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Trial registered on ANZCTR


Registration number
ACTRN12622001037796
Ethics application status
Approved
Date submitted
18/07/2022
Date registered
25/07/2022
Date last updated
7/09/2022
Date data sharing statement initially provided
25/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
TIPTOE - Investigating Peripheral T cell Tolerance in Colorectal Cancer
Scientific title
TIPTOE - Investigating Peripheral T cell Tolerance in Colorectal Cancer
Secondary ID [1] 307612 0
Nil
Universal Trial Number (UTN)
U1111-1280-4151
Trial acronym
TIPTOE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Colorectal Cancer 327086 0
Condition category
Condition code
Cancer 324239 324239 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Individuals with stage IV colorectal cancer who are planned to undergo surgery to remove their primary tumour +/- metastatic disease as part of their routine cancer care will be recruited to this study. At the time of surgery, once the specimen has been surgically resected, a number of fresh tissue samples will be obtained from the specimen for the research study. These samples will include lymph nodes, a small sample of the primary tumour, a sample of normal tissue, and a sample of a metastasis. These samples will be obtained by a senior colorectal surgeon under the supervision of pathology staff. In addition, a blood sample (up to 40ml) will be taken from the participant via their routinely inserted peripheral vein cannula once the participant is under general anaesthesia or at the appropriate time prior to surgery co-ordinated with diagnostic sampling by the anaesthetist.

Samples obtained will be processed for single cell RNA sequencing analysis. Remaining tissue, cells and plasma that have been isolated from tissue and blood will be cryopreserved and stored in a secure manner.

Participants will not be required to attend any follow up study visits for this study. The Peter MacCallum Cancer Centre hospital electronic medical record will be reviewed from time of initial diagnosis up to 3 years post-surgery for all participants who choose to enrol. Only relevant clinical data regarding the participant will be obtained and stored in a secure and de-identified manner. This will include basic demographics, diagnosis, stage and site of primary tumour, site(s) of metastatic disease, prior anti-cancer treatment, relapse date, death date and follow up dates, past and concurrent medical history, and concurrent medications at time of surgery.
Intervention code [1] 324062 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332058 0
Identification of a lymph node restricted CD8+ T cell population with a gene expression profile consistent with peripheral tolerance using single cell RNA sequence (scRNAseq) analysis of all obtained samples.
Timepoint [1] 332058 0
At completion of scRNAseq analysis of all obtained samples
Secondary outcome [1] 412014 0
Frequency of tolerant CD8+ T cells in the tumour draining lymph node assessed by scRNAseq analysis of all obtained samples
Timepoint [1] 412014 0
At completion of scRNAseq analysis of all obtained samples
Secondary outcome [2] 412015 0
Relapse-free survival defined by time (months) from surgery to colorectal cancer recurrence stratified by the frequency of tolerant CD8+ T cells in the tumour draining lymph node assessed by scRNAseq analysis of all obtained samples.
Timepoint [2] 412015 0
Relapse-free survival will be censored for all enrolled participants at the time of completion of scRNAseq analysis of all obtained samples.
Secondary outcome [3] 412016 0
Overall survival defined by time (months) from colorectal cancer diagnosis to death from any cause stratified by the frequency of tolerant CD8+ T cells in the tumour draining lymph node assessed by scRNAseq analysis of all obtained samples.
Timepoint [3] 412016 0
Overall survival will be censored for all enrolled participants at the time of completion of scRNAseq analysis of all obtained samples
Secondary outcome [4] 412017 0
Frequency of tolerant CD8+ T cells in the tumour draining lymph node assessed by scRNAseq analsysis stratified by tumour microsatellite status determined by routine immunohistochemistry.
Timepoint [4] 412017 0
At completion of scRNAseq analysis of all obtained samples
Secondary outcome [5] 412172 0
Frequency of tolerant CD8+ T cells in the tumour draining lymph node, assessed by scRNAseq, stratified by the frequency of tumour immune-cell infiltration, assessed by scRNAseq and immunohistochemistry analysis of all obtained samples.
Timepoint [5] 412172 0
At completion of scRNAseq analysis of all obtained samples.
Secondary outcome [6] 412173 0
Identification of a lymph node restricted tolerant CD8+ T cell population using Visium HD or Opal immunohistochemistry analysis of formalin-fixed paraffin embedded samples of all obtained tissue samples.
Timepoint [6] 412173 0
At completion of Visium HD or Opal immunohistochemistry analysis of formalin-fixed paraffin embedded samples of all obtained tissue samples.

Eligibility
Key inclusion criteria
1. Subjects must have voluntarily provided written informed consent for the study.
2. Subjects must be at least 18 years of age at the time of consent.
3. Subject must have histologically confirmed or suspected colorectal adenocarcinoma.
4. Subjects must have stage IV disease based on the AJCC Cancer Staging Manual 8th edition.
5. Subjects must be undergoing surgical resection of their primary tumour at the Peter
MacCallum Cancer Centre as part of their routine oncological care.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Subjects unable to voluntarily provide written informed consent.
2. Subjects with stage I-III colorectal cancer.
3. Any medical or psychosocial reason that in the opinion of the investigator would make
the subject inappropriate for the study.

Study design
Purpose
Duration
Selection
Timing
Prospective
Statistical methods / analysis
This is an exploratory study and no formal sample size calculation has been performed. The sample size of 25 subjects is a product of projected recruitment numbers within 2 years and available funding.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/08/2022
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
25
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 22849 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment postcode(s) [1] 38148 0
3000 - Melbourne

Funding & Sponsors
Funding source category [1] 311879 0
Commercial sector/Industry
Name [1] 311879 0
AstraZeneca Research Grant
Country [1] 311879 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan St
Melbourne
VIC 3000
Country
Australia
Secondary sponsor category [1] 313356 0
None
Name [1] 313356 0
Address [1] 313356 0
Country [1] 313356 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311314 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 311314 0
305 Grattan St
Melbourne
VIC 3000
Ethics committee country [1] 311314 0
Australia
Date submitted for ethics approval [1] 311314 0
09/06/2022
Approval date [1] 311314 0
27/06/2022
Ethics approval number [1] 311314 0
HREC/85604/PMCC

Summary
Brief summary
Colorectal cancer can develop in the colon (large bowel) and/or rectum. If left undetected, it can spread to lymph nodes and other organs in the body in a process called metastasis. It is thought that the immune system plays a role in preventing some cancers from growing or spreading. However, we do not fully understand why the immune system fails to prevent all cancers. New therapies called ‘immunotherapy’ have been developed that target the immune system in order to treat cancer once it is detected. Unfortunately, this type of treatment does not work well for most individuals with colorectal cancer.
This project aims to investigate whether an immune system process called ‘tolerance’ may explain why the immune system fails to prevent colorectal cancer from growing and spreading. The project also aims to investigate whether ‘tolerance’ may explain why immunotherapy is not effective for most individuals with colorectal cancer.

Who is it for?
You may be eligible for this study if you are aged 18 years or older, you have been diagnosed with a stage 4 colorectal cancer and you have been scheduled to undergo surgery to remove your primary tumour, lymph nodes and other affected sites as part of your cancer treatment.

Study details
If you choose to enrol in this study, you agree that the study investigators may take samples from the tumour, lymph nodes, blood and other affected tissues for this study. Participants will also be asked to grant permission for the investigators to review and collect details of their medical history from their records. The investigators will then complete a series of analyses on the samples to determine whether 'tolerant' cells are present and may explain why immunotherapy does or does not work against these cancers.

It is hoped that knowledge gained from this project may contribute to the development of new and better treatments for individuals with colorectal cancer in the future.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 120678 0
Dr Ian Parish
Address 120678 0
Cancer Immunology Program
Peter MacCallum Cancer Centre
305 Grattan St
Melbourne
VIC 3000
Country 120678 0
Australia
Phone 120678 0
+61 3 85595815
Fax 120678 0
Email 120678 0
Ian.Parish@petermac.org
Contact person for public queries
Name 120679 0
Dr Avraham Travers
Address 120679 0
Peter MacCallum Cancer Centre
305 Grattan St
Melbourne
VIC 3000
Country 120679 0
Australia
Phone 120679 0
+61 3 85595816
Fax 120679 0
Email 120679 0
Avraham.Travers@petermac.org
Contact person for scientific queries
Name 120680 0
Dr Ian Parish
Address 120680 0
Cancer Immunology Program
Peter MacCallum Cancer Centre
305 Grattan St
Melbourne
VIC 3000
Country 120680 0
Australia
Phone 120680 0
+61 3 85595815
Fax 120680 0
Email 120680 0
Ian.Parish@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All clinical and biological data, after de-identification
When will data be available (start and end dates)?
Following publication, no end date.
Available to whom?
Researchers who provide a methodologically sound proposal, case-by-case basis at the discretion of the Primary Sponsor
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Access subject to approvals by Principal Investigator and Primary Sponsor.
Contact via email: Ian.Parish@petermac.org


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.