Clinical trial NCT03428477: EPA for Metastasis Trial 2
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Liver Metastasis
Colon Cancer
Keywords: Liver metastases
Colon Cancer
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: Yorkshire Cancer Research
name: Amarin Pharma Inc.
First posted: 2018-02-09
Enrollment: 418
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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. 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Minimum of 2 years follow-up
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Minimum of 2 years follow-up
measure: Safety and Tolerability of Icosapent Ethyl
timeFrame: Minimum of 2 years follow-up
measure: Patient reported quality of life 1
timeFrame: Minimum of 2 years follow-up
measure: Patient reported quality of life 2
timeFrame: Minimum of 2 years follow-up
measure: Patient reported quality of life 3
timeFrame: Minimum of 2 years follow-up
measure: New Primary Cancers
timeFrame: Minimum of 2 years follow-up
Other outcomes:
measure: Red Blood Cell Membrane EPA content (exploratory endpoint)
timeFrame: Samples taken at baseline, surgery and 6 months after surgery
measure: Change in lean body mass (exploratory endpoint)
timeFrame: 6 months and up to 4 years follow up
Locations:
city: Oxford
country: United Kingdom
facility: Oxford University Hospital NHS Foundation Trust
state: Oxfordshire
city: Basingstoke
country: United Kingdom
facility: Hampshire Hospitals NHS Foundation Trust
state: Royal Hampshire
city: Aintree
country: United Kingdom
facility: Aintree University Hospitals NHS Foundation Trust
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge UniversityHospitals NHS Foundation Trust
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: King's College London
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
city: Newcastle
country: United Kingdom
facility: Newcastle Upon Tyne Hospitals NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
Study officials:
affiliation: University of Leeds
name: Mark Hull
role: PRINCIPAL_INVESTIGATOR
References: