Anti-EGFR Agents in Patients With Right-sided Advanced Colorectal Cancer With Wild-type RAS and AREG/EREG High Status
- Conditions
- Colorectal Cancer
- Interventions
- Registration Number
- NCT07094893
- Lead Sponsor
- Gruppo Oncologico del Nord-Ovest
- Brief Summary
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
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 280
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Doublet or Triplet +/- Bevacizumab Bevacizumab FOLFOX or CAPOX or FOLFIRI or FOLFOXIRI +/- bevacizumab. Treatment regimen and the dosage of each product in both arms will be at Investigators' discretion and in accordance with European guidelines (ESMO). Chemotherapy backbone is at investigators' choice as per clinical practice and guidelines according to the labels of each IMP. Choice of regimen will depend upon individual patient characteristics and choices, as judged by their oncologist. The choice of adding or not bevacizumab will be at investigators' evaluation according to its label and after evaluating any contraindication to its administration. The study treatment consists of the first 16 weeks of 1st line induction chemotherapy, followed by continuation of chemotherapy +/- bevacizumab, maintenance treatment or treatment break as per investigator and patient preference. Doublet or Triplet +/- Bevacizumab Irinotecan (CPT-11) FOLFOX or CAPOX or FOLFIRI or FOLFOXIRI +/- bevacizumab. Treatment regimen and the dosage of each product in both arms will be at Investigators' discretion and in accordance with European guidelines (ESMO). Chemotherapy backbone is at investigators' choice as per clinical practice and guidelines according to the labels of each IMP. Choice of regimen will depend upon individual patient characteristics and choices, as judged by their oncologist. The choice of adding or not bevacizumab will be at investigators' evaluation according to its label and after evaluating any contraindication to its administration. The study treatment consists of the first 16 weeks of 1st line induction chemotherapy, followed by continuation of chemotherapy +/- bevacizumab, maintenance treatment or treatment break as per investigator and patient preference. Doublet or Triplet +/- Bevacizumab Oxaliplatin FOLFOX or CAPOX or FOLFIRI or FOLFOXIRI +/- bevacizumab. Treatment regimen and the dosage of each product in both arms will be at Investigators' discretion and in accordance with European guidelines (ESMO). Chemotherapy backbone is at investigators' choice as per clinical practice and guidelines according to the labels of each IMP. Choice of regimen will depend upon individual patient characteristics and choices, as judged by their oncologist. The choice of adding or not bevacizumab will be at investigators' evaluation according to its label and after evaluating any contraindication to its administration. The study treatment consists of the first 16 weeks of 1st line induction chemotherapy, followed by continuation of chemotherapy +/- bevacizumab, maintenance treatment or treatment break as per investigator and patient preference. Doublet or Triplet +/- Bevacizumab Leucovorin and 5-FU FOLFOX or CAPOX or FOLFIRI or FOLFOXIRI +/- bevacizumab. Treatment regimen and the dosage of each product in both arms will be at Investigators' discretion and in accordance with European guidelines (ESMO). Chemotherapy backbone is at investigators' choice as per clinical practice and guidelines according to the labels of each IMP. Choice of regimen will depend upon individual patient characteristics and choices, as judged by their oncologist. The choice of adding or not bevacizumab will be at investigators' evaluation according to its label and after evaluating any contraindication to its administration. The study treatment consists of the first 16 weeks of 1st line induction chemotherapy, followed by continuation of chemotherapy +/- bevacizumab, maintenance treatment or treatment break as per investigator and patient preference. Doublet or Triplet +/- Bevacizumab Capecitabine FOLFOX or CAPOX or FOLFIRI or FOLFOXIRI +/- bevacizumab. Treatment regimen and the dosage of each product in both arms will be at Investigators' discretion and in accordance with European guidelines (ESMO). Chemotherapy backbone is at investigators' choice as per clinical practice and guidelines according to the labels of each IMP. Choice of regimen will depend upon individual patient characteristics and choices, as judged by their oncologist. The choice of adding or not bevacizumab will be at investigators' evaluation according to its label and after evaluating any contraindication to its administration. The study treatment consists of the first 16 weeks of 1st line induction chemotherapy, followed by continuation of chemotherapy +/- bevacizumab, maintenance treatment or treatment break as per investigator and patient preference. Doublet + Cetuximab Cetuximab (EGFR inhibitor) FOLFOX or FOLFIRI + Cetuximab. Treatment regimen and the dosage of each product in both arms will be at Investigators' discretion and in accordance with European guidelines (ESMO). Chemotherapy backbone is at investigators' choice as per clinical practice and guidelines according to the labels of each IMP. The study treatment consists of the first 16 weeks of 1st line induction chemotherapy, followed by continuation of chemotherapy + cetuximab, maintenance treatment or treatment break as per investigator and patient preference. Doublet + Cetuximab Irinotecan (CPT-11) FOLFOX or FOLFIRI + Cetuximab. Treatment regimen and the dosage of each product in both arms will be at Investigators' discretion and in accordance with European guidelines (ESMO). Chemotherapy backbone is at investigators' choice as per clinical practice and guidelines according to the labels of each IMP. The study treatment consists of the first 16 weeks of 1st line induction chemotherapy, followed by continuation of chemotherapy + cetuximab, maintenance treatment or treatment break as per investigator and patient preference. Doublet + Cetuximab Oxaliplatin FOLFOX or FOLFIRI + Cetuximab. Treatment regimen and the dosage of each product in both arms will be at Investigators' discretion and in accordance with European guidelines (ESMO). Chemotherapy backbone is at investigators' choice as per clinical practice and guidelines according to the labels of each IMP. The study treatment consists of the first 16 weeks of 1st line induction chemotherapy, followed by continuation of chemotherapy + cetuximab, maintenance treatment or treatment break as per investigator and patient preference. Doublet + Cetuximab Leucovorin and 5-FU FOLFOX or FOLFIRI + Cetuximab. Treatment regimen and the dosage of each product in both arms will be at Investigators' discretion and in accordance with European guidelines (ESMO). Chemotherapy backbone is at investigators' choice as per clinical practice and guidelines according to the labels of each IMP. The study treatment consists of the first 16 weeks of 1st line induction chemotherapy, followed by continuation of chemotherapy + cetuximab, maintenance treatment or treatment break as per investigator and patient preference.
- Primary Outcome Measures
Name Time Method Early tumour shrinkage (ETS) 8 weeks after treatment start 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.
Overall survival (OS) 50 months 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 Outcome Measures
Name Time Method Depth of response (DpR) 24 months Depth of response (DpR) is 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.
Objective Response Rate (ORR) 24 months Objective Response Rate (ORR) is defined as the percentage of participants, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria, during the study treatment. The determination of clinical response will be based on investigator reported measurements. Responses will be evaluated every 8 weeks.
Progression-free survival (PFS) 24 months Progression-free survival (PFS) is 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 participants who are alive, on study and progression free at the time of the analysis. Alive participants who have no tumor assessments after baseline will have time to event censored on the date of randomization.
Overall Toxicity Rate 24 months Overall Toxicity Rate is defined as the percentage of participants, 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.
Toxicity Rate 24 months Toxicity Rate is defined as the percentage of participants, 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)3, during the treatment.
Quality of Life as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Questionnaires will be administered at baseline, 8 weeks, 16 weeks, 12- and 24-months post-randomisation. The EORTC QLQ-C30 contains functional scales, symptom scales, single items scale and a global health status/QoL scale. Raw scores are standardized and converted into scale scores ranging from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms on the symptom scales.
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). Questionnaires will be administered at baseline, 8 weeks, 16 weeks, 12- and 24- months post-randomisation. The EORTC QLQ-CR29 includes 29 items that evaluate symptoms (gastrointestinal, urinary, pain and others) and functional areas (sexual, body image and others) that are associated with CRC and its treatments. There are separate items for patients with and without a stoma and separate items to evaluate the sexual function of men and women. Raw scores are standardized and converted into scale scores ranging from 0 to 100. Higher scores represent better functioning on the functional scales and a higher level of symptoms on the symptom scales.
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) Questionnaires will be administered at baseline, 8 weeks, 16 weeks, 12- and 24- months post-randomisation. The EORTC IL126 includes 20 items that evaluate additional items to cover anti-EGFR symptomatic toxicity. Higher scores represent better functioning on the functional scales and a higher level of symptoms on the symptom scales.
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) Questionnaires will be administered at baseline, 8 weeks, 16 weeks, 12- and 24- months post-randomisation. The EQ-5D-3L consists of: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.
The EQ VAS records the patient's self-rated health on a vertical visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'.