Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000632695
Ethics application status
Approved
Date submitted
11/05/2023
Date registered
8/06/2023
Date last updated
23/06/2024
Date data sharing statement initially provided
8/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Imaging biomarkers of response to immunotherapy in patients with malignant mesothelioma
Scientific title
Imaging biomarkers of response to immunotherapy in malignant mesothelioma
Secondary ID [1] 306420 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mesothelioma 330076 0
Condition category
Condition code
Cancer 326972 326972 0 0
Lung - Mesothelioma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Meso ImmunuPET imaging using an 89-Zirconium-Durvalumab tracer (89Zr-durva)

All scans will be performed face to face by physicists from the Sir Charles Gairdner Hospital Nuclear Medicine Department or the Peter MacCallum Cancer Centre. Patient consent and registration may occur face to face or via telephone. This will be provided to the individual patient.

If the doctor confirms eligibility and a PICF is signed, the patient will be registered to this study. The patient’s personal details, medical history, any concomitant medications, the mesothelioma diagnosis and current cancer status will be noted. For stage 1 of the study, the patient will undergo an (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan and an 89Zr-durva PET/CT scan. As part of this safety study, a follow up imaging scan 3 and 5 to 7 days after the first 89Zr-durva PET/CT scan will be performed and vitals and adverse events will be monitored.
For stage 2 of the study, patients must be commencing anti-cancer immunotherapy. Before any anti-cancer systemic therapy, the patient will undergo a baseline FDG PET/CT scan and 89Zr-durva PET/CT scan. The prescribed systemic therapy will be either immunotherapy alone or immunotherapy with chemotherapy. Six weeks (+/- 5 days) after the commencement of systemic therapy, a second FDG PET/CT scan and 89Zr-durva PET/CT scan will be performed. A follow-up appointment to discuss any adverse events, the cancer response and a general physical examination of health will be arranged.

All scans will be performed according to current departmental guidelines on an integrated PET/CT scanner and reported by a qualified PET physician. Baseline scans will be performed prior to the commencement of systemic therapy.

89Zr-durva (the prescribed dose of 89Zr-durva administered to each patient will be 0.88MBq/kg up to a maximum of 74MBq). For stage 1 of the study, the emission scan will be initiated at day 0, 3 and 5 ± 2 day after injection of 89Zr-durva and the precise timing of scan initiation should be recorded. Timing of the subsequent scan will be the same as that used for the baseline scan (± 10% of the elapsed time post injection).

Following current practice, intravenous contrast will not be administered. PET CT scans will be acquired as per local low dose CT protocols and duration of emission imaging will be determined locally. Images will be reconstructed using standard software provided with the cameras and displayed for analysis on dedicated image analysis software. It is anticipated that a patient will be imaged on the same camera and reconstruction parameters will be consistent across all visits.

FDG PET/CT injection and scan will take 1-2 hours. 89Zr-durva PET/CT scans will take approximately 1 hour. No other contrast dyes or markers will b e adminsitered.

Stage 1
Before treatment, patients will undergo an FDG PET/CT injection and scan and a 89Zr-durva PET/CT injection and scan on the same day. There is no further injection from then. This is a study for biodistribution and safety, so the patient will also be asked to get a follow-up scan at day 3 and day 5-7 after the first 89Zr-durva PET/CT scan. Therefore patients will receive a total of 4 scans. There is no follow-up scan post treatment in this stage of the study.

Stage 2
Stage 2 will begin once 5 patients have been recruited for Stage 1 of the study (when we have seen biodistribution results that help inform optimised day of scan). Baseline FDG PET/CT and 89Zr-durva PET/CT injection and scan will be performed on the same day. Subsequent 89Zr-durva PET/CT scans will be performed on the day optimised by Stage 1. FDG and 89Zr-durva PET/CT scans post treatment will also be conducted on the same day. Follow-up appointments will be apart of patient standard of care.

A scan worksheet will be developed separate to the protocol to keep track of scan session attendance and checklist and radiological reports will be stored in a secure XNAT system.
Intervention code [1] 323271 0
Diagnosis / Prognosis
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330949 0
Characterising the uptake and imaging parameters of 89Zr-durva in malignant pleural and peritoneal mesothelioma using PET/CT imaging. We will use RECIST and iPERCIST to provide infromation about the dynamics of Programmed Death Ligand 1 (PDL1) with 89Zr-durva tracers.

The following independently absolute measures will be used:
1. Molecular Tumour Volume (MTV, cc) pre and during concurrent systemic therapy
2. Tumour SUVmax and TBRmax (tumour to background ratio)
3. Tumour SUVmean and TBRmean (tumour to background ratio)
4. Tumour SUVpeak
Timepoint [1] 330949 0
Day 0, 3 and 5-7(+/- 2 days) post injection of 89Zr-durva
Primary outcome [2] 330950 0
The feasibility of 89Zr-durva PET imaging in patients with mesothelioma will be determined by measuring tumour volume and assessed by conventional imagning disease staging on 89Zr-durva and FDG PET/CT before and during systemic therapies.

The tumour volume and tracer uptake is assessed by conventional imaging disease staging on FDG PET/CT will be compared with 89Zr-durva PET/CT using the following independently absolute measures:
1. Molecular Tumour Volume (MTV, cc) pre and during concurrent systemic therapy
2. Tumour SUVmax and TBRmax (tumour to background ratio)
3. Tumour SUVmean and TBRmean (tumour to background ratio)
4. Tumour SUVpeak
Timepoint [2] 330950 0
Baseline and 6 weeks (+/- 5 days) of commencement of systemic therapy.
Primary outcome [3] 334824 0
The characterisation of imaging parameters of 89Zr-durva and the dynamics of PDL1 with 89Zr-durva.

The tracer uptake is assessed by conventional imaging disease staging on FDG PET/CT will be compared with 89Zr-durva PET/CT using the following independently absolute measures:
1. Molecular Tumour Volume (MTV, cc) pre and during concurrent systemic therapy
2. Tumour SUVmax and TBRmax (tumour to background ratio)
3. Tumour SUVmean and TBRmean (tumour to background ratio)
4. Tumour SUVpeak
Timepoint [3] 334824 0
Baseline and 6 weeks (+/- 5 days) of commencement of systemic therapy.
Secondary outcome [1] 408221 0
To compare changes in semiquantitative PET parameters of tumour metabolism and PD-L1 expression (FDG and 89Zr-durva PET/CT) before and during systemic treatment.

The tracer uptake is assessed by conventional imaging disease staging on FDG PET/CT will be compared with 89Zr-durva PET/CT using the following independently absolute measures:
1. Molecular Tumour Volume (MTV, cc) pre and during concurrent systemic therapy
2. Tumour SUVmax and TBRmax (tumour to background ratio)
3. Tumour SUVmean and TBRmean (tumour to background ratio)
4. Tumour SUVpeak
Timepoint [1] 408221 0
Baseline and 6 weeks (+/- 5 days) of commencement of systemic therapy
Secondary outcome [2] 422187 0
PD-L1+ status on pathology biopsy specimens
Timepoint [2] 422187 0
Baseline and 6 weeks (+/- 5 days) of commencement of systemic therapy
Secondary outcome [3] 422188 0
PD-L1 dynamics as visualized by 89Zr-durva
Timepoint [3] 422188 0
Baseline and 6 weeks (+/- 5 days) of commencement of systemic therapy
Secondary outcome [4] 422472 0
Imaging characteristics (SUVmax on 89Zr-durva PET/CT)
Timepoint [4] 422472 0
Baseline and 6 weeks (+/- 5 days) of commencement of systemic therapy
Secondary outcome [5] 422473 0
Response to immunotherapy as measured by progression free survival at 12 months
Timepoint [5] 422473 0
Baseline and 6 weeks (+/- 5 days) of commencement of systemic therapy

Eligibility
Key inclusion criteria
To be eligible for inclusion in Stage 1, patient must satisfy ALL of the following:
• Written informed consent
• Able to undergo study procedures
• Life expectancy > 12 weeks
• Minimum age 18 years, no maximum age
• Body weight > 30kg
• Patients with histologically or cytologically confirmed mesothelioma, pleural or peritoneal
• No prior immune checkpoint therapy
• Estimated glomerular filtration rate (eGFR) > 60ml/min
• An Eastern Cooperative Group Oncology Group (ECOG) performance score of 0-2
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
• Male or female patients of reproductive potential who are employing an effective method of birth control

To be eligible for inclusion in Stage 2, patient must satisfy ALL of the following:
• Written informed consent
• Minimum age > 18, no maximum age
• Body weight > 30kg
• Histologically confirmed malignant pleural mesothelioma
• Planned to undergo systemic treatment incorporating checkpoint blockade for their disease
• eGFR > 60ml/min
• ECOG performance status 0-1
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
• Male or female patients of reproductive potential who are employing an effective method of birth control
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded from the Stage 1 study if ANY of the following apply:
• Currently receiving chemotherapy or radiotherapy
• Pregnant or breastfeeding at the time of study enrolment
• Inadequate English language to complete study outcome measures
• Geographically inaccessible for follow-up
• Less than 18 years of age
• Prior immune checkpoint inhibitor therapy
• Known sensitivity or allergy to any study agents
• Any serious medical condition which the investigator feels may interfere with the procedures or evaluations of the study
• Patients unwilling or unable to comply with protocol or with a history of non-compliance or inability to grant informed consent
• Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control

Patients will be excluded from the Stage 2 study if ANY of the following apply:
• Any previous therapy or condition that precludes treatment of mesothelioma with checkpoint blockade therapy
• Prior immune checkpoint inhibitor therapy
• Recent major surgery within 4 weeks prior to entry into the study that would prevent administration of study drug
• Another concurrent active malignancy which may have the potential to confound imaging findings.
• Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Any condition that, in the opinion of the investigator, would interfere with evaluation of the study drug or interpretation of patient safety or study results

Study design
Purpose of the study
Treatment
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
In stage 1, 5 pleural and 5 peritoneal mesothelioma patients will be recruited in order to characterise tracer bio-distribution and determine the optimal imaging time points post-trace administration. This will inform the imaging protocol for stage 2.

We want to determine the feasibility that will aid in the planning of a larger, sufficiently powered efficacy trial. 30 patients should provide rough estimates of patients who can undergo the steps of recruitment, informed consent, enrolment, and complete the trial within the time frame of interest. Although there is no guideline to suggest the appropriate sample size for a pilot study with PET, we feel that 30 patients are likely to allow sample size estimation for larger subsequent confirmatory studies and feasible within the timescale of this study.

Our site sees 70 new mesothelioma patients annually. As a pilot study, we believe 40 patients (10 in Stage 1 and 30 in Stage 2) is required to demonstrate a clinically relevant symptomatic response, with an alpha of 5% and power of 80%.

Number of patients successfully completing the trial and number of patients experiencing significant toxicity during scans after injection of PET tracer will be recorded. The complete rate will be estimated as the number of patients who complete study procedures, divided by the number of respective patients identified as eligible and recruited into the study. The rate of significant toxicity will be estimated as the number of patients who experience significant toxicity procedures, divided by the number of respective patients identified as eligible and recruited into the study. A 95% exact confidence interval will also be calculated for the primary endpoint.

Quantitative measures on 89Zr-durva PET/CT, FDG PET/CT and PD-L1 immunohistochemistry will be summarized. Correlations between Quantitative measures will be expressed as a Pearson/Spearman correlation coefficient depending on distribution of data.

89Zr-durva PET/CT and FDG PET/CT pre and post treatment in the following absolute measures of MTV, SUVmax, SUVmean, SUVpeak, and %ID will be summarised. Results will be displayed in graphs. Concordance between FDG and 89Zr-durva PET/CT responses will be assessed using a weighted kappa coefficient with weights based on quadratic differences.

Associations between intra-treatment response and overall survival (OS) / disease progression free survival (DFS) will be described graphically using Kaplan-Meier product limit curves.

Proportion of patients in which 89Zr-durva PET/CT provides information not seen on FDG-PET or PD-L1 immunohistochemistry performed at baseline and proportion of patients in which additional information from 89Zr-durva PET/CT with the potential to alter management will be described.


Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2024
Actual
Date of last participant enrolment
Anticipated
1/11/2025
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA,VIC
Recruitment hospital [1] 22095 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 22096 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 24709 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 37218 0
6009 - Nedlands
Recruitment postcode(s) [2] 37219 0
3000 - Melbourne
Recruitment postcode(s) [3] 40328 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 310770 0
Other
Name [1] 310770 0
iCARE Dust Diseases Care
Country [1] 310770 0
Australia
Funding source category [2] 311148 0
Charities/Societies/Foundations
Name [2] 311148 0
Charlies Foundation for Research
Country [2] 311148 0
Australia
Primary sponsor type
University
Name
The University of Western Australia
Address
35 Stirling Hwy, Crawley WA 6009 Australia
Country
Australia
Secondary sponsor category [1] 315758 0
None
Name [1] 315758 0
Address [1] 315758 0
Country [1] 315758 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310346 0
The Sir Charles Gairdner Osborne Park Health Care Group (SCGOPHCG) Human Research Ethics Committee (HREC)
Ethics committee address [1] 310346 0
Ethics committee country [1] 310346 0
Australia
Date submitted for ethics approval [1] 310346 0
30/09/2021
Approval date [1] 310346 0
09/02/2023
Ethics approval number [1] 310346 0
RGS0000005202

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117322 0
Prof Anna Nowak
Address 117322 0
The University of Western Australia, 35 Stirling Hwy, Crawley WA 6009
Country 117322 0
Australia
Phone 117322 0
+61 8 6488 2460
Fax 117322 0
Email 117322 0
[email protected]
Contact person for public queries
Name 117323 0
Tanya Ward
Address 117323 0
National Centre for Asbestos Related Diseases (NCARD), The University of Western Australia, M503, 35 Stirling Highway Crawley WA 6009
Country 117323 0
Australia
Phone 117323 0
+61 08 6151 1078
Fax 117323 0
Email 117323 0
[email protected]
Contact person for scientific queries
Name 117324 0
Tanya Ward
Address 117324 0
National Centre for Asbestos Related Diseases (NCARD), The University of Western Australia, M503, 35 Stirling Highway Crawley WA 6009
Country 117324 0
Australia
Phone 117324 0
+61 08 6151 1078
Fax 117324 0
Email 117324 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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
No additional documents have been identified.