F  activity 
concentrations in whole blood and plasma and of 18F activity excreted in the urine.  Descriptive statistics will 
be generated for bio-distribution data at each time point for each organ and tissue of interest. The amount of 
18F activity excreted in urine in patients will be calculated from the product of concentration of 18F activity 
measured in each sample and the volume of each sample for a subset of patients. 
 
Safety 
Safety parameters will be summarized using 
descriptive statistics 


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FETONET study      version 3.5      12th December 2016 
 
 
 
TABLE OF CONTENTS 
1.   SYNOPSIS ........................................................................................................................................ 4 
2 Table of contents ............................................................................................................................... 6 
3. LIST OF ABBREVIATIONS and Definitions of Terms .......................................................................... 9 
4. SUMMARY ...................................................................................................................................... 10 
4.1  Cohort  1.  . .............................................................................................................................. 10 
4.2 Cohort 2.  .................................................................................................................................. 11 
5. BACKGROUND ................................................................................................................................ 12 
5.1 [18F]-FET-βAG-TOCA-PET ......................................................................................................... 14 
5.2 Rationale and evidence to date ............................................................................................... 15 
6. STUDY OBJECTIVES ......................................................................................................................... 16 
6.1 Primary objective ..................................................................................................................... 16 
7. STUDY ENDPOINTS ............................................................................ Error! Bookmark not defined. 
7.1.1 Primary .............................................................................................................................. 17 
7.1.2 Translational end-points ................................................................................................... 17 
7.2 Cohort 2 .................................................................................................................................... 17 
7.2.1 Primary .............................................................................................................................. 17 
7.2.2 Secondary .......................................................................................................................... 17 
7.2.3 Translational end-points ................................................................................................... 18 
8. STUDY OUTLINE .............................................................................................................................. 18 
8.1 Study design and rational of the chosen approaches .............................................................. 18 
8.1.1 Cohort 1. Dosimetry and safety study in patients with histological diagnosis of NETs of 
any site. ...................................................................................................................................... 18 
8.1.2 Cohort 2. Open label study assessing tumoural uptake of [18F]-FET- βAG-TOCA –PET in 
patients with histological diagnosis of NETs of any site ............................................................. 18 
9. ELIGIBILITY ...................................................................................................................................... 19 
9.1 Inclusion criteria ....................................................................................................................... 19 
9.2 Exclusion Criteria ...................................................................................................................... 19 
10. COMPLETION OR EARLY WITHDRAWAL ....................................................................................... 20 
10.1 Subject completion ................................................................................................................ 20 


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FETONET study      version 3.5      12th December 2016 
 
10.2 Withdrawal criteria ................................................................................................................ 20 
10.3 Blinding ................................................................................................................................... 20 
11. STUDY PROCEDURES .................................................................................................................... 20 
11.1 
Screening period (Day -30 to Day 0) .................................................................................. 23 
11.2 PET Procedure (Day 0) ............................................................................................................ 24 
11.3 Radiation dosimetry. .............................................................................................................. 24 
11.4 PET parameters ...................................................................................................................... 25 
12. ASSESSMENT AND FOLLOW-UP ................................................................................................... 25 
12.1 Clinical Assessments ............................................................................................................... 25 
12.1.1 Screening ......................................................................................................................... 25 
12.1.2 Cohort 1: day of scan (Day 0) .......................................................................................... 25 
12.1.3 Cohort 1: Day 1 post scan................................................................................................ 25 
12.1.4 Cohort 2: day of scan ....................................................................................................... 26 
13. COMPLICATIONS AND RADIATION DOSE ..................................................................................... 26 
13.1 Complications ......................................................................................................................... 26 
13.2   Radiation dose ..................................................................................................................... 26 
14. STATISTICAL ANALYSIS AND SAMPLE SIZE CALCULATION ............................................................ 26 
14.1 Cohort 1 .................................................................................................................................. 26 
14.1.1 Safety ............................................................................................................................... 27 
14.1.2 Biodistribution ................................................................................................................. 27 
14.1.3 Dosimetry ........................................................................................................................ 27 
14.1.4 Somatostatin receptor expression .................................................................................. 27 
14.2 Cohort 2 .................................................................................................................................. 27 
14.2.1 Power and sample size determination ............................................................................ 27 
14.2.3 Somatostatin receptor expression .................................................................................. 28 
15. PHARMACOVIGILANCE ................................................................................................................. 28 
15.1 DEFINITIONS ........................................................................................................................... 28 
15.2 CAUSALITY .............................................................................................................................. 29 
15.3 REPORTING PROCEDURES ...................................................................................................... 29 
15.3.1 Non serious AR/AEs ......................................................................................................... 29 
15.3.2 Serious AR/AEs ................................................................................................................ 30 


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FETONET study      version 3.5      12th December 2016 
 
16. DATA MANAGEMENT ................................................................................................................... 30 
17. ADMINISTRATIVE AND LEGAL CONSIDERATIONS ........................................................................ 30 
17.1   Pre-Trial Requirements ........................................................................................................ 30 
17.2 General Legal Requirements .................................................................................................. 31 
17.3 Protection of Subjects ............................................................................................................ 31 
17.3.2 Informed Consent ............................................................................................................ 31 
17.3.3 Privacy protection ........................................................................................................... 32 
17.4 Protocol Amendments ....................................................................................................... 32 
17.5 Premature Termination of the Trial ....................................................................................... 32 
17.6 Record Retention ................................................................................................................... 33 
17.7 Study Monitoring.................................................................................................................... 33 
17.8 Final Report ............................................................................................................................ 33 
17.9 Publications ............................................................................................................................ 34 
17.10 Liability and insurance .......................................................................................................... 34 
17.11 Audits and Inspections ........................................................................................................ 34 
18. REFERENCES ................................................................................................................................. 35 
19. Appendix A: WHO performance status scale ............................................................................... 36 
 
 
 
 
 
LIST OF TABLES 
Table 1.............................................................................................................................................19 
Table 2.............................................................................................................................................21 
Table 3.............................................................................................................................................22 
Table 4.............................................................................................................................................23 
 
 
 


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FETONET study      version 3.5      12th December 2016 
 
3. LIST OF ABBREVIATIONS and Definitions of Terms 
 
18F 
Fluorine with an Atomic Mass of 18 
68Ga 
99mTc 
Gallium with an Atomic Mass of 68 
Metastable Technetium with an Atomic Mass of 99 
AE 
Adverse Event 
ARSAC 
Administration of Radioactive Substances Advisory Committee 
Bpm 
Beats per Minute (Heart Rate) 
CRF 
Case Report Form 
CT 
Computed Tomography 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ED 
Effective Dose (ie, the sum of risk weighted organ absorbed radiation 
dose used as a measure of stochastic radiation risk) 
EUC 
Electrolytes, Urine, Creatinine 
GCP 
Good Clinical Practice GLP
 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemistry 
i.v. 
Intravenous 
MBq 
MHRA 
Megabecquerel 
Medicines & Healthcare products Regulatory Agency 
MIRD 
Medical Internal Radiation Dose 
NET 
Neuroendocrine tumour 
PET 
Positron Emission Tomography 
PK 
SAE 
Pharmacokinetics 
Serious Adverse Event 
SRS 
Somatostatin Receptor Scintigraphy 
SSTR 
Somatostatin Receptor 


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FETONET study      version 3.5      12th December 2016 
 
4. SUMMARY 
 
 
4.1  Cohort  1.  Dosimetry  and  safety  study  in  patients  with  histological 
diagnosis of NETs of any site. 
 
 
 
 
Screening Visit (D-30) 
Informed consent, Study entry criteria 
Medical history, current medication 
Safety monitoring* 
Pregnancy test, 
Standard of care imaging within 6 months, 
IHC on diagnostic tumour biopsy 
 
 
 
 
 
 
 
 
IMAGING DAY (D0) 
Baseline assessment 
Safety monitoring* 
Pregnancy test 
 
 
PET Imaging 
(Imaging performed 5 min - 4 hours after 
injection) 
Safety monitoring* 
Transmission scan 
Injection site monitoring 
Tracer administration 
Venous blood and urine for activity measurements 
 
 
 
 
 
 
 
 
Safety Follow-up* 
24 hours after tracer administration 
 
 
 
*For safety parameters please refer to the study schedules of events, Table 1 & Table 2 


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FETONET study      version 3.5      12th December 2016 
 
4.2 Cohort 2. Open label study comparing [18F]-FET-βAG-TOCA – PET with 
[68Ga]-DOTATATE-PET/CT in patients with histological diagnosis of NETs 
of any site. 
 
 
 
Screening Visit (≤D-30) 
Informed consent, Study entry criteria 
Medical history, current medication, 
Safety monitoring* 
Pregnancy test 
Standard of care imaging within 6 months 
 
 
 
 
 
 
 
 
IMAGING DAY (D0) 
Baseline assessment 
Safety monitoring* 
Pregnancy test 
 
Static PET Imaging (D0) 
PET/CT scan which will last up to 70 
minutes 
 
 
 
 
 
 
 
 
 
Patient discharged after scan 
IHC on diagnostic tumour biopsy 
 
 
 
 
 
 
*For safety parameters please refer to the study schedules of events, Table 1 & Table 3 


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FETONET study      version 3.5      12th December 2016 
 
5. BACKGROUND 
Neuroendocrine  tumours  (NETs)  are  tumours  derived  from  enterochromaffin 
cells, which are characterised by the presence of neurosecretory granules 
composed of a variety of hormones and biogenic amines. These tumours can 
release vasoactive substances into the systemic circulation, resulting in episodic 
flushing, wheezing, diarrhoea, and eventual right-sided valvular heart disease. All 
of these symptoms negatively impact on patients’ quality of life. NETs can 
originate at any site, however the common site of disease is the midgut 
comprising of 40% to 70% of all NETs1. Whilst initially thought to be relatively 
rare, it is evident from the US Surveillance Epidemiology and End Results 
database that the incidence and prevalence has increased substantially 
(approximately 500%) over the past 30 years, and unlike most other solid 
tumours, the incidence continues to rise 2. Within the UK 3000 patients are 
diagnosed each year making it the 11th most common cancer in the UK, and the 
second most prevalent tumour of the gastrointestinal tract. 
 
The management of NETs is primarily determined by the stage of the disease. 
For patients with localised or limited disease the primary modality of therapy is 
surgery, whilst in patients with metastatic disease, systemic therapy is employed 
with palliative intent.  Accurate imaging is therefore central to the management of 
this disease. 
 
Whilst computer tomography is useful in the initial localisation of NETs, nuclear 
imaging using tumour-specific radiolabelled receptor analogues or amine 
precursors are considerably more sensitive and specific methods for detecting 
NETs and their metastases. Five SSTR subtypes (1-5) have been identified in 
human tissues, with 70 – 90% of NETS expressing subtypes 2 and 5. 
Somatostatin analogues, such as octreotide, bind with high affinity to SSTR2 and 
SSTR5, and with varying affinity to SSTR3 and 4. When chelators such as 
diethylenetriamine pentaacetic acid (DTPA) or 1,4,7,10-tetraazacyclododedcane- 
N, N’, N’’, N’’’ – tetraacetic acid (DOTA) are coupled to these analogues, they 
can be labelled with [111In] or [99mTc] for scintigraphy in order to stage NETs. 
Furthermore, positive uptake on these scans will predict the likelihood of patients 
responding to therapy utilising radiolabelled somatostatin analogues.  Currently, 
[111In]-DTPA-octreotide SRS is the clinical gold standard for the imaging of these 
tumours, however there is an emerging clinical trend for the use of PET based on 
improved sensitivity and specificity. 
 
In a review of pooled data from over 1200 patients, [111In]-DTPA-octreotide SRS 
showed a median detection rate of 89% (range 67% to 100%) and a median 
sensitivity of 84% (range 57% - 93%)3. Whilst SRS is accurate, false positive 
results can be seen from the presence of inflammatory conditions that can be 
associated with an increase in SSTR expression such as in Crohn’s disease 4. 
Furthermore, NETs that are either too small or do not express high levels of 
SSTRs will not be detected. Other reasons for scan failure include low signal in 
areas of high background activity such as the liver and low spatial resolution.  
 


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FETONET study      version 3.5      12th December 2016 
 
Acquisition time is also prolonged, up to 48hours, making it inconvenient for both 
patients and nuclear medicine departments. Therefore, there is clearly a need to 
develop more accurate imaging techniques. The utility of PET imaging for 
visualising NETs has been highlighted with the development of [68Ga]-labelled 
somatostatin analogues. PET has superior physical characteristics compared to 
SRS including spatial resolution, sensitivity and quantification, and [68Ga]-labelled 
ligands also show higher affinity for SSTR 2 and 5 and more rapid clearance from  
the  blood  compared  with  [111-In]-labelled  tracers,  with  images  being obtained 
60-90min following tracer injection. Furthermore, the radiation dose is lower using 
these tracers. 
 
Preclinical and clinical studies have described the use of a number of analogues 
including DOTA-Tyr3 octreotide (DOTA-TOC), DOTA-Tyr3,Thr8octreotide (DOTA- 
TATE) and DOTA-1-NaI3-octreotide (DOTA-NOC) in the imaging of NETs 5-8. 
[18F]-Fluorodeoxyglucose (FDG)-PET has been extensively studied in NETs 
however the sensitivity of this imaging technique is low, 25 to 73%, because of 
the relatively low metabolic activity of NETs, making [18F]-FDG-PET not suitable 
for the routine clinical imaging, with its role currently limited to the visualisation of 
poorly differentiated tumours. Imaging with [68Ga]-DOTA-TOC PET has been 
reported to be more sensitive than [18F]-FDG PET in patients with primary or 
recurrent  NETs  9.  Furthermore,  clinical  studies  comparing  [68Ga]-DOTA-TOC 
PET with [111In]-octreotide scintigraphy suggest that [68Ga]-DOTA-TOC PET is 
more sensitive than SRS in detecting NETs as a result of greater signal-to- 
background contrast 10,  11. Currently it is unclear which [68Ga] tracer - DOTA- 
TOC, DOTA-TATE or DOTA-NOC - is the best and there is no consensus for 
their use partly due to lack of a robust supply mechanism for the radiotracers for 
clinical trials. It is clear, however, that the sensitivities of these tracers are better 
than SRS due to use of PET. 
 
The main limitations with [68Ga]-DOTA-analogues PET are the requirement for an 
on-site Gallium generator for tracer manufacture resulting from the much shorter 
half life of [68Ga] compared to [18F] tracers that can be shipped easily to several 
sites and the low throughput of such generators, the poorer resolution of [68Ga] 
compared to [18F] and the paucity of clinical grade GMP radiotracer for large 
multi-centre trials. We, therefore, sought to develop a fluorine-18 labelled 
octreotate analogue which can be effectively used to image NETs by employing 
a versatile two-step GMP-compatible click chemistry method; embodied in the 
design of these fluorinated analogues, strategies to improve tumour uptake and 
systemic PK 12. Fluorinated somatostatin analogues have been previously 
developed due to their superior physical properties for PET imaging, however, 
their clinical utility have been limited by high background uptake making it very 
difficult to visualise tumours particularly those within the liver, the main site of 
metastatic disease.   We have developed a novel [18F] labelled somatostatin 
analogue with improved in vivo kinetics compared to previously published [18F] 
labelled analogues. 


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FETONET study      version 3.5      12th December 2016 
 
5.1 [18F]-FET-βAG-TOCA-PET 
We have developed a novel [18F]fluoroethyl triazole labelled [Tyr3]Octreotate 
analogue, [18F]-FET-βAG-TOCA, that has been shown to have more favourable 
kinetics  compared  to  other  fluorinated  somatostatin  analogues  and  [68Ga]- 
DOTATATE in vivo 12,  13. We propose to transition [18F]-FET-βAG-TOCA-PET 
into humans within 2 cohorts of patients. Patients in cohort 1 will undergo ‘whole 
body dynamic PET scanning’ with assessment of PK and safety. We will then 
use this information to develop an optimal ‘whole body static PET scanning’ 
protocol that will be used for patients in cohort 2. We will directly compare the 
sensitivity and specificity of [18F]-FET-βAG-TOCA-PET to [68Ga]-DOTATATE 
PET/CT, in the accurate localisation of NETs. It is anticipated that this novel 
tracer will eventually be the new standard in the imaging of these tumours. 
. 
 
 


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FETONET study      version 3.5      12th December 2016 
 
 
 
 
 
 
5.2 Rationale and evidence to date 
NETs have a high density of SSTRs, in particular SSTR 2, on their cell surface. 
This characteristic allows the use of labelled somatostatin analogues to visualise 
these tumours. We developed five structurally-related [18F]fluoroethyltriazole- 
[Tyr3]octreotate analogues with suitable PK for PET imaging: [18F]-FET-G-PEG- 
TOCA, [18F]-FETE-PEG-TOCA, [18F]-FET-G-TOCA, [18F]-FETE-TOCA, and [18F]- 
FET-βAG-TOCA.   To select a lead compound we compared the tissue PKs of 
each novel compound to the recently described [18F]-aluminium fluoride NOTA- 
octreotide ([18F]-AlF-NOTA) and [68Ga]-DOTA-TOCA, a radiotracer widely used in 
the clinical assessment of NETs 14. All [19F]fluoroethyltriazole-[Tyr3]octreotate 
compounds retained high agonist binding affinity to SSTR2 in vitro (EC50 of 4-19 
nM versus somatostatin at 5.6 nM)12.  
 


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FETONET study      version 3.5      12th December 2016 
 
Utilising the AR42J pancreatic cancer xenograft model, which expresses a high 
level of SSTR-2, dynamic PET imaging was performed following administration of 
each tracer.  Tumour uptake was maximal with FET-G-TOCA, followed by FET- 
βAG-TOCA and [18F]-AlF-NOTA, with the least tumour uptake seen with [68Ga]- 
DOTATATE.  Incorporation of polyethylene glycol (PEG) linkers to reduce non- 
specific protein interactions and increase circulation time, as exemplified by 
[18F]- FET-G-PEG-TOCA and FETE-PEG-TOCA, resulted in reduced uptake in 
high SSTR2 expressing AR42J pancreatic cancer xenografts, and these were not 
taken forward.  Whilst tumour uptake was maximal with [18F]-FET-G-TOCA, 
its slow hepatic clearance meant that this was not taken forward, and [18F]-FET- 
βAG-TOCA, which showed the lowest non-specific uptake in liver, was selected 
for further development (13).The specificity of [18F]-FET-βAG-TOCA tumour 
uptake was illustrated through a number of experiments.  Firstly, a radiolabelled 
scrambled peptide derived from [18F]-FET-βAG-TOCA, [18F]-FET-βAG-[W-c-
(CTFTYC)K], did not show tumour uptake. Secondly, there was a 2-fold lower 
uptake of [18F]-FET-βAG-TOCA in AR42J xenografts when mice were pre-
treated with 10 mg/kg of unlabelled octreotide. Finally there was low uptake of 
[18F]-FET-βAG-TOCA in low SSTR-2 expressing HCT116 xenografts.  
 
The safety profile of [18F]-FET-βAG-TOCA as a single microdose study in rats 
was assessed by a commercial GLP laboratory in accordance with MHRA/EMEA 
guidelines (see attached). There was no tracer (or precursor) related toxicity at 
1000x the intended human dose. Rat radiation dosimetry studies, conducted by 
GE Healthcare are complete. The radiotracer showed a suitable organ dose 
profile. The new fluoroethyltriazole-[Tyr]3-octreotate radioligand, FET-βAG- 
TOCA, combines high specific binding with rapid target localization for high 
contrast PET imaging. 
 
 
 
6. STUDY OBJECTIVES 
 
6.1 Primary objective 
 To determine the bidistribution of [18F] following single i.v administration of 
[18F]-FET-βAG-TOCA injection. 
 To assess tumoural uptake of [18F]-FET-βAG-TOCA 
6.2 Secondary objectives 
To assess efficacy of [18F]-FET-βAG-TOCA PET/CT in patients with a histological 
diagnosis of NET and with measurable disease, who have and have not had 
[68Ga]- DOTA-peptide imaging 


17 
FETONET study      version 3.5      12th December 2016 
 
  
6.3 Safety endpoints  
The occurrence of one or more treatment-emergent adverse events (AEs) from 
administration of [18F]-FET-βAG-TOCA injection throughout the study period, and 
changes in serum biochemistry, haematology, coagulation, immunology, urinalysis, 
vital signs, ECG, injection site and physical examination findings. 
 
 
7.1 Cohort 1 
 
7.1.1 Primary 
1.  To determine the biodistribution (clearance from whole blood and plasma, 
and urinary excretion) of [18F] following single i.v. administration of 
[18F]-FET-βAG-TOCA injection in patients with a histological diagnosis 
of NET 
2.  To calculate the internal radiation dosimetry and the Effective Dose (ED) 
 
7.1.2 Translational end-points 
1.  To assess the safety of [18F]-FET-βAG-TOCA 
2.  Assess expression of SSTR1-5 in biopsy specimens and compare with 
PET parameters 
 
7.2 Cohort 2 
 
7.2.1 Primary 
1. To assess tumoural uptake of [18F]-FET-βAG-TOCA –PET/CT 
 
7.2.2 Secondary 
2. Compare diagnostic efficacy of [18F]-FET-βAG-TOCA in those patients 
who have had or not had or are due to have [68Ga]-DOTA-peptide 
imaging. A power of ≥ 80% has been chosen to conclude non-inferiority 
equivalence.  
 
Note**(All patients with a histological diagnosis of NET and lesion on CT is ≥1cm 
irrespective of whether they have had a [68Ga]-DOTA-peptide scan or are waiting 
for one as part of their management will be included in study). 
 
3. Comparison of [18F]-FET-AG-TOCA PET/CT scan and central review 
(nuclear medicine and radiology physician experts) of all imaging received 
by patient. (To account for any discrepancy that may exist between CT, 
[68]Ga-DOTA-peptide imaging and [18F]-FET-AG-TOCA PET/CT scan, 
then patients will be offered an MRI scan. 
 


18 
FETONET study      version 3.5      12th December 2016 
 
7.2.3 Translational end-points 
1.  Assess expression of SSTR1-5 in biopsy specimens and compare with 
PET parameters 
 
2.  Evaluation of possible adverse effects 
 
 
8. STUDY OUTLINE 
 
8.1 Study design and rational of the chosen approaches 
The total sample size will be 56 patients.  Patients from cohort 1 (n=8-12), 4-6 
female and 4-6 male (each cohort minimum 3) will be used in the final analysis. 
Patients with locally advanced or metastatic NETs of any site will be recruited 
from the Endocrinology, Surgical and Oncology Outpatients clinic, Hammersmith 
and Royal Free Hospitals.  After obtaining informed consent, eligible patients will 
have blood taken at baseline for FBC, EUC, LFTs (routine clinical practice), and 
serum biomarkers.   Patients will undergo routine staging.   In addition, patients 
will undergo [18F]-FET-βAG-TOCA PET/CT scanning at Imanova. Patients’ 
original diagnostic tumour biopsy (paraffin fixed) will be obtained. 
 
8.1.1 Cohort 1. Dosimetry and safety study in patients with histological 
diagnosis of NETs of any site. 
In this initial evaluation patients presenting for routine staging will be consented 
to undergo whole body dynamic scanning (multiple whole body scans up to 3.5 
hours) with metabolite analysis in order to develop a suitable protocol for static 
scanning that will be used for patients in cohort 2. We will also calculate the 
internal   radiation   dosimetry, which   may   alter   the   administered   dose   in 
subsequent studies. Although we do not expect any toxicity, we will conduct 
detailed safety assessment in this group of patients. We require a minimum of 8 
patients for final Dosimetry and safety analysis, which should include a minimum 
of either 3 male or 3 female subjects. To ensure both sexes are sufficiently 
represented in the final Dosimetry, for calculating effective dose, Cohort 1 will 
therefore include a minimum of 8, but up to 12 subjects. 
 
8.1.2 Cohort 2. Open label study assessing tumoural uptake of [18F]-FET- 
βAG-TOCA –PET in patients with histological diagnosis of NETs of any site. 
Patients presenting for routine staging will be consented to also undergo a static 
PET/CT imaging with [18F]-FET-βAG-TOCA in order to compare the clinical utility 
of [18F]-FET-βAG-TOCA – PET/CT with standard of care somatostatin receptor 
imaging . As a translational endpoint, patients will also be consented for retrieval 
of their pre-treatment biopsy specimen. Immunohistochemistry (IHC) will be 
performed for expression of SSTR1-5, which will be correlated with PET images 
from both tracers (see section 4.2 for Summary) 
 
 


19 
FETONET study      version 3.5      12th December 2016 
 
9. ELIGIBILITY 
 
9.1 Inclusion criteria 
1.  Written informed consent 
2.  Age ≥ 18 years 
3.  Histological diagnosis of NET of any site, except where ENETS criteria 
does not mandate histology for confirmation of diagnosis or patients who 
have a positive 68Gallium-peptide scan in whom NET diagnosis is pre-
operatively definitive. 
4.  Locally advanced or metastatic disease 
5.  Eastern Cooperative Oncology Group (ECOG) performance status of <2 
(appendix A) 
6.  Life expectancy > 3 months 
7.  Measurable disease defined as a lesion that can be accurately measured 
in at least one dimension with the longest diameter ≥10mm using 
conventional techniques 
8.  Somatostatin receptor imaging within 6 months. (if patient does not have 
somatostatin receptor imaging they may also be included provided they have 
measurable disease (≥10mm) on conventional imaging. 
9.  Adequate organ system function as defined in Table 1 
 
 
Table 1 clinical laboratory parameters 
 
 
 
 
 
 
9.2 Exclusion Criteria 
1.  Patients received chemotherapy within 3 weeks of study 


20 
FETONET study      version 3.5      12th December 2016 
 
 
2.  Patients received radiotherapy within 4 weeks of study 
 
3.  Active uncontrolled infections, gastrointestinal disease, haemolysis or 
any serious co-existing medical illness 
 
4. Psychological, familial, sociological or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule 
 
5.  Pregnant or lactating women 
 
6.  Females of childbearing potential who are unwilling to avoid pregnancy, 
for the duration of the study 
 
7.  Presence of any underlying medical conditions which   in   the 
investigators opinion would make the patients unsuitable for treatment 
 
8.  Patient not expected to be able to tolerate the scanning sessions 
 
10. COMPLETION OR EARLY WITHDRAWAL 
 
 
10.1 Subject completion 
A completed subject is one who has completed all phases of the study. 
The end of the study is defined as the last subject’s last visit. 
 
 
 
10.2 Withdrawal criteria 
Whatever the disease status, the treatment will always be discontinued in case of 
patient refusal. 
Each patient is free to withdraw from the study at any time. 
A complete final evaluation at the time of the subject’s withdrawal will be made 
and an explanation given of why the patient is withdrawing or being withdrawn 
from the study. 
The reason for non-completion and the date and time of the last contact with the 
patient must be noted in the case report form (CRF). 
In the case of patients withdrawal before or after dosing (ie, non-evaluable 
subjects) additional patients may be enrolled to reach a total of 56 evaluable 
patients. 
 
10.3 Blinding 
This is an open label study, therefore blinding is not applicable. 
 
 
11. STUDY PROCEDURES 
Each patient will have one session of PET/CT scanning. Patients in cohort 1 will 
be required to have an overnight stay following their scan whilst those in 
cohort 2 will have up to a 70 minute scan and will be discharged home 
following the scan. All efficacy and safety measurements obtained during the 


21 
FETONET study      version 3.5      12th December 2016 
 
course of the study are summarised in the Study Schedule of Events in table 1 
and 2. 


22 
FETONET study      version 3.5      12th December 2016 
 
-30 days 
screening
-30 to –5 min 
-2 min 
Dose 
+2 min 
+5 min 
+10 min 
+15 min 
+30 min 
+ 1 hour 
+1 hour  30 
min 
+2 h 30 min 
+4 hours 
+ 24 hours 
Informed Consent 

Entry Criteria 

Demographic Information 

Medical History 

Prior/Concomitant Medication 


Physical Exam 



Injection Site Monitoring 
 
 
 
 

Pregnancy Test 


ECG 1 

 
 
 
 
 






Pulse Oximetry 2 


 
 
 






Vital Signs 











Blood 
(Serum 
Biochemistry, 
Haematology, Coagulation)3 






Urinalysis4 
 
 
 
 
 
 

Pre-administration Events 
Transmission Scan 

[18F]-FET-βAG-TOCA injection 

Post-administration Events5 
PET Imaging6 
Blood and    Plasma 
for    Activity 
Counting 







Urine4 for Activity Counting 
 
Table 2. Study Schedule of Events for cohort 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
min=minutes 
1 
Continuous ECG performed from –5 min to +15 min.  Lead II may be used for continuous monitoring. 
12-lead  ECG  should  be  recorded  at  the  times  indicated  ECG  should  remain  under  continuous 
supervision and additional print outs obtained if any abnormality is detected 
2 
At baseline, before vital signs and pulse oximetry are measured, the subject should be resting for at least 
5 minutes (if possible) 
3 
All blood samples for patients will be taken from venous blood. 
4 
Time points indicated are preferred time points, urine will be collected as voided 
5 
Events will be collected throughout the subjects participation in the study 
6 
PET Imaging will be taken at 4 discrete time points for up to 4 hours post administration, with resting 
periods in between 
*   Shaded areas depict continuous monitoring 


23 
FETONET study      version 3.5      12th December 2016 
 
Table 3. Study Schedule of Events for cohort 2. 
 
≤30 days  
-180to –5 min 
Dose 
≤70 - min 
END OF 
SCAN 
Informed Consent 

Entry Criteria 

Demographic Information 

Medical History 

Prior/Concomitant Medication 

Physical Exam 

Pregnancy Test4,5 


Pulse Oximetry1,5 


Vital Signs1,5 


Blood  (Serum  Biochemistry,  Haematology)2 

[18F]-FET-βAG-TOCA injection (max 370MBq) 

PET/CT Imaging 
Adverse event monitoring3 
 
min=minutes 
1 
At baseline, before vital signs and pulse oximetry are measured, the subject should be resting for at least 
5 minutes (if possible) 
2 
All blood samples for patients will be taken from venous blood. If blood results are available which have 
been taken as part of subjects standard care (within 30 days of study scan), these do not need to be repeated. 
3 
Events will be collected throughout the subjects participation in the study 
4    Women of childbearing potential.  
5  Where screening and PET scan are on same day, procedure is done once 
*Shaded areas depict continuous monitoring 
 
11.1 Screening period (Day -30 to Day 0) 
 Patients will be screened up to 30 days before tracer administration and 
confirm eligibility. At the screening visit demographic data/baseline 
characteristics, medical history, and medication will be recorded.   All 
female subjects of childbearing potential will undergo a pregnancy test. 
 Signed and dated informed consent must be obtained from all subjects 
prior to any protocol specific procedures being performed. 
 
Blood samples for serum biochemistry and haematology, will be drawn 
from venous blood if not already taken as part of subjects standard care 
within 30 days of tracer administration. ;.  
 Vital signs and pulse oximetry,  will  be  recorded and a physical 
examination including a limited neurological examination will be 
performed. 
 If [68Ga]-DOTA-peptide imaging PET/CT has been performed within 6 
months of [18F]-FET-βAG- TOCA PET/CT, scans will be retrieved. 


24 
FETONET study      version 3.5      12th December 2016 
 
11.2 PET Procedure (Day 0) 
The tracer is made at GMP standards, at Imanova Limited which are GMP 
certified 
 PET/CT scans will be carried out in the Imanova Limited, at the 
Hammersmith hospital site, Du Cane Road, London 
 Transportation will be arranged as required for patients 
 Between 30 min to 2 min before dosing the different parameters will 
be assessed as reported in Table 2 (Cohort 1). Between 180 min to 5 
min before dosing the different parameters will be assessed as 
reported in Table 3 (Cohort 2). 
 For patients in cohort 1 two Intravenous cannulae will be placed in the 
arm in order to inject the tracer, [18F]-FET-βAG-TOCA and for metabolites 
(approximately 200ml of blood samples will be taken from this line). 
For patients in cohort 2 one Intravenous needle will be placed in the 
arm in order to inject the tracer, [18F]-FET-βAG-TOCA. 
 Patient will be asked to lie flat on the PET-CT scanner bed 
 The bed will move into the scanner which looks like a short tunnel 
 Patients in cohort 1 will have ECG monitoring. Vitals will be assessed 
 (pre-specified time points, as reported in Table 2). 
  A non contrast enhanced CT will be performed to define the region 
of interest.   [18F]-FET-βAG-TOCA   will   be   injected   intravenously.   
PET/CT scanning will be then subsequently performed.  In cohort 1 
patients will undergo 5-6 whole body sweeps (vertex to mid thighs) lasting 
approximately 3-4 hours with a gap in between.  Patients in cohort 2 
will have a PET/CT scan which will last up to 70 minutes 
 Patients in cohort 1 will be admitted for overnight stay.  
 
Tumour biopsies at diagnosis will be retrieved for analysis of SSTR1-5 
expression after Day 0 on successful completion of subject scan. 
 
 
 
11.3 Radiation dosimetry. 
Table 4. Radiation dosimetry description for [18F]-FET-βAG-TOCA PET and 
CT. 
Tracer 
[18F]-FET-βAG-TOCA CT 
Maximum dose per scan(MBq) 
165 
Conversion factor (mSv/MBq) 
0.04 
Effective dose per scan (mSv) 
5.11 
2.4 
No of scans 
1 
2 (cohort 1) 1 (cohort 2) 
Total effective dose (mSv)/ patient 5.11 mSv  cohort 1 
12 mSv 
cohort 2 
4.8 
(cohort 
1), 2.4 
(cohort 2) 
 
Therefore total effective dose per patient is 12mSv for cohort 1 and 14mSv for 
cohort 2 (max dose injected 370Mbq). 


25 
FETONET study      version 3.5      12th December 2016 
 
11.4 PET parameters 
Attenuation corrected images will be reconstructed.  Regions of interest will 
be drawn around the tumour to derive semi-quantitative uptake parameters, 
SUV (standardized uptake value) and AUC (area under curve, total activity over 
scanning time).  Venous blood samples will be taken for assessment of 
counts during the [18F]-FET-βAG-TOCA scan in cohort 1.  These bloods will be 
used to generate  the  blood  input  function  that  is  required  to  derive  
uptake  tracer 
parameters such as Ki (rate constant for net irreversible uptake) and FRT 
(fractional retention of tracer) which will be used to set scanning parameters for 
cohort 2. 
 
12. ASSESSMENT AND FOLLOW-UP 
 
12.1 Clinical Assessments 
12.1.1 Screening 
Confirm eligibility 
 Complete clinical history, including concomitant medications 
 Full clinical examination 
 Vital signs 
 ECG 
 Retrieve original tumour biopsies 
 Somatostatin receptor imaging within 6 months of study entry 
 
12.1.2 Cohort 1: day of scan (Day 0) 
Confirm eligibility 
Concomitant medication recording 
Physical examination 
Vital signs 
ECG 
Bloods 
Urinalysis 
Urine pregnancy test 
[18F]-FET-βAG-TOCA PET/CT imaging 
Baseline adverse event reporting 
Cohort 1: Admit for overnight observation 
Hammersmith Hospital 
at the Phase I unit, 
12.1.3 Cohort 1: Day 1 post scan 
 Physical examination 
 Vital signs 
 ECG 
 Bloods 


26 
FETONET study      version 3.5      12th December 2016 
 
 Urinalysis 
 Adverse events reporting 
 
 
12.1.4 Cohort 2: day of scan 
 Confirm eligibility 
 Vital signs 
 [18F]-FET-βAG-TOCA PET/CT imaging 
 Baseline adverse event reporting 
 Urine pregnancy test 
 
13. COMPLICATIONS AND RADIATION DOSE 
 
13.1 Complications 
All patients will be recruited strictly according to protocol following the principles 
of the Declaration of Helsinki. All inclusion criteria would be satisfied before 
approaching patients.  There are no immediate complications of the PET scan 
except for a potential mild bruising at the site of insertion of the cannula which 
should resolve in 1-2 weeks. 
 
13.2   Radiation dose 
The total effective dose (ED) received from the PET-CT scan is estimated to be 
12mSv for cohort 1 and 14 mSv for cohort 2. In a dosimetry study such as this, 
the estimate is necessarily uncertain but a conservative approach has been 
taken that will overestimate the effective dose by using a high dose conversion 
factor of 0.04 mSv/MBq injected activity. The total effective dose of 14 mSv 
(cohort2)  is equivalent to about 6 times the average yearly exposure (2.3 mSv) 
from natural background radiation in the United Kingdom. For an adult in good 
health, this exposure would result in a risk of around 1 in 1600 (cohort1) and 1 in 
1400  (cohort2)  of  contracting  a  fatal  cancer,  However,  for  someone  in  the 
planned study groups who have shorter life expectancy than the general 
population         it         represents         a         significantly         lower         risk. 
Note that as part of the standard practice for patients included in this study, a 
single [68Ga] Dotatate PET/CT scan will be performed; this is one of the entry 
qualifications but is not an additional examination that is part of the research 
protocol. 
 
14. STATISTICAL ANALYSIS AND SAMPLE SIZE CALCULATION 
 
 
14.1 Cohort 1 
Using results of dynamic scanning and metabolite analysis, in particular the time 
course of tumour radiotracer uptake, we will design the appropriate protocol by 
which we will analyse the diagnostic, static scans in cohort 2.  We will calculate 


27 
FETONET study      version 3.5      12th December 2016 
 
the  internal  radiation  dosimetry  as  well  as  biodistribution  of  the  tracer. 
Depending on these results we may alter the administered dose in cohort 2. 
 
14.1.1 Safety 
Safety data will be collected at baseline and after the administration of the tracer. 
The safety of the regimen will be evaluated by the frequency and grade of 
adverse events. Rates will be reported with a 90% Binomial exact confidence 
interval. With a sample size of N=12 the maximum half-width to the confidence 
interval will be 0.25.Using results of dynamic scanning and metabolite analysis, 
in particular the time course of tumour radiotracer uptake, we will design the 
appropriate protocol by which we will analyse the diagnostic, static scans in sub- 
study 2.Rates of adverse events will be reported by grade and summarized using 
95% Binomial exact confidence interval. 
 
14.1.2 Biodistribution 
The temporal variations of 18F activity concentrations in whole blood and plasma 
and the rate and amount of 18F activity excreted through the urinary pathway will 
be measured in patients and to evaluate the bio-distribution. 
 
 
14.1.3 Dosimetry 
We will calculate the internal radiation dosimetry as well as biodistribution of the 
tracer. Descriptive statistics will be used to summarize the biodistribution of [18F] 
following single i.v. administration of [18F]-FET-βAG-TOCA injection (mean, 
median, range, interquartile range, and standard deviation).Depending on these 
results we may alter the administered dose in sub-study 2. 
 
14.1.4 Somatostatin receptor expression 
SUV measures from [18F]-FET-βAG-TOCA PET/CT will be summarized by lesion. 
The correlation of SUV measures to ordinal measures of SSTR1-5 detected by 
IHC staining of the diagnostic biopsy (-,+,++,+++) will be evaluated using non- 
parametric Kruskal-Wallis tests. 
 
14.2 Cohort 2 
Comparison will be made between FET-βAG-TOCA PET and the standard of 
acre somatostatin receptor imaging based on both a per-patient and per-lesion 
based analysis.  Non-parametric McNemar test with Bonferroni correction for 
multiple comparisons will be used.   The association between SSTR1-5 
expression and imaging parameters obtained will be assessed. Data will be 
analyzed using SPSS 16.0 for Windows. 
 
14.2.1 Power and sample size determination 
Power for the Wilcoxon signed-rank test is calculated by simulation using a 
truncated log-normal distribution parameterized according to Kabasakal et al.15 
(median = 5, range = 1 to 25) to sample the total number of lesions in patients 


28 
FETONET study      version 3.5      12th December 2016 
 
across a range of samples. With a total of N = 48 patients assessed by both 
modalities, there will be 80% power to conclude non-inferiority equivalence if the 
two methods are equivalent ( = 0). 
The  distributions  of  number  of  lesions  detected  by  [18F]-FET-βAG-TOCA  – 
PET/CT and by [68Ga]-DOTA-peptide-PET/CT will be summarized, and will be 
compared using the Wilcoxon signed-rank test with the pre-specified level of 
equivalence of  = 0.64 and a one-sided alpha= 0.1. 
 
14.2.3 Somatostatin receptor expression 
SUV measures from [18F]-FET-βAG-TOCA will be summarized by lesion.  The 
correlation of SUV measures to ordinal measures of SSTR1-5 detected by IHC 
staining of the diagnostic biopsy (-,+,++,+++) will be evaluated using non- 
parametric Kruskal-Wallis tests. 
 
 
15. PHARMACOVIGILANCE 
 
15.1 DEFINITIONS 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical 
trial subject administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational 
medicinal product (IMP), whether or not considered related to the IMP. 
 
Adverse Reaction (AR): all untoward and unintended responses to an IMP 
related to any dose administered. All AEs judged by either the reporting 
investigator or the sponsor as having reasonable causal relationship to a 
medicinal  product  qualify  as  adverse  reactions.  The  expression  reasonable 
causal  relationship  means  to  convey  in  general  that  there  is  evidence  or 
argument to suggest a causal relationship. 
 
Unexpected Adverse Reaction: an AR, the nature or severity of which is not 
consistent with the applicable product information (eg investigator’s brochure for 
an unapproved investigational product or summary of product characteristics 
(SmPC) for an authorised product). When the outcome of the adverse reaction is 
not  consistent  with  the  applicable  product  information  this  adverse  reaction 
should be considered as unexpected. Side effects documented in the SmPC 
which occur in a more severe form than anticipated are also considered to be 
unexpected. 
 
Serious Adverse Event (SAE) or Serious Adverse Reaction: any untoward 
medical occurrence or effect that at any dose 
 
Results in death 
 


29 
FETONET study      version 3.5      12th December 2016 
 
Is life-threatening – refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe 
 
      Requires hospitalisation, or prolongation of existing inpatients’ 
    hospitalisation 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE/AR is serious 
in other situations. Important AE/ARs that are not immediately life-threatening or 
do not result in death or hospitalisation but may jeopardise the subject or may 
require intervention to prevent one of the other outcomes listed in the definition 
above, should also be considered serious. 
Suspected Unexpected Serious Adverse Reaction (SUSAR): any suspected 
adverse reaction related to an IMP that is both unexpected and serious. 
 
15.2 CAUSALITY 
Most adverse events and adverse drug reactions that occur in this study, whether 
they are serious or not, will be expected treatment-related toxicities due to the 
drugs used in this study. The assignment of the causality should be made by the 
investigator responsible for the care of the participant using the definitions in the 
table below. 
If any doubt about the causality exists the local investigator should inform the 
study coordination centre who will notify the Chief Investigators. The 
pharmaceutical companies and/or other clinicians may be asked to advise in 
some cases. 
In the case of discrepant views on causality between the investigator and others, 
all parties will discuss the case. In the event that no agreement is made, the 
MHRA will be informed of both points of view. 
 
15.3 REPORTING PROCEDURES 
All adverse events should be reported. Depending on the nature of the event the 
reporting procedures below should be followed. Any questions concerning 
adverse event reporting should be directed to the study coordination centre in the 
first instance. A flowchart is given below to aid in the reporting procedures. 
 
15.3.1 Non serious AR/AEs 
All such toxicities, whether expected or not, should be recorded in the toxicity 
section of the relevant case report form and sent to the study coordination centre 
within one month of the form being due. 


30 
FETONET study      version 3.5      12th December 2016 
 
 
15.3.2 Serious AR/AEs 
Fatal or life threatening SAEs and SUSARs should be reported on the day that 
the local site is aware of the event. The SAE form asks for nature of event, date 
of onset, severity, corrective therapies given, outcome and causality (i.e. 
unrelated, unlikely, possible, probably, definitely). The responsible investigator  
 
should sign the causality of the event. Additional information should be sent 
within 5 days if the reaction has not resolved at the time of reporting. 
 
SAEs 
An SAE form should be completed and faxed to the study coordination centre for 
all SAEs within 24 hours. However, relapse and death due to <condition>, and 
hospitalisations for elective treatment of a pre-existing condition do not need 
reporting as SAEs. 
 
SUSARs 
In the case of suspected unexpected serious adverse reactions, the staff at the 
site should: 
Complete the SAE case report form & send it immediately (within 24 hours, 
preferably by fax), signed and dated to the study coordination centre together 
with relevant treatment forms and anonymised copies of all relevant 
investigations. 
Or 
Contact the study coordination centre by phone and then send the completed 
SAE form to the study coordination centre within the following 24 hours as above. 
The study coordination centre will notify the MHRA, REC and the Sponsor of all 
SUSARs occurring during the study according to the following timelines; fatal and 
life-threatening within 7 days of notification and non-life threatening within 15 
days. All investigators will be informed of all SUSARs occurring throughout the 
study. 
 
16. DATA MANAGEMENT 
Data will be collected on electronic CRFs. 
 
17. ADMINISTRATIVE AND LEGAL CONSIDERATIONS 
To ensure compliance of this trial with Good Clinical Practice (GCP) principles, 
the following procedures will be followed by the Investigators. 
 
 
 
17.1   Pre-Trial Requirements 
 
Treatment within this study will only start if the following prerequisites have been 
fulfilled and documentation is at hand: 
 


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FETONET study      version 3.5      12th December 2016 
 
       Signed copy (original) of the approved protocol 
 
       EC approval of the protocol, consent form and information sheet 
 
       Approval / notification of local authorities 
 
The Investigator will hold an Investigator’s File containing the relevant study 
documents. 
 
 
 
17.2 General Legal Requirements 
 
The study will be conducted in agreement with the following directives and 
guidelines: 
 
- 
The Declaration of Helsinki ( version of Edinburgh, Scotland, October 2000) 
 
- 
The respective guidelines of the European Community: Guideline for Good 
Clinical Practice (Note for Guidance on Good Clinical Practice / ICH E6) 
 
- 
Statutory Instrument 2004 No. 1031 – The Medicines for Human Use (Clinical 
Trials) Regulations 2004 as amended. 
 
 
All clinical work conducted under this protocol will be subject to Good Clinical 
Practice rules. This includes an inspection by health authority representatives at 
any time. The Investigator agrees to the inspection of study-related records by 
health authority representatives and/or the sponsor. 
 
 
 
 
 
17.3 Protection of Subjects 
 
17.3.1 Ethics Committee 
 
The protocol and a copy of the subject information and informed consent form 
will be submitted to the competent EC(s). Written approval of the protocol and 
the proposed information and consent form will be obtained prior to the start of 
the trial. 
 
 
 
17.3.2 Informed Consent 
 
It is the Investigator’s responsibility to explain to each subject the study 
procedure, potential benefits and hazards of trial participation, the right to 
withdraw from the study at any time, and to obtain written informed consent prior 
to any study-specific procedures. The original copy of the signed and dated 
Informed Consent Form must be filed in the patient’s notes. The subject, the 
subject’s legally authorized representative, or both will be given a copy of the 


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FETONET study      version 3.5      12th December 2016 
 
signed and dated Informed Consent Form. 
 
 
 
17.3.3 Privacy protection 
 
In order to maintain subject privacy, all CRFs, study drug accountability records, 
study reports and communications will identify the subject by initials and the 
assigned subject number. 
 
The investigator will grant monitor(s) and auditor(s) access to the subject’s 
original medical records for verification of data gathered on the CRFs and to 
audit the data collection process. The subject’s confidentiality will be maintained 
and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
 
 
 
17.4 Protocol Amendments 
 
The protocol must be read thoroughly and the instructions must be followed 
exactly. 
 
Any changes in the protocol will require a formal amendment. Such amendments 
will be agreed upon and approved in writing by the Principal Investigator. 
Amendments to the protocol will be submitted to the relevant authorities and the 
EC for approval prior to implementation. 
 
Administrative  changes  which  have  no  significant  impact  on  the  medical  or 
scientific validity of the study will be documented in a statement. The EC will be 
notified of administrative changes, if applicable. 
 
 
 
17.5 Premature Termination of the Trial 
 
The Investigator reserves the right to terminate the trial for well-documented 
reasons. Instructions will be provided in a separate document should it be 
determined that assessments beyond those defined by the protocol are required. 
 
 
 
Further recruitment of subjects will not take place under the following conditions:  
 
- 
Premature termination of the trial. 
 
- 
Drug-related  events,  i.e.  SUSARs,  emerging  adverse  effects  that  are 
serious and the risk/benefit ratio is unacceptable. 
 
- 
Procedure-related  events,  i.e.,  the  recruitment  rate  is  too  low  or  the 
number of dropouts for administrative reasons is too high. 
 


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FETONET study      version 3.5      12th December 2016 
 
 
An ‘End of Trial Form’ must be completed for each subject who completes the 
study or who withdraws prematurely from this study. 
 
 
 
17.6 Record Retention 
 
After the end of study, the Investigator will maintain all site study records in a 
safe and secure location.  The records will be stored in a location allowing easy 
and  timely  retrieval  when  needed  (for  example,  for  an  audit  or  inspection). 
Where permitted by local regulations or institutional policy, some or all of these 
records may be maintained in a format other than hard copy (for example, in an 
electronic format), but caution should be exercised.  The Investigator will ensure 
that all reproductions are legible and are a true and accurate copy of the original. 
All study records must be retained for at least 2 years after the last approval of a 
marketing application in an ICH region and until (1) there are no pending or 
contemplated marketing applications in an ICH region; or (2) at least 2 years 
have elapsed since the formal discontinuation of clinical development of the IP. 
The PI/institution should retain subject identifiers for at least 15 years after the 
completion or discontinuation of the study.  Subject files and other source data 
must be kept for the maximum period of time permitted by the hospital, institution 
or private practice, but not less than 15 years. These documents should be 
retained for a longer period, however, if required by the applicable regulatory 
requirements. The PI must be notified and will assist with retention should 
institution be unable to continue maintenance of subject files for the full 15 years. 
It is the responsibility of PI to inform the institution as to when these documents 
no longer need to be retained. 
 
If an Investigator moves, withdraws from an investigation, retires, requests to 
move records to another location or to assign these records to another party or 
(e.g. other Investigator) who will accept the responsibility, written notice of this 
transfer must be made to and agreed upon by each party. 
 
 
 
17.7 Study Monitoring 
 
The Investigator is responsible for ensuring that the study is monitored 
appropriately in order to ensure compliance with GCP and local regulatory 
guidelines. The monitor will check the completeness of medical records, verify 
the accuracy of entries in the CRF, and ensure adherence to the protocol and 
compliance with local regulatory requirements. 
 
 
17.8 Final Report 
 
A final integrated report will be prepared under the responsibility of the 
Investigator(s). It will include the tabulated raw data and the biostatistical report 
on the data. 
 
 


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FETONET study      version 3.5      12th December 2016 
 
 
17.9 Publications 
 
Publication of the results of the study, whether in whole or in part, shall be within 
the sole and absolute discretion of the Investigator. 
 
 
 
17.10 Liability and insurance 
 
All patients participating in the study will have insurance coverage by the sponsor 
which is in line with all applicable laws and/or regulations. 
 
 
17.11 Audits and Inspections 
 
To ensure compliance with GCP and all applicable regulatory requirements, the 
sponsor may conduct a quality assurance audit in accordance with their local 
internal procedures. 
 
Audits and/or inspections may also be carried out by local authorities, or 
authorities to which information on this trial has been submitted. All documents 
pertinent  to  the  trial  must  be  made  available  for  such  inspection  after  an 
adequate announcement. 


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FETONET study      version 3.5      12th December 2016 
 
 
18. REFERENCES 
 
1. 
Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. 
Lancet Oncol. Jan 2008;9(1):61-72. 
 
2. 
Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of 
and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J 
Clin Oncol. Jun 20 2008;26(18):3063-3072. 
 
3. 
Koopmans KP, Neels ON, Kema IP, et al. Molecular imaging in neuroendocrine tumors: 
molecular  uptake  mechanisms  and  clinical  results.  Crit  Rev  Oncol  Hematol.  Sep 
2009;71(3):199-213. 
 
4. 
Marko J, Lamba R, Miller F, Buchman A, Spies S, Nikolaidis P. OctreoScan positive 
Crohn's  disease  mimicking  an   ileal  carcinoid  tumor.  J   Clin  Gastroenterol.  Jan 
2008;42(1):66-68. 
 
5. 
Frilling A, Sotiropoulos GC, Radtke A, et al. The impact of 68Ga-DOTATOC positron 
emission tomography/computed tomography on the multimodal management of patients 
with neuroendocrine tumors. Ann Surg. Nov;252(5):850-856. 
 
6. 
Gabriel  M,  Decristoforo  C,  Kendler  D,  et  al.  68Ga-DOTA-Tyr3-octreotide  PET  in 
neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J 
Nucl Med. Apr 2007;48(4):508-518. 
 
7. 
Krausz Y, Freedman N, Rubinstein R, et al. (68)Ga-DOTA-NOC PET/CT Imaging of 
Neuroendocrine Tumors: Comparison with (111)In-DTPA-Octreotide (OctreoScan(R)). 
Mol Imaging Biol. Jul 22. 
 
8. 
Haug AR, Auernhammer CJ, Wangler B, et al. 68Ga-DOTATATE PET/CT for the early 
prediction of response to somatostatin receptor-mediated radionuclide therapy in patients 
with well-differentiated neuroendocrine tumors. J Nucl Med. Sep;51(9):1349-1356. 
 
9. 
Binderup T, Knigge U, Loft A, et al. Functional imaging of neuroendocrine tumors: a 
head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, 
and 18F-FDG PET. J Nucl Med. May;51(5):704-712. 
 
10. 
Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68Ga-DOTATOC PET and 
111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J 
Nucl Med Mol Imaging. Oct 2007;34(10):1617-1626. 
 
11. 
Srirajaskanthan R, Kayani I, Quigley AM, Soh J, Caplin ME, Bomanji J. The role of 68Ga- 
DOTATATE PET in patients with neuroendocrine tumors and negative or equivocal 
findings on 111In-DTPA-octreotide scintigraphy. J Nucl Med. Jun 2010;51(6):875-882. 
 
12. 
Iddon L, Leyton J, Indrevoll B, et al. Synthesis and in vitro evaluation of [18F]fluoroethyl 
triazole labelled [Tyr3]octreotate analogues using click chemistry. Bioorg Med Chem Lett. 
May 15 2011;21(10):3122-3127. 
 
13. 
Leyton J,  Iddon L,  Perumal M,  et  al.  Targeting Somatostatin Receptors: Preclinical 
Evaluation of  Novel 18F-Fluoroethyltriazole-Tyr3-Octreotate Analogs for PET. J  Nucl 
Med. 2011;52(9):1-8. 
 
14. 
Laverman P, McBride WJ, Sharkey RM, et al. A novel facile method of labeling octreotide 


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FETONET study      version 3.5      12th December 2016 
 
with (18)F-fluorine. J Nucl Med. Mar;51(3):454-461.15. Kabasakal L, Demirci E, Ocak M, 


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FETONET study      version 3.5      12th December 2016 
 
Decristoforo C, Araman A, Ozsoy Y, Uslu I, Kanmaz B. Comparison of 68Ga-DOTATATE 
and 68Ga-DOTANOC PET/CT imaging in the same patient group with neuroendocrine 
tumours.Eur J Nucl Med Mol Imaging. 2012;1271-7. 


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FETONET study      version 3.5      12th December 2016 
 
19. Appendix A: WHO performance status scale 
 
 
Grade 
Performance scale 
0 
Able to carry out all normal activity without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out light work. 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work; up and about more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair.