Evaluation of [18F]Fluoroethyl Triazole Labelled [Tyr3]-Octreotate Analogues for the Imaging of Neuroendocrine Tumours. (FETONET)

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.

Study Overview

• Status: Completed
• Conditions: Neuroendocrine Tumors
• Intervention / Treatment: Drug: [18F]-FET-βAG-TOCA

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.

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent
• Age ≥ 18 years
• 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.
• Locally advanced or metastatic disease.
• Eastern Cooperative Oncology Group (ECOG) performance status of <2 (appendix A).
• Life expectancy > 3 months.
• Measurable disease defined as a lesion that can be accurately measured in at least one dimension with the longest diameter ≥10mm using conventional techniques.
• 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.
• Adequate organ system function as defined within Table 1.

Exclusion Criteria:

• Patients received chemotherapy within 3 weeks of study.
• Patients received 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.
• Patient not expected to be able to tolerate the scanning sessions.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: [18F]-FET-βAG-TOCA-PET/CT performed in patients with histologically-confirmed NET.; 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.	Drug: [18F]-FET-βAG-TOCA; 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.
Experimental: Part B: [18F]FET-βAG-TOCA PET/CT compared with [68Ga]Ga-DOTA-peptide PET/CT in patients with NET.; 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.	Drug: [18F]-FET-βAG-TOCA; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Determine the Biodistribution of [18F] Following Single I.V Administration of [18F]-FET-βAG-TOCA Injection in Patients With a Histological Diagnosis of NET.	Mean residence time (MRT) was used to characterise the biodistribution of [18F]-FET-βAG-TOCA throughout the body. Mean residence time is a pharmacokinetic/uptake parameter that describes the average length of time a radiotracer resides within the body, or a particular organ, before being eliminated. Understanding MRT helps researchers to determine how long a radiotracer remains in the system, which is crucial for drug dosing, therapeutic efficacy, and potential toxicity assessment.	Baseline (on day of scan over 4 hours)
To Calculate the Effective Dose (ED) of [18F]-FET-βAG-TOCA	Effective dose is an estimate of the overall risk of potential harm from exposure to ionising radiation. ED takes into account, the absorbed dose to all organs of the body, the relative harm level of the radiation and the sensitivities of each organ to radiation. ED may help in understanding the risk of potential long-term health effects from radiation exposure, such as the risk of developing cancer later in life. The unit of measure for ED is millisievert per megabecquerel (mSv/MBq), which refers to the effective dose (amount of radiation absorbed by the body) per unit of activity administered.	Baseline (on the day of the scan over 4 hours)
To Assess Tumoural Uptake of [18F]-FET-βAG-TOCA	Standardised uptake value (SUV) is a semiquantitative measurement of radiotracer uptake in tissue. It is a ratio that compares the activity concentration in a specific region of interest to the activity concentration in the whole body. SUVmax is the highest value of the SUV measured within a region of interest.	Baseline (on the scan day over 4 hours)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Compare the Diagnostic Efficacy of [18F]-FET-βAG-TOCA PET/CT With Standard of Care Somatostatin Receptor Imaging in Patients With a Histological Diagnosis of NET.	To determine the clinical utility of [18F]-FET-βAG-TOCA-PET/CT compared with standard of care [68Ga]Ga-DOTA-peptide imaging. Standardised uptake value (SUV) is a semiquantitative measurement of radiotracer uptake in tissue. It is a ratio that compares the activity concentration in a specific region of interest to the activity concentration in the whole body. SUVmax is the highest value of the SUV measured within a region of interest. The median SUVmax of [18F]-FET-βAG-TOCA and [68Ga]-DOTA-peptide per anatomic region were calculated to determine diagnostic efficacy. Diagnostic efficacy is the ability of a test to correctly identify a disease or condition when it's present and correctly identify the absence of a disease when it's not present.	[68Ga]Ga-DOTA-peptide PET/CT imaging performed within 6 months of the [18F]-FET-βAG-TOCA PET/CT scan.
Comparison of [18F]-FET-βAG-TOCA PET/CT Scan and Central Review (Nuclear Medicine and Radiology Physician Experts) of All Imaging Received.	The [18F]FET-βAG-TOCA and [68Ga]Ga-DOTA-peptide PET/CT scans were reviewed by independent imaging experts to obtain an objective inter-reader lesion detection rate. To avoid recall bias, the [18F]FET-βAG-TOCA and [68Ga]Ga-DOTA-peptide PET/CT scans for each subject were reviewed at less 4 weeks apart in random order Percentage of agreement, also known as percent agreement, is a simple method to measure inter-rater reliability (IRR), calculating the proportion of times raters agree without considering chance. It's calculated by dividing the number of agreements by the total number of ratings and multiplying by 100	[68Ga]Ga-DOTA-peptide PET/CT imaging assessed within 6 months of the [18F]-FET-βAG-TOCA PET/CT scan.

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Royal Marsden NHS Foundation Trust; Newcastle University; University of Manchester; The Christie NHS Foundation Trust; Imperial College Healthcare NHS Trust; Invicro
• Investigators: Study Chair: Rohini Sharma, Imperial College London

Publications and helpful links

General Publications

• Dubash SR, Keat N, Mapelli P, Twyman F, Carroll L, Kozlowski K, Al-Nahhas A, Saleem A, Huiban M, Janisch R, Frilling A, Sharma R, Aboagye EO. Clinical Translation of a Click-Labeled 18F-Octreotate Radioligand for Imaging Neuroendocrine Tumors. J Nucl Med. 2016 Aug;57(8):1207-13. doi: 10.2967/jnumed.115.169532. Epub 2016 May 12.
• Dubash S, Barwick TD, Kozlowski K, Rockall AG, Khan S, Khan S, Yusuf S, Lamarca A, Valle JW, Hubner RA, McNamara MG, Frilling A, Tan T, Wernig F, Todd J, Meeran K, Pratap B, Azeem S, Huiban M, Keat N, Lozano-Kuehne JP, Aboagye EO, Sharma R. Somatostatin Receptor Imaging with [18F]FET-betaAG-TOCA PET/CT and [68Ga]Ga-DOTA-Peptide PET/CT in Patients with Neuroendocrine Tumors: A Prospective, Phase 2 Comparative Study. J Nucl Med. 2024 Feb 8;65(3):416-22. doi: 10.2967/jnumed.123.266601. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2014
• Primary Completion (Actual): October 17, 2018
• Study Completion (Actual): October 17, 2018

Study Registration Dates

• First Submitted: May 28, 2024
• First Submitted That Met QC Criteria: June 7, 2024
• First Posted (Actual): June 13, 2024

Study Record Updates

• Last Update Posted (Actual): May 1, 2025
• Last Update Submitted That Met QC Criteria: April 14, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Positron Emission Tomography
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors
• Other Study ID Numbers: 13HH0807

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no plan to make individual participant data available to other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No