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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

15/09/2024

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]

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

infection

Condition category

Condition code

Cancer

Any cancer

Infection

Studies of infection and infectious agents

Intervention/exposure

Study type

Observational

Patient registry

True

Target follow-up duration

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]

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]

Number of CTC by cytology using a light microscope

Timepoint [1]

baseline and follow-ups (3-12 monthly depending on CTC count at baseline) for 5 years

Primary outcome [2]

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]

baseline and follow-ups (3-12 monthly depending on CTC count at baseline) for 5 years

Secondary outcome [1]

number of Circulating Rare Cells (CRC) by light miscroscopy

Timepoint [1]

baseline and follow-ups (3-12 monthly depending on CTC count at baseline) for 5 years

Secondary outcome [2]

Percentage of CTC/CRC positive for marker tested, if applicable

Timepoint [2]

Secondary outcome [3]

Percentage of CTC/CRC positive for marker tested, if applicable

Timepoint [3]

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?

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

31/12/2025

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]

3122 - Hawthorn

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

National Institute of Integrative Medicine

Address [1]

21 Burwood Rd
Hawthorn VIC 3122

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

National Institute of Integrative Medicine HREC

Ethics committee address [1]

National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn VIC 3122

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

20/09/2017

Approval date [1]

02/10/2017

Ethics approval number [1]

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

A/Prof Karin Ried

Address

National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn VIC 3122

Country

Australia

Phone

+61 3 9912 9545

Fax

[email protected]

Contact person for public queries

Name

Karin Ried

Address

National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn VIC 3122

Country

Australia

Phone

+61 3 9912 9545

Fax

[email protected]

Contact person for scientific queries

Name

Karin Ried

Address

National Institute of Integrative Medicine
21 Burwood Rd
Hawthorn VIC 3122

Country

Australia

Phone

+61 3 9912 9545

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
8330	Other			[email protected]	test request form including informed consent	380067-(Uploaded-01-03-2024-17-55-42)-Study-related document.pdf

Results publications and other study-related documents

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No additional documents have been identified.

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