Colon Cancer Liver MetastasisNCT04682665
Prebiotic Effect of Eicosapentaenoic Acid Treatment for Colorectal Cancer Liver Metastases
An observational study of Colon Cancer Liver Metastasis, run by University of Leeds at 2 sites in United Kingdom.
Trial summary
A significant proportion of patients who undergo liver surgery to remove bowel cancer that has spread to the liver (metastases) develop disease recurrence and die from the disease. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colon Cancer Liver Metastasis
- What is being tested?
- Icosapent Ethyl Oral Capsule
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 81 participants
- Where
- 2 sitesUnited Kingdom
- Study dates
- 16 Sep 2021to 31 Jul 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Any participant who has already been enrolled in the EMT2 trial is eligible for inclusion in the biospecimen collection study.
Who may be able to join
- Only individuals who have already been enrolled in the EMT2 trial are eligible for inclusion in the biospecimen collection study.
Who cannot join
- There are NO exclusions for entry to the biospecimen collection study if an individual has already been recruited to the EMT2 trial.
Trial locations and contacts
2 sites in 1 country.
United Kingdom2 sites
St James's University Hospital
Leeds
University of Liverpool
Liverpool
About this study
Official title: Biospecimen Collection for:Prebiotic Effect of Eicosapentaenoic Acid Treatment for Colorectal Cancer Liver Metastases
A significant proportion of patients who undergo liver surgery to remove bowel cancer that has spread to the liver (metastases) develop disease recurrence and die from the disease. The EMT2 study (NCT03428477) is a clinical trial of the omega-3 fatty acid EPA, investigating whether patients who EPA ethyl ester remain free of disease recurrence for longer than those taking placebo. Recent data suggest that the anti-cancer effect of EPA may result from changes to the microbiota (gut bacteria) which lead to an improved anti-cancer response by the immune system. This study will collect biospecimens (stool, urine, blood, tumour tissue) from participants in the EMT2 trial in order to interrogate the microbiome and immune mechanisms associated with EPA treatment, in relation to participant survival. Insights from this study will identify those most likely to benefit from treatment, leading to more targeted, personalised use of EPA.
Read the detailed description
Despite advance in the diagnosis and treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the US and the UK. The majority of deaths from CRC are related to distant metastases, predominantly to the liver.
There are observational and laboratory data supporting the notion that the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anti-CRC activity. These include a phase 2 'window of opportunity' randomised, placebo-controlled trial of EPA provided before surgery for resection of CRC liver metastasis (called the EMT study). A signal that EPA improved progression-free and overall survival after liver surgery provided the rationale for the EMT2 trial, which is a randomised, double-blind placebo-controlled phase 3 trial of the effect of EPA (started before surgery but continued post-operatively) on CRC recurrence and survival after surgery for resectable liver metastases [ClinicalTrials.gov NCT03428477 and EudraCT Number: 2016-000628-24].
The mechanism(s) by which EPA might influence post-operative survival are not well understood. Recent data support the idea that the anti-CRC benefit of EPA may be mediated by modulating the intestinal microbiota and ameliorating tumour-permissive immunosuppressive mechanisms, including inhibition of the activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as reduced synthesis of inflammatory mediators such as prostaglandin (PG) E2 and chemokine (C-C motif) ligand 2 (CCL2). Mice fed with a high-EPA-containing diet demonstrate 1) increased abundance of gut bacteria, such as Bifidobacterium and Lactobacillus genera that support the host anti-tumour immune response and improve the efficacy of cancer immunotherapy, and 2) decreased abundance of lipopolysaccharide (LPS)-producing bacteria that trigger chronic inflammation and can promote CRC. These data support a hypothesis that a prebiotic effect of EPA abrogates intra-tumoural immunosuppression and ameliorates systemic inflammation to improve survival of CRCLM patients.
EMT2 trial participants are ideally placed to provide biospecimens that can be analysed in order to understand the mechanism(s) of action of EPA given that the laboratory data can eventually be linked to the clinical outcomes from the trial. Biospecimens can be obtained without interference with the EMT2 trial protocol. Stool, urine, and blood samples will be obtained 1) after EMT2 trial randomization, before starting EPA or placebo, 2) just before surgery, and 3) at 6-monthly intervals thereafter, plus liver metastases tumour tissue during surgery. Using these biospecimens, the microbiome and immune pathways altered by EPA will be investigated in relation to participant survival. Mechanistic insights about the anti-CRC activity of EPA from the biospecimen collection project will maximize the knowledge and insights gained from the EMT2 trial and its participants, thereby leading to personalized use of EPA, which will be targeted at those most likely to benefit.
- Conditions
- Colon Cancer Liver Metastasis
- Being tested
- Icosapent Ethyl Oral Capsule, Placebo
- Keywords
- Colon Cancer, Liver Metastases, Microbiome
- Medical subject headings
- Colonic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Icosapent Ethyl Oral CapsuleDrug
Soft gelatin capsules containing 1g pure EPA-EE. Administered as 4g per day to be taken as 2 capsules in the morning and 2 capsules in the evening.
PlaceboOther
Soft gelatin capsules containing light mineral oil. 4 capsules to be taken per day (2 in the morning and 2 in the evening).
| Study group | Role | What they receive |
|---|---|---|
| Experimental | Patients randomized to the experimental arm of the EMT2 trial, receiving Icosapent Ethyl (EPA-EE) according to the EMT2 protocol. Receives: Drug: Icosapent Ethyl Oral Capsule | |
| Placebo comparator | Patients randomized to the placebo comparator arm of the EMT2 trial, receiving placebo capsules according to the EMT2 protocol. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Abundance of individual bacterial taxa in the gut microbiome (eg. Bifidobacterium, Lactobacillus, and Fusobacterium) in stool samples.
16S rRNA and metagenomic methods
Measured: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Microbial gene expression in stool samples
Bacterial gene expression analysis
Measured: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Levels of polyunsaturated fatty acids and lipid mediators in stool samples
Liquid chromatography-mass spectrometric measurement of lipids
Measured: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Relationship between changes in the gut microbiome induced by EPA and survival of patients
16S rRNA and metagenomic methods
Measured: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Treg cells and myeloid-derived suppressor cells in colorectal cancer liver metastasis tissue
Immunohistochemistry and flow cytometry for immune cell populations
Measured: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Levels of expression of immune checkpoint regulators in colorectal cancer liver metastasis tissue
Immunohistochemistry for CTLA-4, TIGIT, TIM-3, PD-1 in colorectal cancer liver metastasis tissue
Measured: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Blood levels of chemokines and lipid mediators
Immunoassay and mass spectrometry of chemokines (plasma CCL2) and lipid metabolites (urinary PGE-M)
Measured: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Effect of human faecal samples from patients treated with EPA or placebo on tumour burden in gnotobiotic mice with colorectal cancer liver metastasis
Liver tumour size
Measured: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Effect of human faecal samples from patients treated with EPA or placebo on anti-tumour immune response in gnotobiotic mice with colorectal cancer liver metastasis
Flow cytometry and immunohistochemistry for immune cell populations and cytokine/chemokine levels
Measured: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2020
- Study start16 Sep 2021
- Primary completion31 Jul 2024
- Study completion31 Jul 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colon Cancer Liver MetastasisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 81 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Leeds
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI), Massachusetts General Hospital, Massachusetts Institute of Technology, Harvard School of Public Health (HSPH), University of Bradford
- Responsible party
- Principal investigator, Mark A Hull, PhD FRCP, University of Leeds
- Investigators
- Mark Hull, Principal investigator, University of Leeds
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04682665
- Sponsor's protocol ID
- 20/YH/0306
- Other IDs
- 1R01CA243454-01A1
- Status last verified
- Dec 2024
- First submitted
- 2 Dec 2020
- Last updated
- 4 Dec 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided: Anonymised individual patient experimental data may be shared depending on experimental outcomes
Study at a glance
From the registry record, last updated by the sponsor on 4 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Biospecimen Collection for:Prebiotic Effect of Eicosapentaenoic Acid Treatment for Colorectal Cancer Liver Metastases
- ClinicalTrials.gov ID
- NCT04682665
- Acronym / sponsor ID
- 20/YH/0306
- Conditions
- Colon Cancer Liver Metastasis
- Keywords
- Colon Cancer, Liver Metastases, Microbiome
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 81 participants (actual)
- Lead sponsor
- University of LeedsUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI), Massachusetts General Hospital, Massachusetts Institute of Technology, Harvard School of Public Health (HSPH), University of Bradford
- Study start
- 16 Sep 2021 (actual)
- Primary completion
- 31 Jul 2024 (actual)
- Study completion
- 31 Jul 2024 (actual)
- First posted
- 24 Dec 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A significant proportion of patients who undergo liver surgery to remove bowel cancer that has spread to the liver (metastases) develop disease recurrence and die from the disease. The EMT2 study (NCT03428477) is a clinical trial of the omega-3 fatty acid EPA, investigating whether patients who EPA ethyl ester remain free of disease recurrence for longer than those taking placebo. Recent data suggest that the anti-cancer effect of EPA may result from changes to the microbiota (gut bacteria) which lead to an improved anti-cancer response by the immune system. This study will collect biospecimens (stool, urine, blood, tumour tissue) from participants in the EMT2 trial in order to interrogate the microbiome and immune mechanisms associated with EPA treatment, in relation to participant survival. Insights from this study will identify those most likely to benefit from treatment, leading to more targeted, personalised use of EPA.
Detailed description
Despite advance in the diagnosis and treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the US and the UK. The majority of deaths from CRC are related to distant metastases, predominantly to the liver.
There are observational and laboratory data supporting the notion that the omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) has anti-CRC activity. These include a phase 2 'window of opportunity' randomised, placebo-controlled trial of EPA provided before surgery for resection of CRC liver metastasis (called the EMT study). A signal that EPA improved progression-free and overall survival after liver surgery provided the rationale for the EMT2 trial, which is a randomised, double-blind placebo-controlled phase 3 trial of the effect of EPA (started before surgery but continued post-operatively) on CRC recurrence and survival after surgery for resectable liver metastases [ClinicalTrials.gov NCT03428477 and EudraCT Number: 2016-000628-24].
The mechanism(s) by which EPA might influence post-operative survival are not well understood. Recent data support the idea that the anti-CRC benefit of EPA may be mediated by modulating the intestinal microbiota and ameliorating tumour-permissive immunosuppressive mechanisms, including inhibition of the activity of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), as well as reduced synthesis of inflammatory mediators such as prostaglandin (PG) E2 and chemokine (C-C motif) ligand 2 (CCL2). Mice fed with a high-EPA-containing diet demonstrate 1) increased abundance of gut bacteria, such as Bifidobacterium and Lactobacillus genera that support the host anti-tumour immune response and improve the efficacy of cancer immunotherapy, and 2) decreased abundance of lipopolysaccharide (LPS)-producing bacteria that trigger chronic inflammation and can promote CRC. These data support a hypothesis that a prebiotic effect of EPA abrogates intra-tumoural immunosuppression and ameliorates systemic inflammation to improve survival of CRCLM patients.
EMT2 trial participants are ideally placed to provide biospecimens that can be analysed in order to understand the mechanism(s) of action of EPA given that the laboratory data can eventually be linked to the clinical outcomes from the trial. Biospecimens can be obtained without interference with the EMT2 trial protocol. Stool, urine, and blood samples will be obtained 1) after EMT2 trial randomization, before starting EPA or placebo, 2) just before surgery, and 3) at 6-monthly intervals thereafter, plus liver metastases tumour tissue during surgery. Using these biospecimens, the microbiome and immune pathways altered by EPA will be investigated in relation to participant survival. Mechanistic insights about the anti-CRC activity of EPA from the biospecimen collection project will maximize the knowledge and insights gained from the EMT2 trial and its participants, thereby leading to personalized use of EPA, which will be targeted at those most likely to benefit.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Experimental | – | Drug: Icosapent Ethyl Oral CapsulePatients randomized to the experimental arm of the EMT2 trial, receiving Icosapent Ethyl (EPA-EE) according to the EMT2 protocol. |
| Placebo comparator | – | Other: PlaceboPatients randomized to the placebo comparator arm of the EMT2 trial, receiving placebo capsules according to the EMT2 protocol. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Any participant who has already been enrolled in the EMT2 trial is eligible for inclusion in the biospecimen collection study.
Key inclusion criteria (1 listed)
- Only individuals who have already been enrolled in the EMT2 trial are eligible for inclusion in the biospecimen collection study.
Key exclusion criteria (1 listed)
- There are NO exclusions for entry to the biospecimen collection study if an individual has already been recruited to the EMT2 trial.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Icosapent Ethyl Oral CapsuleSoft gelatin capsules containing 1g pure EPA-EE. Administered as 4g per day to be taken as 2 capsules in the morning and 2 capsules in the evening. | Drug | Experimental |
| PlaceboSoft gelatin capsules containing light mineral oil. 4 capsules to be taken per day (2 in the morning and 2 in the evening). | Other | Placebo comparator |
Primary outcome
Abundance of individual bacterial taxa in the gut microbiome (eg. Bifidobacterium, Lactobacillus, and Fusobacterium) in stool samples.
Time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
16S rRNA and metagenomic methods
Microbial gene expression in stool samples
Time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Bacterial gene expression analysis
Levels of polyunsaturated fatty acids and lipid mediators in stool samples
Time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Liquid chromatography-mass spectrometric measurement of lipids
Relationship between changes in the gut microbiome induced by EPA and survival of patients
Time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
16S rRNA and metagenomic methods
Treg cells and myeloid-derived suppressor cells in colorectal cancer liver metastasis tissue
Time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Immunohistochemistry and flow cytometry for immune cell populations
Levels of expression of immune checkpoint regulators in colorectal cancer liver metastasis tissue
Time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Immunohistochemistry for CTLA-4, TIGIT, TIM-3, PD-1 in colorectal cancer liver metastasis tissue
Blood levels of chemokines and lipid mediators
Time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Immunoassay and mass spectrometry of chemokines (plasma CCL2) and lipid metabolites (urinary PGE-M)
Effect of human faecal samples from patients treated with EPA or placebo on tumour burden in gnotobiotic mice with colorectal cancer liver metastasis
Time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Liver tumour size
Effect of human faecal samples from patients treated with EPA or placebo on anti-tumour immune response in gnotobiotic mice with colorectal cancer liver metastasis
Time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.
Flow cytometry and immunohistochemistry for immune cell populations and cytokine/chemokine levels
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Dec 2024.
- Individual participant dataSharing planned: Undecided. Anonymised individual patient experimental data may be shared depending on experimental outcomes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark Hull principal investigator
University of Leeds
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Colon Cancer Liver Metastasis, run by University of Leeds at 2 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Abundance of individual bacterial taxa in the gut microbiome (eg. Bifidobacterium, Lactobacillus, and Fusobacterium) in stool samples. (time frame: A) Change between baseline (pre-treatment) and before liver surgery. B) Change between baseline (pre-treatment) and 6 months after liver surgery. C) Change between baseline (pre-treatment) and time points up to two years follow up.). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Dec 2024.