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Trial registered on ANZCTR


Registration number
ACTRN12620000986976
Ethics application status
Approved
Date submitted
24/06/2020
Date registered
30/09/2020
Date last updated
15/04/2024
Date data sharing statement initially provided
30/09/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Cytology-based Circulating Tumour Cell (CTC) Testing in cancer patients and for early detection screening: The ISET-CTC study
Scientific title
Isolation of CTC (Circulating Tumour Cells) and other rare cells from blood by ISET (Isolation by SizE Of Tumour cells) technology to monitor treatment effectiveness in cancer patients, and to screen for early detection or relapse of cancer.
Secondary ID [1] 301616 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record
Follow-on study of ACTRN12614001143617

Health condition
Health condition(s) or problem(s) studied:
cancer 318002 0
infection 318003 0
Condition category
Condition code
Cancer 316035 316035 0 0
Any cancer
Infection 316036 316036 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
5
Target follow-up type
Years
Description of intervention(s) / exposure
A doctor's referral is required to undertake the CTC test as part of this study.
Local participants: Participants will attend the National Institute of Integrative Medicine to have their blood samples taken at two separate visits.
Non-local participants: A test kit will be posted to the participant at 2 time points. CTC blood samples will be collected by the participant's referring doctor at their usual clinic and will then be sent to the National Institute of Integrative Medicine for analysis.

CTC reports will be sent to the referring doctor to discuss with the patient.
The CTC test will allow:
a) Monitoring of treatment effectiveness in cancer patients.
b) Monitoring of cancer patients to facilitate detection of relapse, tumour progression.
c) Screening test: Early Detection of CTC and other rare cells in patients with a family history of cancer or patients with chronic illness, advanced age, or as part of a health check.

For all groups a-c, follow-up testing time frame is dependent on CTC count, e.g.
- if no CTC are detected or the CTC count is low (<3 CTC/ml), repeat testing is suggested on a yearly bases.
- if CTC count is 3-10 CTC/ml, repeat testing is recommended at 6-9 months.
- if CTC count is >10 CTC/ml, repeat testing is recommended at 3-6 months.

Method: CTC are isolated for blood (10ml in ACD) by ISET (Rarecells, France) using filtration technology before treatment (baseline) and 3-4 weeks after treatment (follow-up). CTC analysis by microscopy using cytological criteria.
Participants will be followed up for 5 years.

Add-on secondary testing available (Marker testing) on same participants' blood sample as initial CTC test. No additional visits required.
Immuno-cyto-chemistry (ICC) staining with cancer markers (= specific antibodies) or viral markers
ICC staining to be conducted as per protocol *
Markers include:
PSA = Prostate specific marker
Mammaglobin (MG) = breast specific marker
Other cancer markers, including CD45, prostein, etc
EBV = Epstein-Barr-Virus specific marker (to ascertain viral reactivation often associated with cancer)
HSV = Herpes Simplex Virus specific marker
CMV = Cyto-Megalo-Virus specific marker
HPV = Human Papilloma Virus specific marker

*ICC Protocol (published in Ried et al 2020 Front Oncol 10:582):
“ICC staining was conducted with the Dako EnVision Flex Mini Kit, high pH, and antibodies a) PSA (Dako monoclonal mouse anti-human prostate-specific antigen Clone ER-PR8, concentrate), and b) Prostein/P501S (Dako Flex Monoclonal mouse anti-human Prostein Clone 10E3, Ready-to-Use (RTU)).
For antigen retrieval, ISET® filters were placed into a 50 ml tube and heated in a water bath at 99 ºC for 40 min in 50 mL of 2% v/v target retrieval solution (high pH (50x): 3x30 mL, 50x concentrate Tris/EDTA buffer, pH9; Dako Agilent). Next, the ISET® filters were washed 15x in 0.2M PBS and incubated with permeabilisation buffer (0.1% Triton) for 2 min. After washing the ISET® filter as before, the ISET® filter was incubated for 30 min with peroxidase-blocking reagent (80 µL of H2O2, 15 mmol/L Na3N and detergent), and washed with distilled water 15 times.
Each ISET®-filter spot was incubated overnight at 4 ºC in 600 µL solution of the primary antibody (a) 1:200 dilution of concentrated PSA antibody or b) 1:4 dilution of Prostein antibody RTU in a buffer of 1xPBS / 5%BSA in a 1.5 ml Eppendorf tube.
After incubation with the primary antibody, ISET®-filter spots were washed in PBS as before, placed on a clean slide, for incubation with 80 µL of the secondary antibody (Dako Envision Flex Kit goat secondary antibody) for 45 min at RT.
The ISET®-filter spots were washed again, before incubation with 80 µL of chromogen (Dako Liquid DAB + Substrate Chromogen (3,3 diaminobenzidine tetrahydrochloride) on a glass slide in the dark for 10 min. The excess chromogen was removed by washing in 0.2 M PBS. The filter spots were allowed to air-dry, then counterstained with hematoxylin for 2 min. After washing in PBS as before, each air-dried immuno-stained spot was mounted on a clean glass slide for microscopic analysis.”
Intervention code [1] 317920 0
Early Detection / Screening
Comparator / control treatment
Intra-individual: Number and type (single, cluster) of CTC at follow-up compared to baseline.
Definition: single CTC = single cell
CTC cluster = multiple cells in a cell group, cells within the cluster to be counted
e.g. 3 single CTC + 1 CTC cluster of 10 cells = 13 CTC
Control group
Active

Outcomes
Primary outcome [1] 324244 0
Number of CTC by cytology using a light microscope
Timepoint [1] 324244 0
baseline and follow-ups (3-12 monthly depending on CTC count at baseline) for 5 years
Primary outcome [2] 324245 0
Type of CTC (Single CTC or CTC-clusters) by cytology with a light microscope,
cells within a cluster are counted individually, CTC clusters have more metastasing potential, therefore the type of CTC provides important information in addition to CTC count
Timepoint [2] 324245 0
baseline and follow-ups (3-12 monthly depending on CTC count at baseline) for 5 years
Secondary outcome [1] 384146 0
number of Circulating Rare Cells (CRC) by light miscroscopy
Timepoint [1] 384146 0
baseline and follow-ups (3-12 monthly depending on CTC count at baseline) for 5 years
Secondary outcome [2] 434079 0
Percentage of CTC/CRC positive for marker tested, if applicable
Timepoint [2] 434079 0
Secondary outcome [3] 434080 0
Percentage of CTC/CRC positive for marker tested, if applicable
Timepoint [3] 434080 0
at baseline

Eligibility
Key inclusion criteria
Group 1: Cancer patients
a) have previously received (at least 3 weeks ago) or will receive treatment within one week; treatment may include chemotherapy, radiotherapy, hyperthermia, intravenous Vit C, IV Curcumin, or other complementary treatment as prescribed by the treating physician
b) for regular monitoring . detection of relapse or tumour progression

Group 2: Early detection screening: Patients with a family history of cancer of patients with a chronic disease, advanced age, or as part of a health check
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
no exclusion

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
ongoing longitudinal observational study
1-way repeated measures ANOVA to compare CTC number at follow-up(s) to a baseline
& simple comparison of number and type of CTC over time.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/10/2020
Actual
2/11/2020
Date of last participant enrolment
Anticipated
20/12/2024
Actual
Date of last data collection
Anticipated
1/03/2028
Actual
Sample size
Target
5000
Accrual to date
4000
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment postcode(s) [1] 30638 0
3122 - Hawthorn

Funding & Sponsors
Funding source category [1] 306047 0
Charities/Societies/Foundations
Name [1] 306047 0
National Institute of Integrative Medicine
Country [1] 306047 0
Australia
Primary sponsor type
Individual
Name
AProf Dr Karin Ried
Address
National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn VIC 3122
Country
Australia
Secondary sponsor category [1] 306509 0
None
Name [1] 306509 0
Address [1] 306509 0
Country [1] 306509 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306274 0
National Institute of Integrative Medicine HREC
Ethics committee address [1] 306274 0
National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn VIC 3122
Ethics committee country [1] 306274 0
Australia
Date submitted for ethics approval [1] 306274 0
20/09/2017
Approval date [1] 306274 0
02/10/2017
Ethics approval number [1] 306274 0
0040N_2017

Summary
Brief summary
This trial consists of two components recruiting people who have been diagnosed with cancer, and people who may be at high risk of cancer, for example because of family history.

Cancer patient study:
This study will determine whether there is a difference between the number and type of circulating tumour cells in cancer patients before and after treatment.

Who is it for?
You may be eligible to join this study if you are aged 18-80 years, diagnosed with any cancer and have received treatment at least 3 weeks ago or will receive treatment within one week.

Cancer patient study details
The study aims to establish the Circulating Tumour Cell (CTC) detection method using the ISET (Isolation by SizE Of Tumour cells) device (Rarecells, France) in conjunction with cancer therapies including those offered at NIIM. There will be no changes to the participants’ cancer treatment plans. Participants will be required to provide a blood sample at the beginning of their treatment and 3-4 weeks after commencement of treatment. The blood will be processed using the ISET technology to determine the number and types of Circulating Tumour Cells.

Early detection screening study:
This component of the study aims to determine whether the ISET screening blood test can be used for early detection of cancer.

Who is it for?
You may be eligible to join this part of the study if you are aged between 18-80 years and have a family history of cancer, or have been diagnosed with chronic disease, or are attending a health check.

Early detection screening study details:
Participants in this part of the study will undergo a blood test at baseline and at 3-12 months following the baseline test.
The ISET test has the potential to detect potentially malignant cells, and other illness causing rare cells.

Additional cancer marker testing can tell, whether cancer cells are from the prostate (in men) or breast (in women).
In 2023 we introduced viral activation testing using viral markers to test in chronic fatigue patients for reactivation of dormant Epstein-Barr-Virus, Cyto-Megalo-Virus, or Herpes Simplex Virus reactivation, as a high number of Circulating Rare Cells (CRC) may be linked to viral reactivation and a suppressed immune system.

It is hoped that this research using a simple blood test will assist in determining both cancer treatment efficacy, and early detection of cancer when used as a cancer screening tool by measuring the presence of cancer-specific cells.
Furthermore, additional marker testing on the same patient's blood sample may shed light on the origin of cancer cells, or assess potential reactivation of dormant viruses.
Trial website
https://niim.com.au/research-education/circulating-tumour-cells-ctc-trial
Trial related presentations / publications
Public notes
Trial related publications:
1) Ried K, Eng P, Sali A et al. Screening for Circulating Tumour Cells Allows Early Detection of Cancer and Monitoring of Treatment Effectiveness: An Observational Study. Asian Pac J Cancer Prev 18 (8), 2275-2285. 2017 Aug 27.
https://pubmed.ncbi.nlm.nih.gov/28843267/

2) Ried K, Tamanna T, Matthews S, Eng P, Sali A. New Screening Test improves Detection of Prostate Cancer using Circulating Tumour Cells and Prostate-specific Markers. Frontiers Oncol Apr 2020, 10, 582.
https://www.frontiersin.org/articles/10.3389/fonc.2020.00582/full

Contacts
Principal investigator
Name 103326 0
A/Prof Karin Ried
Address 103326 0
National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn VIC 3122
Country 103326 0
Australia
Phone 103326 0
+61 3 9912 9545
Fax 103326 0
Email 103326 0
[email protected]
Contact person for public queries
Name 103327 0
A/Prof Karin Ried
Address 103327 0
National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn VIC 3122
Country 103327 0
Australia
Phone 103327 0
+61 3 9912 9545
Fax 103327 0
Email 103327 0
[email protected]
Contact person for scientific queries
Name 103328 0
A/Prof Karin Ried
Address 103328 0
National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn VIC 3122
Country 103328 0
Australia
Phone 103328 0
+61 3 9912 9545
Fax 103328 0
Email 103328 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
Due to privacy no individual data will be shared. Summary data is however available in our publications.


What supporting documents are/will be available?




Results publications and other study-related documents

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

Documents added automatically
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