ARIEL

Trial Info

Status: Open

Specialty: Colorectal

Date Opened: 29/07/2022

Planned Close Date:

Sponsor: University of Leeds

Principal Investigator: Dr Lau

Study Title: ARIEL

Trial Description

For patients with advanced colorectal (bowel) cancer (aCRC) who have a gene (RAS) which is normal i.e. RAS wild-type (RAS-wt), standard first-line treatment is chemotherapy, sometimes given in combination with a type of drug called an anti-EGFR agent (cetuximab or panitumumab). However, not all RAS-wt patients benefit from anti-EGFR therapy. Anti-EGFR therapy has severe side-effects and is expensive. It should not be used for patients who will not benefit, or may even be harmed. Better selection of patients is therefore needed.

We know that patients with tumours that start in the right side of the body (right-sided) in general do not respond very well to anti-EGFR treatment. In the UK, there is no agreed standard of care for the treatment of right-sided patients, some doctors routinely use an anti-EGFR drug, but some do not.

However, we also know that patients who have high levels of the proteins epiregulin (EREG) and/or amphiregulin (AREG) respond well to anti-EGFR treatment. EGFR therapy decisions based purely on RAS status and tumour location, risk harming some patients through over-treatment, or risk withholding potentially beneficial therapy from others.

By measuring levels of EREG and AREG, we may be able to identify patients with right-sided tumours who will benefit from anti-EGFR treatment, and also identify patients who will not benefit and may be harmed if given anti-EGFR therapy.

However, before we can introduce this test into routine practice, we need to know that EREG and AREG levels can be measured and the results delivered to doctors quickly enough to inform treatment decisions. We also need to confirm that EGFR therapy is beneficial for patients with EREG/AREG-high, right-sided cancer. This trial aims to answer these questions.

Inclusion Criteria

Inclusion criteria for registration:

• Age > = 18 years

• Biopsy-confirmed adenocarcinoma of the colon with a right primary tumour location

• aCRC defined as either M1 or locally inoperable disease.

• Tumour RAS status either wild-type ( by local testing) or unknown

• Tumour measurable by RECIST v1.1 criteria

• Pre-registration laboratory tests:

o Neutrophils > = 1.5 x10^9/l and platelet count > = 100 x10^9/l

o Serum bilirubin < = 1.25 x upper limit of normal (ULN), alkaline phosphatase < = 5x ULN, and serum transaminase (either AST or ALT) < = 2.5 x ULN

o Estimated creatinine clearance > = 50ml/min.

• Medically fit for the trial treatments

• Sufficient tumour material for EREG/AREG analysis

• Written informed consent for registration

Inclusion criteria for randomisation:

• Registered in ARIEL

• ARIEL central or local testing confirms tumour RAS-wt status

• ARIEL central testing confirms tumour EREG/AREG high

• Patients have had CT scan within the timeframes stipulated in protocol

• WHO performance status (PS) 0, 1 or 2

• For women of childbearing potential, negative pregnancy test as per standard practice and adequate contraceptive precautions.

• Effective contraception for male patients if the risk of conception exists.

• Fit for combination chemotherapy plus cetuximab/panitumumab

• Written informed consent for randomisation

Exclusion Criteria

Exclusion criteria for registration:

• Tumour RAS-mutation present

• Prior chemotherapy for mCRC (may have received neoadjuvant or adjuvant chemotherapy provided disease did not progress on treatment, and > 6 months since last dose)

• Prior anti-EGFR agent therapy

Exclusion criteria for randomisation:

• Patient has received more than one cycle of chemotherapy since registration

• Women who are breastfeeding

• Patients with history of hypersensitivity to irinotecan, oxaliplatin, 5-fluorouracil or any of their excipients

• Patients in receipt of live vaccine within four weeks prior to randomisation.

• Patients with a history interstitial pneumonitis/idiopathic lung disease (ILD)

• Patients with a history of keratitis, ulcerative keratitis or severe dry eye

• Patients with a history of severe skin reaction which in the clinicians opinion could be exacerbated by EGFR Mab (cf Steven’s Johnson Syndrome)

Contacts

Research Nurse: Emma Davies (Ext No. 55649) Emma.davies16@nhs.net

Administrator: Arun Prakash

Link to EDGE

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