Prebiotic Effect of Eicosapentaenoic Acid Treatment for Colorectal Cancer Liver Metastases

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.

Study Overview

• Status: Recruiting
• Conditions: Colon Cancer Liver Metastasis
• Intervention / Treatment: 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 Type: Observational
• Enrollment (Estimated): 250

Contacts and Locations

• Study Contact: Name: Mark Hull; Phone Number: +44 113 3438650; Email: m.a.hull@leeds.ac.uk
• Study Contact Backup: Name: Tim Brend; Phone Number: +44 7510 908117; Email: t.brend@leeds.ac.uk

Study Locations

• United Kingdom
  • Leeds, United Kingdom
    • Recruiting
    • St James's University Hospital
    • Contact: Cath Moriarty
  • Liverpool, United Kingdom
    • Recruiting
    • University of Liverpool
    • Contact: Robert Jones, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• 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.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Abundance of individual bacterial taxa in the gut microbiome (eg. Bifidobacterium, Lactobacillus, and Fusobacterium) in stool samples.	16S rRNA and metagenomic methods	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	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	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	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	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	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)	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	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	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.

Collaborators and Investigators

• Sponsor: University of Leeds
• Collaborators: National Cancer Institute (NCI); Massachusetts General Hospital; Massachusetts Institute of Technology; Harvard School of Public Health (HSPH); University of Bradford
• Investigators: Principal Investigator: Mark Hull, University of Leeds

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2021
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: December 2, 2020
• First Submitted That Met QC Criteria: December 18, 2020
• First Posted (Actual): December 24, 2020

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Microbiome; Colon Cancer; Liver Metastases
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Liver Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Liver Neoplasms; Colonic Neoplasms; Platelet Aggregation Inhibitors; Lipid Regulating Agents; Eicosapentaenoic acid ethyl ester
• Other Study ID Numbers: 20/YH/0306; 1R01CA243454-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Anonymised individual patient experimental data may be shared depending on experimental outcomes

Drug and device information, study documents

• 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