EPA for Metastasis Trial 2

Study Overview
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Brief Summary
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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. A previous small study (the EMT study) suggested a possible survival benefit in patients who took the naturally-occurring omega-3 fatty acid EPA (a fish oil supplement) before liver surgery. The EMT2 study is a larger study which will recruit 448 men and women with liver metastases from bowel cancer. Trial participants will receive either Icosapent Ethyl (pure EPA derived from fish oil) or placebo (dummy capsules). EMT2 will investigate whether patients who take this supplement before liver surgery and for up to four years after surgery, remain free of recurrence for longer than those who take placebo (dummy capsules)

Detailed Description
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Despite significant advances in diagnosis and treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the UK. The majority of deaths from CRC are related to distant metastasis, predominantly to the liver. Overall 5-year survival following liver resection and adjuvant chemotherapy for colorectal cancer liver metastases (CRCLM) is, at best, 40-60%. Despite surgery with curative intent, up to 60% of patients develop recurrence within 2 years of surgery. The preliminary EMT study was a Phase II RCT of EPA 2 g daily in patients (n=88) undergoing liver resection surgery for CRCLM. Although there was no difference in the primary endpoint (tumour proliferation index), metastases from the EPA arm had a lower vascularity score (suggesting possible anti-angiogenic activity) than placebo-treated tumours. Although EPA (or placebo) treatment was limited to the pre-operative period, overall survival (OS) and disease-free survival (DFS) were specified as exploratory end-points on the basis that oral dosing with EPA before liver surgery would provide tissue EPA exposure in the immediate peri-operative period with prolonged bioavailability in the post-operative period due to the slow tissue 'washout' kinetics of EPA. Survival analysis demonstrated that the median DFS in the EPA group was 22.6 months compared with 14.7 months in the placebo group. Any DFS benefit was explained by a reduction in CRC recurrence from 12 months after surgery onwards. The EMT2 study is a randomised, double-blind, placebo-controlled, multi-centre, phase III trial of the omega-3 fatty acid (O3FA) eicosapentaenoic acid (EPA) as the ethyl ester (icosapent ethyl [IPE; Vascepa®]) in patients undergoing liver resection surgery for colorectal cancer liver metastasis (CRCLM) with curative intent designed to determine whether EPA treatment improves Progression-Free Survival (PFS). A key secondary objective is overall survival (OS). Investigators will recruit adult individuals listed for CRCLM resection with curative intent. Randomisation will be 1:1 to receive either IPE capsules or placebo capsules. 4 capsules per day containing IPE (equivalent to 4 g EPA-ethyl ester [EE] daily) or 4 placebo capsules per day. Participants will start treatment a prior to CRCLM surgery and will continue to receive treatment for a minimum of 2 years and a maximum of 4 years post-liver resection. Participants are followed up for 60 days beyond the end of treatment. Participants are clinically assessed 6 months post-operatively (from liver resection) and at 6-monthly intervals thereafter for disease progression/recurrence.

Official Title
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A Randomised Placebo-controlled Phase III Trial of the Effect of the Omega-3 Fatty Acid Eicosapentaenoic Acid (EPA) on Colorectal Cancer Recurrence and Survival After Surgery for Resectable Liver Metastases

Conditions
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Liver Metastasis, Colon Cancer

Intervention / Treatment
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* Drug: Icosapent Ethyl
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years Able to provide written informed consent Histological diagnosis of colorectal cancer with evidence of liver metastases Planned liver resection surgery for colorectal cancer liver metastases with curative intent, including repeat 're-do' colorectal cancer liver metastases surgery (a second independent resection for a separate colorectal cancer liver recurrence) Intention to receive IMP prior to colorectal cancer liver metastases surgery Exclusion Criteria: Previous CRCLM surgery for the management of the current metastatic disease Incurable extra-hepatic metastases Current (in the last 2 months) or planned regular (>3 doses per week) use of O3FA-containing drugs or supplements, including Vazkepa®, Omacor®, fish oil and cod-liver oil supplements Fish/seafood allergy Diagnosis of hereditary fructose intolerance Soya or peanut allergy Inability to comply with trial treatment and follow-up schedule Known bleeding tendency/condition (e.g. von Willebrand disease) A previous malignancy within the last 5 years other than: colorectal cancer non-melanoma skin cancer where treatment consisted of resection only or radiotherapy ductal carcinoma in situ (DCIS) where treatment consisted of resection only cervical carcinoma in situ where treatment consisted of resection only superficial bladder carcinoma where treatment consisted of resection only A previous malignancy where the patient has been disease free for ≤ 5 years Pregnant or breastfeeding women or women of childbearing potential not willing to use effective contraceptive measures. Women of childbearing potential are defined as fertile, following menarche and until becoming post-menopausal, unless permanently sterile Men defined as fertile (post-pubescent and not permanently sterile by vasectomy or bilateral orchidectomy) and not willing to use effective contraceptive measures if appropriate.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Icosapent Ethyl (EPA-EE)<br>Soft gelatin capsules containing 1g pure EPA-EE equivalent to 914mg EPA-FFA. Administered as 4g per day to be taken as 2 capsules in the morning and 2 capsules in the evening. | Drug: Icosapent Ethyl<br>* Composition: soft amber to light yellow, oblong gelatin capsules. One capsule contains 1g pure EPA-EE Dose: 4 capsules per day<br>* Other names: Vascepa;|
| Placebo Comparator: Placebo<br>Soft gelatin capsules containing light mineral oil. 4 capsules to be taken per day (2 in the morning and 2 in the evening). | Other: Placebo<br>* Composition: soft, amber to light yellow, oblong gelatin capsules containing light mineral oil: Dose: 4 capsules per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS is defined as the time from randomisation to death (from any cause), first documented evidence of disease progression, new recurrence or clinical deterioration unequivocally due to disease progression | Minimum of 2 years follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The time from randomisation to death, from any cause (key secondary endpoint) | Minimum of 2 years follow-up | 
| Safety and Tolerability of Icosapent Ethyl | The number of participants with treatment-emergent adverse events as defined by CTCAE v4.0 | Minimum of 2 years follow-up | 
| Patient reported quality of life 1 | Measured using the EQ-5D questionnaire | Minimum of 2 years follow-up | 
| Patient reported quality of life 2 | Measured using the EORTC QLQ-C30 questionnaire | Minimum of 2 years follow-up | 
| Patient reported quality of life 3 | Measured using the QLQ-LMC21 questionnaire | Minimum of 2 years follow-up | 
| New Primary Cancers | Excluding DCIS, cervical carcinoma in situ, superficial bladder carcinoma where treatment consisted of resection only and non-melanoma skin cancer where treatment consisted of resection or radiotherapy only) | Minimum of 2 years follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver metastases, Colon Cancer