Biospecimen Collection for:Prebiotic Effect of Eicosapentaenoic Acid Treatment for Colorectal Cancer Liver Metastases
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 81
- 试验地点
- 2
- 主要终点
- Microbial gene expression in stool samples
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Only individuals who have already been enrolled in the EMT2 trial are eligible for inclusion in the biospecimen collection study.
排除标准
- •There are NO exclusions for entry to the biospecimen collection study if an individual has already been recruited to the EMT2 trial.
研究组 & 干预措施
Experimental
Patients randomized to the experimental arm of the EMT2 trial, receiving Icosapent Ethyl (EPA-EE) according to the EMT2 protocol.
干预措施: Icosapent Ethyl Oral Capsule (Drug)
Placebo comparator
Patients randomized to the placebo comparator arm of the EMT2 trial, receiving placebo capsules according to the EMT2 protocol.
干预措施: Placebo (Other)
结局指标
主要结局
Microbial gene expression in stool samples
时间窗: 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
Relationship between changes in the gut microbiome induced by EPA and survival of patients
时间窗: 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
Effect of human faecal samples from patients treated with EPA or placebo on tumour burden in gnotobiotic mice with colorectal cancer liver metastasis
时间窗: 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
Levels of polyunsaturated fatty acids and lipid mediators in stool samples
时间窗: 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
Treg cells and myeloid-derived suppressor cells in colorectal cancer liver metastasis tissue
时间窗: 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
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
时间窗: 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
Levels of expression of immune checkpoint regulators in colorectal cancer liver metastasis tissue
时间窗: 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
时间窗: 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)
Abundance of individual bacterial taxa in the gut microbiome (eg. Bifidobacterium, Lactobacillus, and Fusobacterium) in stool samples.
时间窗: 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
次要结局
未报告次要终点
研究者
Mark A Hull, PhD FRCP
Professor of Gastroenterology
University of Leeds