Colorectal Cancer
Conditions
Keywords
metastatic colorectal cancer, first-line, right primary tumour location, AREG, EREG, RAS wild-type, anti-EGFR
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
Interventions
Administration according to the labels of each IMP.
DRUGBevacizumab
Administration according to the labels of each IMP.
Administration according to the labels of each IMP.
DRUGOxaliplatin
Administration according to the labels of each IMP.
Administration according to the labels of each IMP.
DRUGCapecitabine
Administration according to the labels of each IMP.
Sponsors
Merck Serono International SA
Gruppo Oncologico del Nord-Ovest
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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'. |
| 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. |
| 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. |
Contacts
Primary ContactLaura Delliponti
Backup ContactAriel Engic
Outcome results
None listed