Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001735145
Ethics application status
Approved
Date submitted
27/08/2019
Date registered
9/12/2019
Date last updated
12/07/2023
Date data sharing statement initially provided
9/12/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Prospective, multicentre trial evaluating O-(2-[18F]-fluoroethyl)-L-tyrosine Positron Emission Tomography in Glioblastoma (FET-PET in Glioblastoma)
FIG Study
Scientific title
A prospective, multicentre trial evaluating the use of O-(2-[18F]-fluoroethyl)-L-tyrosine Positron Emission Tomography (FET-PET) imaging in radiotherapy planning and clinical management of people with glioblastoma.
Secondary ID [1] 299099 0
TROG 18.06
Universal Trial Number (UTN)
U1111-1222-4710
Trial acronym
FIG
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 314143 0
Glioblastoma 314145 0
Condition category
Condition code
Cancer 312516 312516 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants in this study are newly diagnosed Glioblastoma patients who will undergo post-operative chemo-radiation as per standard of care.
In addition to the current standard of care imaging with MRI, a new form of imaging has been developed where the tumours can be imaged by utilising a radio tracer FET which detects whether tumour cells are active
This study addresses an imaging based intervention assessing the additional use of FET-PET imaging throughout the patients treatment trajectory assessing FET-PET utility in 3 aspects:
1) The impact on post operative radiotherapy planning
2) Differentiation between treatment-related changes(pseudo-progression) from true tumour progression.
3) FET-PET imaging as a prognostic marker

200MBq +/- 10% of FET will be administered via a slow IV injection over 20-30seconds followed by a minimum 20mL saline flush. A head first CT followed by list mode acquisition for 40 minutes commencing at the start of the slow injection over 20-30 seconds of FET. Image acquisition commences immediately once the FET is administered.

Group 1 will receive a total of 3 FET-PET scans. FET-PET1 is done at the time of post-operative radiotherapy planning.
Both Group 1 and 2 will receive FET-PET2 four weeks post radiation therapy completion and FET-PET3 will be received post chemotherapy once changes are seen on routine MRIs.
With the intervention of FET-PET the assessment of more accurate tumour progression in Glioblastoma patients to improve treatment decisions, outcomes and patient care is the hope.
Intervention code [1] 315364 0
Diagnosis / Prognosis
Comparator / control treatment
No comparator or control - Single arm phase II study- comparison to standard imaging.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321145 0
The comparison of the radiation target volume delineation determined by MRI imaging compared to FET-PET imaging
Assessed by: Review of imaging and radiation therapy planning files by Nuclear Medicine and Radiation Oncology clinicians
Timepoint [1] 321145 0
MRI and FET-PET imaging will be collected at the time of initial radiation treatment planning (baseline), this will be a comparison of the standard radiation target volume delineation by radiation oncologist as delineated by MRI, compared to FET-PET defined target volume delineation (not for treatment use),
Primary outcome [2] 321146 0
To determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression and / or tumour recurrence.
Assessed by: Management impact questionnaire (designed specifically for the study) completed by the treating oncology team both pre and post FET-PET3 reporting.
Review of FET-PET imaging files by Nuclear Medicine and Radiation Oncology clinicians conducted suspected progression as seen on standard MRI scan
Timepoint [2] 321146 0
At time FET-PET 3 scan is acquired (variable time-point) – and then 6 months post FET-PET 3 scan
Secondary outcome [1] 374124 0
To investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio [TBR], metabolic tumour volume) and progression-free and overall survival outcomes in Glioblastoma.
Assessed by: FET-PET images (reviewed by Nuclear Medicine clinicians), MRI scans, clinical assessment of patient status as documented in medical records.
Timepoint [1] 374124 0
4 weeks, 3 months, 6 months and 12 months post chemo-radiation treatment and
and at suspected progression (variable time-point).
Secondary outcome [2] 374125 0
Assessing the change in the blood and tissue biomarkers as determined by serum assay (this is an exploratory outcome)
Assessed by: FET-PET images (reviewed by Nuclear Medicine clinicians), MRI scans, clinical examination and review of case report form.
Timepoint [2] 374125 0
This will be assessed following chemoradiotherapy as per standard of care until date of first progression, Or up to 12 months post chemo-radiation, with Progression free survival and overall survival as defined from the date of initial surgery.
Secondary outcome [3] 374126 0
Looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with the MRI and FET-PET images
Assessed by: FET-PET images (reviewed by Nuclear Medicine clinicians), MRI scans, clinical examination and review of case report form.
Timepoint [3] 374126 0
3 months, 6 months and 12 months post chemo-radiation treatment and at suspected time of tumour progression (variable time-point).
Secondary outcome [4] 375650 0
To estimate the health economic impact costs of incorporating FET-PET imaging into the management strategy of patients with GBM undergoing chemo-radiotherapy, and in assessment of post-treatment pseudoprogression or recurrence/progression.
Assessed by: QLQ-C30, MBS/PBS data,
Timepoint [4] 375650 0
The health economic cost incorporating FET-PET in the management of GBM patients as measured by QLQ-C30, this data will be collected at each follow-up up to the end of the 12-month follow-up.

Eligibility
Key inclusion criteria
• Age greater than or equal to 18 years
• Histologically confirmed newly diagnosed histologically confirmed GBM IDH1 wild type or IDH1 mutant via IHC (2016 WHO grade IV glioma) following surgery, with methylated or unmethylated MGMT promoter gene
NOTE - Patients who had previous grade I-III glioma and have progressed to GBM are eligible assuming that they have not received prior cranial radiotherapy or Temozolomide for the treatment of glioma
• ECOG 0-2
• Life expectancy of greater then 12 weeks
• Adequate bone marrow reserve or organ function to allow Temozolomide (TMZ) -based chemotherapy,
• Available tissue for MGMT and biomarker analysis
• Participants capable of childbearing are using adequate contraception
• Willing and able to comply with all study requirements, including treatment, timing and/or nature of required imaging and study assessments
• Signed, written and informed consent

Group 1 participants
• Considered suitable for radiotherapy (with one of the two dose fractionation schedules outlined as below) plus concurrent TMZ followed by adjuvant TMZ

Group 2 participants (entering study at Imaging time-point 2)
• Are currently undergoing or have recently completed concurrent radiotherapy with TMZ and one of the two dose fractionation schedules ie. 60Gy/30 fractions or 40Gy/15 fractions, and logistically able to be recruited
• Have commenced adjuvant chemo-radiation 7 weeks from surgery
• Considered suitable for adjuvant TMZ-based therapy
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
All participants;
• Participants with implanted medical or electronic devices deemed by the MRI radiologist to be a contra-indication to performing a brain MRI scan (e.g. implanted defibrillator, cardiac pacemaker, a cochlear implant, a metallic joint prosthesis, nerve stimulators, metal pins, screws, plates, stents or surgical staples)
• Any concurrent comorbidities, conditions or illness, including severe infection or medical or psychiatric conditions that may jeopardise the ability of the patient to undergo t procedures outlined in this protocol with reasonable safety or that may compromise assessment of key outcomes
• History of another malignancy within 2 years prior to registration. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 5 years after definitive primary treatment

Group 1 participants;
• Prior chemotherapy or recent cranial radiation within the last 2 years

Group 2 participants
• Patients that have a duration of more than 7 weeks from surgery to the start of RT

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Up to 140 patients to undergo initial post-surgery and pre-chemoradiation therapy FET-PET scan (FET-PET 1). Up to 140 patients to undergo post treatment FET-PET scans for the assessment of relapse vs pseudoprogression (FET-PET 2 and FET-PET 3).
Recruitment will be accepted in to two groups;
Group 1: FET1 , FET2 and FET3
Group 2: FET2 and FET3 only
This gives a total to up to 210 patients, whom are projected to be recruited.
It is anticipated it will take 18 months to complete accrual. All participants will be followed for another 12 months after the end of accrual to allow evaluation of PFS and OS with analysis at 12 months after the final patient has completed chemo-radiation treatment. This means that the trial will be conducted over a total duration of 4 years.
Statistical analysis plan:
Analysis will occur 12 months after the final patient has completed chemo-radiation treatment
Primary Aim 1: The value of FET-PET1 scan in radiotherapy planning will be described by the percentage volume of FET-PET-avid disease that would be excluded from the a) Gross tumour Volume (GTV) for each patient and b) Planning Target volume (PTV) for each patient, and c) The proportion of patients in whom this occurs for GTV and/or PTV - if MRI data alone were used for GBM radiation treatment planning. If the GTV and/or PTV changes in fewer than 10% of patients then the addition of FET-PET1 would not be considered worthwhile. If FET-PET1 scans are obtained for at least 120 patients, the study will have more than 80% power at 2.5% one-sided alpha (alpha reduced to 2.5% to account for the two main primary outcomes) to rule out a percentage of less than 10% if the true rate is 20% or higher. A sample of at least 120 patients will enable accuracy to be estimated with a 95% confidence interval of maximum width ±9%.
Primary Aim 2: The accuracy of FET-PET3 scan is defined as the percentage of patients for whom the classification of pseudo-progression or true progression at FET-PET3 agrees with the final clinical determination of pseudo- or true progression observed after clinical follow-up and sequential MRI. If accuracy is 80% or lower, then FET-PET3 would not be considered sufficiently accurate. If FET-PET3 can be obtained for at least 120 participants, the study will have at least 80% power at 2.5% one-sided alpha (alpha reduced to 2.5% to account for the two primary outcomes) to detect this. A sample size of at least 120 participants will enable accuracy to be estimated with a 95% confidence interval of maximum width ±9%.
Secondary Aim 1: The study will have power to detect only large differences in PFS between groups of patients categorised as having poor or good prognosis according to information in FET1. One hundred patients followed to progression/death will enable a difference in PFS to be detected with 80% power at 5% two-sided alpha if the true HR is at least 1.75 and the two groups of patients are of approximately equal size. Based on pilot data that up to two thirds of patients may be “early responders”, a conservative sample size estimate would require 140 events be observed, deemed achievable in this population of GBM patients in whom disease progression is inevitable.
For all other endpoints a detailed statistical analysis plan will be developed prior to database lock.


Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
4/05/2020
Actual
27/01/2021
Date of last participant enrolment
Anticipated
1/12/2023
Actual
Date of last data collection
Anticipated
1/06/2024
Actual
Sample size
Target
210
Accrual to date
131
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 14613 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 14614 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 14873 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [4] 14874 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [5] 14875 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [6] 14876 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [7] 14878 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [8] 14879 0
The Canberra Hospital - Garran
Recruitment hospital [9] 14880 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [10] 21603 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 28143 0
2065 - St Leonards
Recruitment postcode(s) [2] 27636 0
2170 - Liverpool
Recruitment postcode(s) [3] 36526 0
2217 - Kogarah
Recruitment postcode(s) [4] 28146 0
2605 - Garran
Recruitment postcode(s) [5] 28140 0
3000 - Melbourne
Recruitment postcode(s) [6] 27637 0
3084 - Heidelberg
Recruitment postcode(s) [7] 28142 0
4029 - Herston
Recruitment postcode(s) [8] 28147 0
4102 - Woolloongabba
Recruitment postcode(s) [9] 28145 0
5000 - Adelaide
Recruitment postcode(s) [10] 28141 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 303634 0
Charities/Societies/Foundations
Name [1] 303634 0
Cure Brain Cancer Foundation
Country [1] 303634 0
Australia
Funding source category [2] 303636 0
Government body
Name [2] 303636 0
Cancer Australia Australian Brain Cancer Mission
Country [2] 303636 0
Australia
Funding source category [3] 303638 0
Government body
Name [3] 303638 0
Medical Research Future Fund
Country [3] 303638 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Trans Tasman Radiation Oncology Group
Address
PO Box 88 Waratah
NSW, 2298
Country
Australia
Secondary sponsor category [1] 303879 0
None
Name [1] 303879 0
Address [1] 303879 0
Country [1] 303879 0
Other collaborator category [1] 280921 0
Other Collaborative groups
Name [1] 280921 0
ARTnet: Australasian Radiopharmaceutical Trials Network
Address [1] 280921 0
PO Box 73 Balmain, NSW 2041.
Country [1] 280921 0
Australia
Other collaborator category [2] 280922 0
Other Collaborative groups
Name [2] 280922 0
Cooperative Trials Group for Neuro-Oncology
Address [2] 280922 0
COGNO NHMRC Clinical Trials Centre Locked Bag 77 Camperdown NSW 1450.
Country [2] 280922 0
Australia
Other collaborator category [3] 280989 0
Other
Name [3] 280989 0
Olivia Newton-John Cancer Research Institute
Address [3] 280989 0
Level 5 ONJCWRC
145 Studley Road,
Heidelberg
VIC 3084
Country [3] 280989 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304163 0
Austin Health
Ethics committee address [1] 304163 0
145 Studley Road
PO Box 5555
Heidelberg Victoria 3084
Ethics committee country [1] 304163 0
Australia
Date submitted for ethics approval [1] 304163 0
02/10/2019
Approval date [1] 304163 0
02/01/2020
Ethics approval number [1] 304163 0

Summary
Brief summary
The aim of this study is to evaluate the the PET imaging agent, O-(2-[18F]-fluoroethyl)L-tyrosine (FET) to definitively establish the role of FET-PET in the management of brain cancer (Glioblastoma).

Glioblastoma (GBM) is the most common primary brain cancer in adults representing approx. 50% of brain tumours. Standard treatment entails surgery followed by chemoradiation and then adjuvant chemotherapy.

Imaging plays a key role in diagnosis, radiotherapy planning, and monitoring of treatment response in GBM. The current standard of care with respect to imaging is MRI. A alternate form of imaging has been developed using Positron Emission Tomography (PET), where tumours can be imaged by utilising a newer radiotracer (FET) which detects whether tumour cells are active.

You may be eligible for this study if you are 18 years or older with a newly diagnosed brain cancer, specifically a histologically confirmed GBM IDH1 wild type or IDH1 mutant via IHC (2016 WHO grade IV glioma) following surgery.

All participants in this study will continue with their usual care, and undergo additional FET-PET scans following chemo-radiation treatment, and at the time of subsequent suspected progression of disease. Group 1 patients will undergo an additional FET-PET prior to their radiation therapy at the time of their routine MRI scan for planning, Biomarkers obtained from participants tumour and blood will also be analysed. Participants will be asked to complete QOL questionnaires in their clinical assessment follow ups at 4 weeks, 3 months, 6 months and 12 months after the completion of chemo-radiation and at the time that the FET-PET3 scan is done.

It is hoped that this new imaging approach with FET-PET scans will lead to more accurate assessment, and improve both treatment decisions and outcomes for patients with Glioblastoma. Currently FET-PET scans are not part of routine care for patients diagnosed with Gliobastoma. The use of FET-PET is experimental.
Trial website
NA
Trial related presentations / publications
NA
Public notes
NA

Contacts
Principal investigator
Name 96010 0
Prof Andrew Scott
Address 96010 0
Olivia Newton-John Cancer Research Institute and Department of Molecular imaging and Therapy.
145 Studley Rd
Heidelberg
VIC 3084
Country 96010 0
Australia
Phone 96010 0
+61 394963335
Fax 96010 0
Email 96010 0
andrew.scott@onjcri.org.au
Contact person for public queries
Name 96011 0
Mr Hamish Evans
Address 96011 0
TROG Cancer Research
Edith st Waratah
NSW 2298
Country 96011 0
Australia
Phone 96011 0
+61 240143911
Fax 96011 0
Email 96011 0
fig@trog.com.au
Contact person for scientific queries
Name 96012 0
Prof Andrew Scott
Address 96012 0
Olivia Newton-John Cancer Research Institute and Department of Molecular imaging and Therapy.
145 Studley Rd
Heidelberg
VIC 3084
Country 96012 0
Australia
Phone 96012 0
+61 394963335
Fax 96012 0
Email 96012 0
andrew.scott@onjcri.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification.
When will data be available (start and end dates)?
Data will be available after the publication of the final analysis (no end date).
Available to whom?
Only researchers who provide a methodologically sound proposal that has sufficient detail to ascertain the purpose of the study, the specific data required (including formats), access methods and analysis plan.

NOTE: Prior to data transfer, proof of IRB and/or ethics approval is required and a data sharing agreement is to be executed.
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Access subject to approval by the TROG Scientific Committee (TSC), who will consult with the FIG Trial Management Committee and, if required, the TROG Secondary Data Analysis Committee (SDAC).

To submit an application go to https://www.trog.com.au/New-proposals


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseFET-PET incorporation for GBM radiotherapy planning: multi-site FIG Study credentialling programme.2023https://dx.doi.org/10.1016/S0167-8140%2823%2908942-9
EmbaseBoosting the acceptance of 18F-FET PET for image-guided treatment planning with a multi-centric prospective trial.2023https://dx.doi.org/10.1007/s00259-023-06426-7
Embase[18f]-fluoroethyl-L-tyrosine (FET) in glioblastoma (FIG) TROG 18.06 study: Protocol for a prospective, multicentre PET/CT trial.2023https://dx.doi.org/10.1136/bmjopen-2022-071327
Dimensions AIThe Australasian Radiopharmaceutical Trials Network: Clinical Trials, Evidence, and Opportunity2020https://doi.org/10.2967/jnumed.120.258152
N.B. These documents automatically identified may not have been verified by the study sponsor.