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Prebiotic Effect of Eicosapentaenoic Acid Treatment for Colorectal Cancer Liver Metastases

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ClinicalTrials.gov Identifier: NCT04682665
Recruitment Status : Recruiting
First Posted : December 24, 2020
Last Update Posted : November 28, 2023
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Massachusetts General Hospital
Massachusetts Institute of Technology
Harvard School of Public Health (HSPH)
University of Bradford
Information provided by (Responsible Party):
Mark A Hull, PhD FRCP, University of Leeds

Study Description
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Brief 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. 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.

Condition or disease Intervention/treatment
Colon Cancer Liver Metastasis Drug: Icosapent Ethyl Oral Capsule Other: Placebo

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
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Study Type : Observational
Estimated Enrollment : 250 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Biospecimen Collection for:Prebiotic Effect of Eicosapentaenoic Acid Treatment for Colorectal Cancer Liver Metastases
Actual Study Start Date : September 16, 2021
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : July 2025

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
Experimental
Patients randomized to the experimental arm of the EMT2 trial, receiving Icosapent Ethyl (EPA-EE) according to the EMT2 protocol.
 Drug: Icosapent Ethyl Oral Capsule
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.
Placebo comparator
Patients randomized to the placebo comparator arm of the EMT2 trial, receiving placebo capsules according to the EMT2 protocol.
 Other: Placebo
Soft gelatin capsules containing light mineral oil. 4 capsules to be taken per day (2 in the morning and 2 in the evening).


Outcome Measures
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Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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)

  8. 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

  9. 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


Biospecimen Retention:   Samples With DNA
Whole blood, serum, stool, urine, tumour tissue (colorectal cancer liver metastases).

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Any participant who has already been enrolled in the EMT2 trial is eligible for inclusion in the biospecimen collection study.
Criteria

Inclusion Criteria:

  • Only individuals who have already been enrolled in the EMT2 trial are eligible for inclusion in the biospecimen collection study.

Exclusion Criteria:

  • There are NO exclusions for entry to the biospecimen collection study if an individual has already been recruited to the EMT2 trial.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04682665


Contacts
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Contact: Mark Hull +44 113 3438650 m.a.hull@leeds.ac.uk
Contact: Tim Brend +44 7510 908117 t.brend@leeds.ac.uk

Locations
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United Kingdom
St James's University Hospital Recruiting
Leeds, United Kingdom
Contact: Cath Moriarty         
University of Liverpool Recruiting
Liverpool, United Kingdom
Contact: Robert Jones, MD         
Sponsors and Collaborators
University of Leeds
National Cancer Institute (NCI)
Massachusetts General Hospital
Massachusetts Institute of Technology
Harvard School of Public Health (HSPH)
University of Bradford
Investigators
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Principal Investigator: Mark Hull University of Leeds
More Information
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Responsible Party: Mark A Hull, PhD FRCP, Professor of Gastroenterology, University of Leeds
ClinicalTrials.gov Identifier: NCT04682665    
Other Study ID Numbers: 20/YH/0306
1R01CA243454-01A1 ( U.S. NIH Grant/Contract )
First Posted: December 24, 2020    Key Record Dates
Last Update Posted: November 28, 2023
Last Verified: November 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Anonymised individual patient experimental data may be shared depending on experimental outcomes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Mark A Hull, PhD FRCP, University of Leeds:
Colon Cancer
Liver Metastases
Microbiome
Additional relevant MeSH terms:
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Neoplasm Metastasis
Colonic Neoplasms
Liver Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
 Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Neoplastic Processes
Pathologic Processes
Liver Diseases
Eicosapentaenoic acid ethyl ester
Platelet Aggregation Inhibitors
Lipid Regulating Agents