A biomarker enrichment trial of anti-EGFR agents in patients with advanced colorectal cancer (aCRC) with wild-type RAS and right primary tumour location (right-PTL) - ARIEL-ENGIC trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione GONO G.I.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-10-07

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

- To determine whether first-line chemotherapy (doublet) with cetuximab is more effective than chemotherapy (doublet or triplet) with or without bevacizumab in achieving early tumour shrinkage (ETS) after 8 weeks of treatment in randomised patients.
- To assess whether the effectiveness of first-line chemotherapy (doublet) with cetuximab is more effective than chemotherapy (doublet or triplet) with or without bevacizumab in terms of overall survival (OS).

Secondary objectives 5

1. Depth of response (DpR)
2. Objective response rate (ORR) according to RECIST version 1.1 criteria
3. Progression free-survival (PFS)
4. Patient-reported Health-related Quality of life (HRQOL) as measured by PROs questionnaires
5. Toxicity

Conditions and MedDRA coding

advanced colorectal cancer with wild-type RAS and right primary tumour location (right-PTL)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Age ≥18 years
2. Biopsy-confirmed adenocarcinoma of the colon with a right primary tumour location (defined as proximal to and including the splenic flexure)
3. colorectal adenocarcinoma (aCRC) defined as either M1 or locally inoperable disease
4. Tumour RAS status either wild-type (by local testing) or unknown
5. Fit for combination chemotherapy plus anti-EGFR agent
6. Sufficient tumour material for EREG/AREG analysis
7. Written informed consent for registration
8. Registered in ARIEL-ENGIC
9. Local testing confirms tumour RAS-wt status
10. Central testing confirms tumour EREG/AREG high
11. Tumour measurable by RECIST v1.1 criteria on CT scan
12. Participants have had CT scan within the timeframes stipulated (If there is a contrast reaction, then non-contrast CT with MRI is acceptable, assuming at least one of these modalities shows measurable disease at baseline for ETS evaluation and both modalities are repeated at the trial timepoints at week 8 and 16 and every 8 weeks until disease progression.)
13. Pre-randomisation laboratory tests: - Neutrophils ≥1.5 x109/l and platelet count ≥100 x109/l - 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 - Estimated creatinine clearance ≥50ml/min (creatinine clearance estimated as per local practice)
14. WHO performance status (PS) 0, 1 or 2
15. Fit for combination chemotherapy plus anti-EGFR agent
16. Life expectancy of at least 12 weeks
17. Women of childbearing potential must have a negative blood pregnancy test at the baseline visit
18. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
19. Written informed consent for randomization

Exclusion criteria 22

1. Tumour RAS-mutation present
2. Prior chemotherapy for aCRC
3. Prior anti-EGFR agent therapy
4. Participant has received more than one cycle of chemotherapy since registration
5. Participants with history of hypersensitivity to any component of their proposed trial treatment regimen or any of their excipients
6. Participants in receipt of live vaccine within four weeks prior to randomisation
7. Participants with a history interstitial pneumonitis/idiopathic lung disease (ILD) or pulmonary fibrosis
8. Participants with a history of keratitis, ulcerative keratitis or severe dry eye
9. Participants with a history of severe skin reaction which in the clinicians’ opinion could be exacerbated by EGFR Mab (cf Steven’s Johnson Syndrome)
10. Complete dihydropyrimidine dehydrogenase (DPYD) deficiency
11. Untreated brain metastases or spinal cord compression or primary brain tumours
12. History or evidence upon physical examination of CNS disease unless adequately treated
13. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration
14. Clinically significant (e.g. active) cardiovascular disease for example cerebrovascular accidents, myocardial infarction, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), serious cardiac arrhythmia requiring medication
15. Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer)
16. Other co-existing malignancies or malignancies diagnosed within the last 5 years that are likely to have an impact upon survival or treatment delivery
17. Known human immunodeficiency virus (HIV) except where all the below criteria are satisfied: - Is receiving a stable regimen of Highly Active Antiretroviral Therapy (HAART) - No history of acquired immunodeficiency syndrome–defining opportunistic infections within 12 months before enrolment 20 - Cluster of differentiation 4 (CD4) count ≥250 cells/μL and an undetectable viral load on standard PCR-based tests
18. Documented presence of hepatitis B surface antigen (HbsAg) at screening or within 3 months prior to enrolment
19. Positive hepatitis C virus (HCV) antibody test result at screening or within 3 months prior to enrolment. Note: Participants with a positive HCV antibody test result due to prior resolved disease can be randomised, only if a confirmatory HCV RNA test is obtained
20. Definite contraindications for the use of corticosteroids and antihistamines as premedication
21. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies
22. Woman pregnant or lactating or expecting to conceive children within the projected duration of the study through 6 months after the last dose of bevacizumab and/or fluorouracil

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Early tumour shrinkage (ETS) defined as the percentage of patients, relative to the total of the enrolled subjects, achieving a ≥30% decrease in the sum of maximum diameters (SMD) of RECIST target lesions at week 8 compared to the SMD recorded at baseline.
2. Overall survival (OS) defined as the time from randomization to the date of death due to any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive

Secondary endpoints 7

1. Depth of response (DpR) defined as the maximum tumour shrinkage of RECIST target lesions at the nadir, in the absence of new lesions or progression of non-target lesions, when compared with baseline, assessed at 16 weeks from start of treatment.
2. Objective Response Rate (ORR) defined as the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria, during the treatment. The determination of clinical response will be based on investigator reported measurements. Responses will be evaluated every 8 weeks
3. Progression-free survival defined as the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis.
4. Patient-reported QOL, measured using the EORTC QLQ-C30 and EORTC QLQ-CR29 disease specific module with additional items to cover anti-EGFR symptomatic toxicity using the EORTC-QLQ item library. This will be assessed at baseline, 8 weeks, 16 weeks, 12- and 24-months post-randomisation
5. Overall Toxicity Rate defined as the percentage of patients, relative to the total of enrolled subjects, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during the treatment.
6. Toxicity Rate defined as the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 5.0), during the treatment
7. Assessment of prognostic and predictive ability of other candidate biomarkers with regard to participant outcomes and anti-EGFR efficacy, including negative hyperselection by gene alterations in circulating tumour DNA (ctDNA) related to primary resistance to anti-EGFR therapy

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione GONO G.I.

Sponsor organisation

Fondazione GONO G.I.

Address

Via Goffredo Mameli 3/1

City

Genoa

Postcode

16122

Country

Italy

Scientific contact point

Organisation

Fondazione GONO G.I.

Contact name

Prof. Chiara Cremolini

Public contact point

Organisation

Fondazione GONO G.I.

Contact name

Prof. Chiara Cremolini

Locations

3 EU/EEA countries · 37 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 39 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications