Advanced colorectal cancer Cancer
Conditions
Interventions
Current interventions as of 22/07/2026:
Patients will be consented for registration and access to stored tumour material. RAS-wt or unknown RAS-status patients can be registered (central testing offer
Sponsors
University of Leeds
Eligibility
Sex/Gender
All
Age
18 Years to 120 Years
Inclusion criteria
Inclusion criteria: Current key inclusion criteria as of 22/07/2026: Inclusion criteria for registration: 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. aCRC defined as either M1 or locally inoperable disease. 4. Tumour RAS status either wild-type ( by local testing) or unknown 5. Tumour measurable by RECIST v1.1 criteria on CT scan (scans are not required to be reported to RECIST at site) 6. Pre-registration laboratory tests: 6.1. Neutrophils >=1.5 x10^9/l and platelet count >=100 x10^9/l 6.2. Serum bilirubin =50ml/min 7. Medically fit for the trial treatments 8. Sufficient tumour material for EREG/AREG analysis 9. Written informed consent for registration Inclusion criteria for randomisation: 1. Registered in ARIEL-ENGIC04 UK 2. ARIEL-ENGIC04 UK local testing confirms tumour RAS-wt status 3. ARIEL-ENGIC04 UK central testing confirms tumour EREG/AREG high 4. Patients have had CT scan within the timeframes stipulated in the protocol. (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 two trial timepoints at weeks 8 and 16.) 5. WHO performance status (PS) 0, 1 or 2 6. For women of childbearing potential, negative pregnancy test as per standard practice and adequate contraceptive precautions. 7. Effective contraception for male patients if the risk of conception exists. 8. Fit for combination chemotherapy plus cetuximab/panitumumab 9. Written informed consent for randomisation 10. DPYD testing performed as per national guidelines 11. Life expectancy of at least 12 weeks _____ Previous inclusion criteria as of 30/04/2024: Inclusion criteria for registration: 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. aCRC defined as either M1 or locally inoperable disease. 4. Tumour RAS status either wild-type ( by local testing) or unknown 5. Tumour measurable by RECIST v1.1 criteria on CT scan (scans are not required to be reported to RECIST at site) 6. Pre-registration laboratory tests: 6.1. Neutrophils >=1.5 x10^9/l and platelet count >=100 x10^9/l 6.2. Serum bilirubin =50ml/min 7. Medically fit for the trial treatments 8. Sufficient tumour material for EREG/AREG analysis 9. Written informed consent for registration Inclusion criteria for randomisation: 1. Registered in ARIEL 2. ARIEL central or local testing confirms tumour RAS-wt status 3. ARIEL central testing confirms tumour EREG/AREG high 4. Patients have had CT scan within the timeframes stipulated in the protocol. (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 two trial timepoints at weeks 8 and 16.) 5. WHO performance status (PS) 0, 1 or 2 6. For women of childbearing potential, negative pregnancy test as per standard practic
Exclusion criteria
Exclusion criteria: Current key exclusion criteria as of 22/07/2026: Exclusion criteria for registration: 1. Tumour RAS-mutation present 2. Prior chemotherapy for mCRC (may have received neoadjuvant or adjuvant chemotherapy provided disease did not progress on treatment, and > 6 months since last dose) 3. Prior anti-EGFR agent therapy Exclusion criteria for randomisation: 1. Patient has received more than one cycle of chemotherapy since registration 2. Women who are breastfeeding 3. Patients with history of hypersensitivity to irinotecan, oxaliplatin, 5-fluorouracil or any of their excipients 4. Patients in receipt of live vaccine within four weeks prior to randomisation. 5. Patients with a history interstitial pneumonitis/idiopathic lung disease (ILD) 6. Patients with a history of keratitis, ulcerative keratitis or severe dry eye 7. Patients with a history of severe skin reaction which in the clinicians opinion could be exacerbated by EGFR Mab (cf Steven’s Johnson Syndrome) 8. Untreated brain metastases or spinal cord compression or primary brain tumours 9. History or evidence upon physical examination of CNS disease unless adequately treated 10. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration 11. 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 12. Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer) 13. Other co-existing malignancies or malignancies diagnosed within the last 5 years that are likely to have an impact upon survival or treatment delivery 14. Known human immunodeficiency virus (HIV) except where specific criteria listed in the protocol are satisfied 15. Has documented presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to enrolment 16. Has a positive hepatitis C virus (HCV) antibody test result at screening or within 3 months prior to enrolment 17. Definite contraindications for the use of corticosteroids and antihistamines as premedication 18. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies _____ Previous inclusion criteria: Exclusion criteria for registration: 1. Tumour RAS-mutation present 2. Prior chemotherapy for mCRC (may have received neoadjuvant or adjuvant chemotherapy provided disease did not progress on treatment, and > 6 months since last dose) 3. Prior anti-EGFR agent therapy Exclusion criteria for randomisation: 1. Patient has received more than one cycle of chemotherapy since registration 2. Women who are breastfeeding 3. Patients with history of hypersensitivity to irinotecan, oxaliplatin, 5-fluorouracil or any of their excipients 4. Patients in receipt of live vaccine within four weeks prior to randomisation. 5. Patients with a history interstitial pneumonitis/idiopathic lung disease (ILD) 6. Patients with a history of keratitis, ulcerative keratitis or severe dry eye 7. Patients with a history of severe skin reaction which in the clinicians opinion could be exacerbated by EGFR Mab (cf Steven’s Johnson Syndrome)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Current primary outcomes as of 22/07/2026: 1. Early tumour shrinkage (ETS), measured 8 weeks after the start of treatment. This is taken as a binary variable with ETS defined as a 30% or greater reduction in the sum of maximum diameters (SMD) of RECIST target lesions when compared with the SMD recorded at baseline. SMD is measured from CT scans using calipers. 2. Overall survival (OS), measured from time of randomisation to death from any cause. Participants who are alive or lost to follow-up at the time of analysis will be censored at the last date they were known to be alive. Previous primary outcome: Early tumour shrinkage (ETS), measured 8 weeks after the start of treatment. This is taken as a binary variable with ETS defined as a 30% or greater reduction in the sum of maximum diameters (SMD) of RECIST target lesions when compared with the SMD recorded at baseline. SMD is measured from CT scans using calipers. | — |
Secondary
| Measure | Time frame |
|---|---|
| Current key secondary outcomes as of 22/07/2026: 1. Depth of response at 16 weeks from the start of treatment, measured as the maximum tumour shrinkage observed in a patient compared with baseline. This will be taken as a continuous measure. 2. Overall Treatment Utility (OTU), assessed at 8 weeks from the start of treatment. This is based on responses by clinician and participant regarding whether they were glad they gave or received their treatment allocation. OTU is scored as good, intermediate or poor, dependent on subjective measures of benefit or harm. 3. Overall survival (OS), measured from time of randomisation to death from any cause. 4. Patient-reported health-related quality of life (HRQOL), 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 and 12 months post-randomisation. 5. Cost-effectiveness, assessed by cost per incremental quality-adjusted life-year over a lifetime. 6. Toxicity, reported based on adverse events, as graded by CTCAE V5.0, and determined by routine clinical assessments at each centre 7. Objective Response Rate (ORR) 8. Progression-Free Survival (PFS) Previous key secondary outcomes as of 30/04/2024: 1. Depth of response at 16 weeks from the start of treatment, measured as the maximum tumour shrinkage observed in a patient compared with baseline. This will be taken as a continuous measure. 2. Overall Treatment Utility (OTU), assessed at 8 weeks from the start of treatment. This is based on responses by clinician and participant regarding whether they were glad they gave or received their treatment allocation. OTU is scored as good, intermediate or poor, dependent on subjective measures of benefit or harm. 3. Overall survival (OS), measured from time of randomisation to death from any cause. 4. Patient-reported health-related quality of life (HRQOL), measured using | — |
Countries
England, Northern Ireland, Scotland, United Kingdom, Wales
Outcome results
None listed