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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
10/12/2018
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] 252436 0
nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
colorectal cancer. 257948 0
Condition category
Condition code
Cancer 258115 258115 0 0
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) at 6 weeks, post treatment, then at 6 monthly intervals or whenever attending doctors appointments at Flinders Medical Centre.
Intervention code [1] 257004 0
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] 262273 0
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] 262273 0
two years
Primary outcome [2] 262274 0
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] 262274 0
two years
Primary outcome [3] 294891 0
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] 294891 0
Two years
Secondary outcome [1] 273435 0
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] 273435 0
two years
Secondary outcome [2] 314289 0
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] 314289 0
Two years
Secondary outcome [3] 349159 0
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] 349159 0
Three years

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
Gender
Both males and females
Can healthy volunteers participate?
No
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
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 1857 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [2] 1858 0
Repatriation Hospital - Daw Park
Recruitment hospital [3] 11388 0
Noarlunga Health Service - Noarlunga Centre
Recruitment postcode(s) [1] 3859 0
5042
Recruitment postcode(s) [2] 23287 0
5168 - Noarlunga Centre

Funding & Sponsors
Funding source category [1] 264610 0
Government body
Name [1] 264610 0
National Health and Medical Research Council
Address [1] 264610 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
GPO Box 1421
Canberra ACT 2601
Country [1] 264610 0
Australia
Primary sponsor type
Hospital
Name
Flinders Medical Centre
Address
1 Flinders Drive
Bedford Park
5042
South Australia
Country
Australia
Secondary sponsor category [1] 256683 0
Commercial sector/Industry
Name [1] 256683 0
Clinical Genomics Pty Ltd
Address [1] 256683 0
11 Julius Ave
Riverside Life Science Bldg
North Ryde NSW 2113
Country [1] 256683 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 266642 0
Southern Adelaide Health Service/Flinders University Human Reserach Ethics Committee
Ethics committee address [1] 266642 0
Human Research Ethics
Southern Adelaide Health Service
SA Health
Flinders Medical Centre
Bedford Park
SA 5042
Ethics committee country [1] 266642 0
Australia
Date submitted for ethics approval [1] 266642 0
Approval date [1] 266642 0
19/01/2011
Ethics approval number [1] 266642 0
134/045

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 31518 0
Prof Graeme P Young,
Address 31518 0
Flinders Centre for Innovation in Cancer, Flinders University.
Bedford Park SA 5042
Country 31518 0
Australia
Phone 31518 0
+61 417 860 540
Fax 31518 0
Email 31518 0
graeme.young@flinders.edu.au
Contact person for public queries
Name 14765 0
Ms Susie Byrne
Address 14765 0
Department of Gastroenterology,
Flinders Centre for Innovation in Cancer,
Flinders Medical Centre, Bedford Park 5042
Country 14765 0
Australia
Phone 14765 0
+61 8 8204 7402
Fax 14765 0
+618 8204 6330
Email 14765 0
susie.byrne@sa.gov.au
Contact person for scientific queries
Name 5693 0
Dr Erin Symonds
Address 5693 0
Principal Medical Scientist
Bowel Health Service Repatriation General Hospital
Daw Park SA 5041 /
Flinders Centre for Innovation in Cancer , Bedford Park , 5042
Country 5693 0
Australia
Phone 5693 0
+618 8275 1070
Fax 5693 0
+618 82751838
Email 5693 0
erin.symonds@sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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?
Clinical study report
Summary results
No Results