Anti-EGFR Agents in Patients With Right-sided Advanced Colorectal Cancer With Wild-type RAS and AREG/EREG High Status

Official title

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).

Overview

The aim of this trial is to assess the feasibility of EREG/AREG assessment as a clinical diagnostic standard, used to guide clinical decision making in right-PTL, RAS-wt aCRC. Further to this, the aim is to determine whether EREG/AREG status identifies right-PTL participants who will benefit from the addition of anti-EGFR therapy to first-line chemotherapy.

Detailed description

ARIEL-ENGIC is a multi-centre, phase IV, open label, randomised controlled biomarker enrichment trial with an internal pilot phase in which participants with wild-type RAS, right-PTL and EREG/AREG high aCRC will be randomized in a 1:1 ratio to receive chemotherapy (doublet) plus cetuximab versus chemotherapy (doublet or triplet) alone or with bevacizumab.

ARIEL-ENGIC is an international trial in which the UK (recruitment ongoing) and EU (Italy, Germany and Spain) are participating. ARIEL-ENGIC aims to randomize 280 participants at a global level. In Europe 60 centers will be involved and 120 participants (40 pts per Member State involved) will be randomized.

Given the biomarker prevalence, 660 participants will be registered to identify sufficient RAS-wt participants with high tumour EREG/AREG expression.

The ARIEL-ENGIC study has 2 phases, registration and randomization (the main trial). Participants meeting all of the inclusion criteria and none of the exclusion criteria for registration will be considered for trial eligibility and biomarker analysis. Tumour samples will be sent for centralized biomarker (EREG/AREG) assessment. Participants with high tumour EREG/AREG will be eligible for randomisation. Participants eligible for the randomisation phase will be allocated 1:1 to chemotherapy alone or with bevacizumab or chemotherapy plus anti-EGFR agent.

Stratification factors will be:

* Choice of first-line chemotherapy (irinotecan-based doublet; oxaliplatin-based doublet; FOLFOXIRI) * Tumour location (transverse vs caecum vs ascending) * Prior adjuvant or neoadjuvant chemotherapy (yes vs no) * Primary tumour resected * Country of registration

Interventions

• Drug Cetuximab (EGFR inhibitor)
  Administration according to the labels of each IMP.
• Drug Bevacizumab
  Administration according to the labels of each IMP.
• Drug Irinotecan (CPT-11)
  Administration according to the labels of each IMP.
• Drug Oxaliplatin
  Administration according to the labels of each IMP.
• Drug Leucovorin and 5-FU
  Administration according to the labels of each IMP.
• Drug Capecitabine
  Administration according to the labels of each IMP.

Primary outcome measures

• Early tumour shrinkage (ETS) [Time frame: 8 weeks after treatment start]
• Overall survival (OS) [Time frame: 50 months]

Secondary outcome measures (9)

• Depth of response (DpR) [Time frame: 24 months]
• Objective Response Rate (ORR) [Time frame: 24 months]
• Progression-free survival (PFS) [Time frame: 24 months]
• Overall Toxicity Rate [Time frame: 24 months]
• Toxicity Rate [Time frame: 24 months]
• Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [Time frame: Questionnaires will be administered at baseline, 8 weeks, 16 weeks, 12- and 24-months post-randomisation.]
• Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Module for Colorectal cancer 29 (EORTC QLQ-CR29). [Time frame: Questionnaires will be administered at baseline, 8 weeks, 16 weeks, 12- and 24- months post-randomisation.]
• Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life - Additional items to cover anti-EGFR (IL126) [Time frame: Questionnaires will be administered at baseline, 8 weeks, 16 weeks, 12- and 24- months post-randomisation.]
• Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life EQ-5D-3L (3-level version of EQ-5D by the EuroQol Group) [Time frame: Questionnaires will be administered at baseline, 8 weeks, 16 weeks, 12- and 24- months post-randomisation.]

Eligibility 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
• Fit for combination chemotherapy plus anti-EGFR agent
• Sufficient tumour material for EREG/AREG analysis
• Written informed consent for registration

Exclusion Criteria for Registration

• Tumour RAS-mutation present
• Prior chemotherapy for aCRC
• Prior anti-EGFR agent therapy

Inclusion Criteria for Randomisation:

• Registered in ARIEL-ENGIC
• Local testing confirms tumour RAS-wt status
• ARIEL-ENGIC central testing confirms tumour EREG/AREG high
• Tumour measurable by RECIST v1.1 criteria on CT scan
• 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.)
• 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)
• WHO performance status (PS) 0, 1 or 2
• Fit for combination chemotherapy plus anti-EGFR agent
• Life expectancy of at least 12 weeks
• Women of childbearing potential must have a negative blood pregnancy test at the baseline visit.
• Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception
• Written informed consent for randomization.

Exclusion Criteria for Randomisation:

• Participant has received more than one cycle of chemotherapy since registration
• Participants with history of hypersensitivity to any component of their proposed trial treatment regimen or any of their excipients
• Participants in receipt of live vaccine within four weeks prior to randomisation
• Participants with a history interstitial pneumonitis/idiopathic lung disease (ILD) or pulmonary fibrosis
• Participants with a history of keratitis, ulcerative keratitis or severe dry eye
• Participants with a history of severe skin reaction which in the clinicians' opinion could be exacerbated by EGFR Mab (cf Steven's Johnson Syndrome)
• Complete dihydropyrimidine dehydrogenase (DPYD) deficiency
• Untreated brain metastases or spinal cord compression or primary brain tumours
• History or evidence upon physical examination of CNS disease unless adequately treated
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration
• 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
• Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer)
• Other co-existing malignancies or malignancies diagnosed within the last 5 years that are likely to have an impact upon survival or treatment delivery
• Known human immunodeficiency virus (HIV)
• Has documented presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to enrolment
• Has a 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 - Definite contraindications for the use of corticosteroids and antihistamines as premedication.
• Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07094893 · ARIEL-ENGIC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗