ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12611000318987

Ethics application status

Approved

Date submitted

16/03/2011

Date registered

25/03/2011

Date last updated

14/01/2024

Date data sharing statement initially provided

10/12/2018

Type of registration

Prospectively registered

Titles & IDs

Public title

Development of a better screening test for bowel cancer.

Scientific title

Evaluation of blood-based screening tests for colorectal neoplasia; from biomarker candidates to accurate and acceptable tests.

Secondary ID [1]

nil

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

colorectal cancer.

Condition category

Condition code

Cancer

Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure

Study type

Observational

Patient registry

Target follow-up duration

Target follow-up type

Description of intervention(s) / exposure

Colorectal cancer (CRC) is the second leading cause of death from cancer despite the fact that the disease is curable when detected in its early stages. Furthermore, CRC is preventable by a number of methods which include adenoma detection and removal

Studies of faecal occult blood testing have demonstrated that annual screening with such tests leads to a reduction in mortality

Studies clearly show that screening can also lower cancer incidence through the early detection and removal of precancerous polyps including adenomas.

Based on this evidence, to effectively decrease incidence at the population level, we need to identify and remove adenomas. The current methods for identifying people likely to have adenomas are largely ad hoc and limited.

Conversely, a sensitive and specific marker with strong positive predictive value for colorectal adenomas would provide an effective selection process for individuals to undergo colonoscopy, and polypectomy when an adenoma is found.

The literature now describes a number of molecular characteristics of adenomas that may be useful in this setting but none of these has been explored for its value in blood or faeces. In addition, preliminary molecular studies here at Flinders University using materials from the tissue bank have identified approximately 67 genes that show promise differentiating adenomas from normal tissue.

We now have a need to establish a clinical bank of relevant target clinical materials (specifically faeces and blood), that would allow us to determine the presence of these markers in faeces and blood and to relate them to the neoplastic status of patients.

Phase 1 research and research by others has identified several colorectal neoplasia-associated biomarkers in blood that may be useful, individually or together, for the development of new screening tests for early detection of colorectal neoplasia.

Phase 2 of the research will evaluate the accuracy in larger population samples of several candidate biomarkers for detection of screen-relevant colorectal neoplasia, relative to a proven immunochemical faecal occult blood test (iFOBT, FIT) and the diagnostic test colonoscopy. The panel includes at least one candidate biomarker, KIAA1199, highly expressed in colorectal neoplasia relative to normal colonic epithelium, and which is also detectable in blood of CRC patients.

To evaluate the accuracy of a panel of blood-based candidate biomarkers for detection of screen-relevant colorectal neoplasia, relative findings at colonoscopy, a commercial blood based test for CRC and to a proven faecal occult blood test (FOBT).
We will invite participants who are scheduled for a colonoscopy to complete an FOBT (Faecal Occult Blood Test), on one occasion only, prior to their colonoscopy.
The participant will be asked to collect a sample of approximately 0.5 g of stool using provided scoop and transfer the scoop with faeces into a double sealed, self-contained transport vessel that stabilizes and disperses the faecal sample for storage and transport.
We will take one blood sample only just prior to the participant’s colonoscopy procedure.
We will view the results (histopathology) of colonoscopy or/and any ensuing colorectal surgery

Phase 2b
Some patients resected for CRC will be subsequently diagnosed with further (recurrent) cancer, not necessarily located within the bowel. Some current simple methods to monitor patients for recurrence of CRC, such as CEA, are not optimal. A blood test using the biomarker panel may more sensitive for detection of recurrent cancers and blood samples will be assayed for our markers during monitoring as approved for serial sampling after diagnosis.
To explore this possibility, we first need to determine whether the CRC biomarkers we have identified are detectable in tumour tissues from both an initial and any subsequent cancer from the same patient. We propose an initial small retrospective observational sub-study within BiBCoN to determine the pattern of expression of the markers across time and tumour locations. One or both of the tumour samples would be derived from the Joint RGH and FMC Tissue Bank where patients have consented for tissue to be accessed for research. Where possible the level of expression of other clinical biomarkers for recurrent cancer may be determined on the same tissue samples.
If both samples from the same patient prove to be positive for the biomarker test panel in a small initial sample, further prospective studies using tissues and blood from patients with recurrent cancer will be proposed to explore the feasibility of the blood test to detect cancer recurrence.Each patient will be followed for 2 years.

Phase 3
Patients aged between 18 - 85 who are diagnosed with a primary adenocarcinoma of the bowel, and those who attend clinic appointments at Flinders Medical Centre, will be enrolled into the study after obtaining informed consent.
Blood will be collected through venepuncture (4 x 9mL K3-EDTA tubes) by trained nurses prior to any type of cancer treatment (ie. prior to chemotherapy, radiotherapy and surgery). Whole blood samples will be centrifuged, and plasma and serum will be isolated and stored in cryovial aliquots at -80 degrees until analysis for concentrations of methylated BCAT1 and IKZF1 and other novel biomarkers.
For patients that undergo cancer resection prior to chemotherapy or radiotherapy, consent will be asked to obtain some tissue samples from any excess specimen from surgery (a cancer specimen and adjacent normal tissue). The collection of this tissue will be stored in the Flinders Medical Centre tissue bank. Tissue will have DNA extracted for analysis of biomarker levels to allow direct comparison to blood biomarker levels within the same patient.
Cancer pathology details (including stage of disease, pathological features) will be recorded. Other blood indicators that have been taken as part of clinical care prior to surgery will be recorded. Patients will be interviewed by nurses to record current medications and other medical conditions, as well as any previous cancers.
Levels of methylated BCAT1 and IKZF1 in the blood and surgical tissue will be determined for all samples. Each patient will be followed up for 3 years, for any signs of CRC recurrence. Information related to routine CRC surveillance will be collected and patients may be asked to provide further blood samples, (2 x 9mL K3-EDTA tubes) during neoadjuvant/adjuvant treatment, at 6 weeks post treatment, then at 6 monthly intervals or whenever attending doctors appointments at Flinders Medical Centre.

Genomic material (DNA or RNA) will be extracted from blood and/or tissue samples for genetic sequencing analysis to uncover genomic locations that are associated with the patient’s tumour, that are commonly found in adenocarcinomas.

Intervention code [1]

Not applicable

Comparator / control treatment

Cases are those patients with a neoplastic diagnosis and where a positive FOBT test would be regarded as a true-positive, namely: cancer (also subcategorised into late Dukes C/D or early Dukes A/B stages), advanced adenoma (size >9mm, villous change, HGD, serrated morphology, number >2), or non-advanced adenoma.
Controls are those without neoplasia where a positive test would represent a false-positive. They will include a range of benign disease such as inflammatory bowel disease (IBD) since biomarkers might be non-specifically elevated in such conditions. Co-variates that might influence test results to be ascertained include: benign colorectal disease such as IBD, age band by decade, family history of colorectal neoplasia and gender.
Phase 3
The levels of methylated BCAT1 and IKZF1 in the blood and surgical tissue for each cancer patient, will be compared to established levels of tumour marker CEA blood tests of CRC patients. These will further be compared to the the blood levels of patients with and without CRC recurrence and how they change over time.

Control group

Active

Outcomes

Primary outcome [1]

To evaluate the accuracy of a panel of blood-based candidate biomarkers for detection of screen-relevant colorectal neoplasia, relative findings at colonoscopy, a commercial blood based test for CRC and to a proven faecal occult blood test (FOBT).

Timepoint [1]

two years

Primary outcome [2]

The goal/objective is: To develop a more accurate screening test for CRC.

The aim is to determine whether a blood based gene test is as accurate as an FOBT in determining whether a person is at high risk of having curable CRC or advanced adenoma, relative to colonoscopy as the gold standard

There are specific aims relating to each of the potential new marker ie is SEPT9 as accurate as FIT.

The primary outcomes are the specific measurement used. These will be the levels of gene expression in each genetic marker in the panel of markers and the haemoglobin level in the FOBT.

Relative accuracy is determined by comparison of each of the blood based genetic markers and the FOBT result versus colonoscopy

Timepoint [2]

two years

Primary outcome [3]

Phase 2b) To determine whether there is potential for recurrent cancers to be detected earlier with the new biomarker panel than the currently available blood tests (such as CEA).

Timepoint [3]

Two years

Secondary outcome [1]

Putative screening test markers need to be validated in larger population samples against a diagnostic test as well as the best available alternative screening test.

Timepoint [1]

two years

Secondary outcome [2]

The biomarkers are also present in tumour tissues. We therefore wish to obtain data on expression status of the biomarker panel in tumour and/or adenoma samples in CRC cases where cancer has recurred, to determine, in cases where the markers are expressed in the primary (initial) cancer, whether they are also expressed in subsequently developing lesions.

Timepoint [2]

Two years

Secondary outcome [3]

Phase 3
To compare the blood and surgical tissue samples using methylated BCAT1 and IKZF1 sequencing in people with a new diagnosis of colorectal neoplasia. Blood will be collected at a single timepoint for each participant shortly after enrollment and before any treatment. All collected blood samples will have plasma extracted and frozen at -80 degrees. If the participant undergoes surgery (prior to undergoing chemotherapy or radiotherapy), any spare cancer and normal tissue at surgery will be collected and will be frozen at -80 degrees. Further blood samples at 4-6 weeks post-op and 6 monthly intervals, will be process as described above to monitor for signs of CRC recurrance.

Timepoint [3]

Three years

Secondary outcome [4]

A secondary outcome of this study will be to assess if the novel blood biomarker positivity rate using the BCAT1 and IKZF1 DNA methylation test, is independent of the genetic profile of the primary adenocarcinomas in a total of 150 bowel cancer samples.

Timepoint [4]

Pre-treatment blood and/or tissues will be collected for genetic analysis and stored at -80 degrees C until sent for genetic sequencing. For participants who do not have tissue samples collected fresh at surgery, small samples of paraffin-embedded tissue of biopsy/surgery material stored within pathology archives will be requested retrospectively by the research investigators and collected from the site’s central histology archive after obtaining informed written consent.

Eligibility

Key inclusion criteria

Patients scheduled for colonoscopy for standard clinical indications.
Patients must be capable of providing satisfactory informed consent
In addition for Phase 2b
Cases with a diagnosis of CRC who have been treated and are being monitored for recurrence.
Cases where tumour tissues and/or blood samples with associated consent for use in research are available

Minimum age

18 Years

Maximum age

85 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Inability to provide informed consent
Patients who undergo an incomplete colonoscopy which raises doubt as to the status of the colon (post-hoc exclusion).

Study design

Purpose

Screening

Duration

Cross-sectional

Selection

Defined population

Timing

Prospective

Statistical methods / analysis

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

18/04/2011

Actual

6/09/2011

Date of last participant enrolment

Anticipated

30/06/2026

Actual

Date of last data collection

Anticipated

30/06/2026

Actual

Sample size

Target

5000

Accrual to date

4138

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Flinders Medical Centre - Bedford Park

Recruitment hospital [2]

Repatriation Hospital - Daw Park

Recruitment hospital [3]

Noarlunga Health Service - Noarlunga Centre

Recruitment hospital [4]

The Queen Elizabeth Hospital - Woodville

Recruitment hospital [5]

Lyell McEwin Hospital - Elizabeth Vale

Recruitment postcode(s) [1]

5011 - Woodville

Recruitment postcode(s) [2]

5042

Recruitment postcode(s) [3]

5112 - Elizabeth Vale

Recruitment postcode(s) [4]

5168 - Noarlunga Centre

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

Level 1
16 Marcus Clarke Street
Canberra ACT 2601
GPO Box 1421
Canberra ACT 2601

Country [1]

Australia

Funding source category [2]

Government body

Name [2]

Cancer Australia

Address [2]

Level 14, 300 Elizabeth Street, Surry Hills NSW 2010

Country [2]

Australia

Primary sponsor type

Hospital

Name

Flinders Medical Centre

Address

1 Flinders Drive
Bedford Park
5042
South Australia

Country

Australia

Secondary sponsor category [1]

Commercial sector/Industry

Name [1]

Clinical Genomics Pty Ltd

Address [1]

11 Julius Ave
Riverside Life Science Bldg
North Ryde NSW 2113

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Southern Adelaide Health Service/Flinders University Human Reserach Ethics Committee

Ethics committee address [1]

Human Research Ethics
Southern Adelaide Health Service
SA Health
Flinders Medical Centre
Bedford Park
SA 5042

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

19/01/2011

Ethics approval number [1]

134/045

Ethics committee name [2]

Southern Adelaide Clinical Human Research Ethics Committee

Ethics committee address [2]

Human Research Ethics Southern Adelaide Health Service SA Health Flinders Medical Centre Bedford Park SA 5042

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

11/04/2022

Approval date [2]

09/05/2022

Ethics approval number [2]

20.22

Summary

Brief summary

This study aims to develop a more accurate screening test for colorectal cancer (CRC) by evaluating the accuracy of a panel of blood-based candidate biomarkers and to determine whether there is potential for recurrent cancers to be detected earlier with the new biomarker panel than the currently available blood tests. Who is it for? You may be eligible to join this study if you are aged 18 to 85 years old and are scheduled for colonoscopy for standard clinical indications.
Participants with a diagnosis of colorectal cancer (CRC) who have been treated and are being monitored for recurrence will also be eligible for the second and third phase of the study.

Study details: All participants in this study will be asked to undergo several tests for bowel cancer at the time of their routine hospital colonoscopy, the established gold standard bowel examination.
The tests include, blood and saliva samples; and faecal occult blood tests which we will compare to new tests that we are developing that detect specific markers in blood. If we can reliably detect these markers then we will be able to develop a better screening test for bowel cancer.
In patients who have been previously treated for bowel cancer and who are being monitored for signs of recurrence, we will also explore the use of the new biomarker blood test. It is hoped that this test may be more sensitive and detect recurrence much earlier than is now possible. The overall duration of observation in each participant is three years post surgery. For patients that undergo cancer resection prior to chemotherapy or radiotherapy, consent will be asked to obtain some tissue samples from any excess specimen from surgery (a cancer specimen and adjacent normal tissue). Tissue will have DNA extracted for analysis of biomarker levels to allow direct comparison to blood biomarker levels, as well as methylated BCAT1 and IKZF1 in the blood and surgical tissue. This will help to evaluate the accuracy and efficacy of the new blood-based screening test for bowel cancer.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Graeme P Young,

Address

Flinders Centre for Innovation in Cancer, Flinders University.
Bedford Park SA 5042

Country

Australia

Phone

+61 417 860 540

Fax

graeme.young@flinders.edu.au

Contact person for public queries

Name

Ms Kathryn Cornthwaite

Address

Department of Gastroenterology,
Flinders Centre for Innovation in Cancer,
Flinders Medical Centre, Bedford Park 5042

Country

Australia

Phone

+61 8 8204 5534

Fax

+618 8204 6330

Kathryn.Cornthwaite@sa.gov.au

Contact person for scientific queries

Name

A/Prof Erin Symonds

Address

Principal Medical Scientist
Bowel Health Service Repatriation General Hospital
Daw Park SA 5041 /
Flinders Centre for Innovation in Cancer , Bedford Park , 5042

Country

Australia

Phone

+618 8275 1070

Fax

+618 82751838

erin.symonds@sa.gov.au

Data sharing statement

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

No/undecided IPD sharing reason/comment

No individual data / or any raw data will be shared without appropriate future consent and/or ethical approval.

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

Source	Title	Year of Publication	DOI
Embase	Methylation and Gene Expression of BCAT1 and IKZF1 in Colorectal Cancer Tissues.	2018	https://dx.doi.org/10.1177/1179554918775064
Embase	Evaluation of methylation biomarkers for detection of circulating tumor DNA and application to colorectal cancer.	2016	https://dx.doi.org/10.3390/genes7120125
Embase	A cross-sectional study comparing a blood test for methylated BCAT1 and IKZF1 tumor-derived DNA with CEA for detection of recurrent colorectal cancer.	2016	https://dx.doi.org/10.1002/cam4.868
Embase	A blood test for methylated BCAT1 and IKZF1 vs. a fecal immunochemical test for detection of colorectal neoplasia.	2016	https://dx.doi.org/10.1038/ctg.2015.67
Embase	Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia.	2015	https://dx.doi.org/10.1186/s12885-015-1674-2
Embase	Circulating epigenetic biomarkers for detection of recurrent colorectal cancer.	2020	https://dx.doi.org/10.1002/cncr.32695
Embase	Detection of hypermethylated BCAT1 and IKZF1 DNA in blood and tissues of colorectal, breast and prostate cancer patients.	2022	https://dx.doi.org/10.3233/CBM-210399
Embase	Detection of recurrent colorectal cancer with high specificity using a reporting threshold for circulating tumor DNA methylated in BCAT1 and IKZF1.	2022	https://dx.doi.org/10.1002/cncr.34159
Embase	Assessment of tumor burden and response to therapy in patients with colorectal cancer using a quantitative ctDNA test for methylated BCAT1/IKZF1.	2022	https://dx.doi.org/10.1002/1878-0261.13178
Embase	Detection of methylated BCAT1 and IKZF1 after curative-intent treatment as a prognostic indicator for colorectal cancer recurrence.	2023	https://dx.doi.org/10.1002/cam4.5008
Dimensions AI	Evaluation of a panel of tumor-specific differentially-methylated DNA regions in IRF4, IKZF1 and BCAT1 for blood-based detection of colorectal cancer	2021	https://doi.org/10.1186/s13148-020-00999-y
Dimensions AI	Epigenetic liquid biopsies for minimal residual disease, what’s around the corner?	2023	https://doi.org/10.3389/fonc.2023.1103797

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically