Ignite Creation Date:
2024-05-06 @ 1:18 PM
Last Modification Date:
2024-10-26 @ 1:12 PM
Study NCT ID:
NCT03986541
Status:
COMPLETED
Last Update Posted:
2024-05-28
First Post:
2019-06-13
Brief Title:
AREG EREG and EGFR Response to Anti-EGFR Agents in Colorectal Cancer
Sponsor:
University of Leeds
Organization:
University of Leeds
Study Overview
Official Title:
Association Between Tumour Amphiregulin Epiregulin and Epidermal Growth Factor Receptor EGFR Expression and Response to Anti-EGFR Agents in Colorectal Cancer
Status:
COMPLETED
Status Verified Date:
2024-05
Last Known Status:
Active not recruiting
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Observational study investigating the relationship between tumour amphiregulin epiregulin and epithelial growth factor receptor expression and response to anti-EGFR agents in advanced colorectal cancer
Detailed Description:
Background
The anti-EGFR agents cetuximab and panitumumab are approved by NICE for the first-line treatment of patients with RAS wild-type RAS-wt advanced colorectal cancer aCRC However RAS-wt status is not sufficient to guarantee anti-EGFR benefit Differential tumour expression of the EGFR ligands amphiregulin AREG and epiregulin EREG as well as the EGFR receptor itself are putative predictive biomarkers for response to anti-EGFR agents and may therefore help better identify patients who will benefit from treatment
Objectives
This study aims to assess the utility of tumour AREG EREG andor EGFR expression alone or in combination as predictive biomarkers for response to anti-EGFR agents in aCRC The investigators will develop a scoring system and categorical cut off points to differentiate AREGEREGEGFR positive and negative cases and correlate these with response to therapy as assessed by
Primary endpoint Progression Free Survival PFS Secondary endpoints Overall Survival OS Objective Response Rate ORR Disease Control Rate DCR Finally the investigators will utilise digital pathology and artificial intelligence AI technologies to automate as far as possible the process of evaluating AREGEREGEGFR status
During the study the investigators will monitor the costs of implementing the test and time taken to derive test results in order to facilitate cost-effectiveness calculations and assess the feasibility of delivering the test in future routine clinical practice
Study Design
A multicentre UK observational cohort study retrospective and prospectively recruited cohorts
Study population
Patients with RAS-wt aCRC who received or are receiving standard care palliative treatment with an anti-EGFR agent and chemotherapy of physicians choice Within the retrospective cohort patients who received single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria will be accepted
Key Inclusion Criteria
Biopsy proven advanced colorectal adenocarcinoma at time treatment commenced either inoperable metastatic disease at diagnosis or inoperable recurrent disease
Aged 18 or over at time treatment commenced
The patient has received or has consented to receive treatment with cetuximab or panitumumab
Key Exclusion Criteria
Stage I II or III colorectal adenocarcinoma
RAS mutant disease
Eligible for potentially curative surgery prospective cohort
Underwent cancer surgery subsequent to anti-EGFR therapy retrospective cohort
Unable to provide informed consent with the exception of patients in the retrospective cohort who have passed away
Procedures
The study is observational and does not involve participants undergoing any study-specific investigations or treatments Results of routine investigations and outcomes from standard care with an anti-EGFR agent will be collected from medical notes and for the prospective cohort during routine clinic appointments Date of death will also be recorded Initial and follow-up radiological and clinical assessments will occur as per local standard practice Previously obtained pathological specimens will be retrieved for immunohistochemical analysis of tumour AREG EREG and EGFR expression
Treatment During Study
This study will observe outcomes from standard first line palliative treatment of RAS-wt aCRC In line with current NICE guidelines such treatment will involve physicians choice of panitumumab or cetuximab in combination with
5-fluorouracil folinic acid and oxaliplatin FOLFOX or
5-fluorouracil folinic acid and irinotecan FOLFIRI Where RAS mutation status is only available after commencement of treatment and the anti-EGFR agent is therefore commenced in cycle two patients may still be recruited to the study
It is anticipated that most patients in the retrospective cohort will have received current standard first line palliative treatment of RAS-wt aCRC as above However patients who were treated with single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria may still be recruited
Statistical Methods
Sample size
Data from 480 patients will be collected for the retrospective cohort and 480 patients will be recruited to the prospective cohort
Primary endpoint analysis
PFS will be calculated from date of commencing treatment to date of progression or death from any cause whichever is sooner Time of progression will be determined clinically or radiologically by the participants treating oncologist Where the anti-EGFR agent was commenced in cycle 2 the definition of the start of treatment will remain cycle 1 day 1 of palliative chemotherapy
Key secondary endpoint analyses
OS will be determined from date of commencing treatment to death ORR is the proportion of patients with documented radiological complete or partial response on first follow-up imaging whereas DCR is the proportion of patients with either radiologically stable disease or a response For the purpose of these analyses those without follow-up imaging will be assumed to have progressed
AREGEREGEGFR expression will be assessed as a continuous variable and using dichotomous classifiers high and low for each marker individually and in combination Subgroup analyses will be performed for BRAF mutation positive tumours primary tumour location right versus left colon and rectum and previous surgery primary excised versus in situ Within the retrospective cohort those who received single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria will be analysed separately
The anti-EGFR agents cetuximab and panitumumab are approved by NICE for the first-line treatment of patients with RAS wild-type RAS-wt advanced colorectal cancer aCRC However RAS-wt status is not sufficient to guarantee anti-EGFR benefit Differential tumour expression of the EGFR ligands amphiregulin AREG and epiregulin EREG as well as the EGFR receptor itself are putative predictive biomarkers for response to anti-EGFR agents and may therefore help better identify patients who will benefit from treatment
Objectives
This study aims to assess the utility of tumour AREG EREG andor EGFR expression alone or in combination as predictive biomarkers for response to anti-EGFR agents in aCRC The investigators will develop a scoring system and categorical cut off points to differentiate AREGEREGEGFR positive and negative cases and correlate these with response to therapy as assessed by
Primary endpoint Progression Free Survival PFS Secondary endpoints Overall Survival OS Objective Response Rate ORR Disease Control Rate DCR Finally the investigators will utilise digital pathology and artificial intelligence AI technologies to automate as far as possible the process of evaluating AREGEREGEGFR status
During the study the investigators will monitor the costs of implementing the test and time taken to derive test results in order to facilitate cost-effectiveness calculations and assess the feasibility of delivering the test in future routine clinical practice
Study Design
A multicentre UK observational cohort study retrospective and prospectively recruited cohorts
Study population
Patients with RAS-wt aCRC who received or are receiving standard care palliative treatment with an anti-EGFR agent and chemotherapy of physicians choice Within the retrospective cohort patients who received single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria will be accepted
Key Inclusion Criteria
Biopsy proven advanced colorectal adenocarcinoma at time treatment commenced either inoperable metastatic disease at diagnosis or inoperable recurrent disease
Aged 18 or over at time treatment commenced
The patient has received or has consented to receive treatment with cetuximab or panitumumab
Key Exclusion Criteria
Stage I II or III colorectal adenocarcinoma
RAS mutant disease
Eligible for potentially curative surgery prospective cohort
Underwent cancer surgery subsequent to anti-EGFR therapy retrospective cohort
Unable to provide informed consent with the exception of patients in the retrospective cohort who have passed away
Procedures
The study is observational and does not involve participants undergoing any study-specific investigations or treatments Results of routine investigations and outcomes from standard care with an anti-EGFR agent will be collected from medical notes and for the prospective cohort during routine clinic appointments Date of death will also be recorded Initial and follow-up radiological and clinical assessments will occur as per local standard practice Previously obtained pathological specimens will be retrieved for immunohistochemical analysis of tumour AREG EREG and EGFR expression
Treatment During Study
This study will observe outcomes from standard first line palliative treatment of RAS-wt aCRC In line with current NICE guidelines such treatment will involve physicians choice of panitumumab or cetuximab in combination with
5-fluorouracil folinic acid and oxaliplatin FOLFOX or
5-fluorouracil folinic acid and irinotecan FOLFIRI Where RAS mutation status is only available after commencement of treatment and the anti-EGFR agent is therefore commenced in cycle two patients may still be recruited to the study
It is anticipated that most patients in the retrospective cohort will have received current standard first line palliative treatment of RAS-wt aCRC as above However patients who were treated with single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria may still be recruited
Statistical Methods
Sample size
Data from 480 patients will be collected for the retrospective cohort and 480 patients will be recruited to the prospective cohort
Primary endpoint analysis
PFS will be calculated from date of commencing treatment to date of progression or death from any cause whichever is sooner Time of progression will be determined clinically or radiologically by the participants treating oncologist Where the anti-EGFR agent was commenced in cycle 2 the definition of the start of treatment will remain cycle 1 day 1 of palliative chemotherapy
Key secondary endpoint analyses
OS will be determined from date of commencing treatment to death ORR is the proportion of patients with documented radiological complete or partial response on first follow-up imaging whereas DCR is the proportion of patients with either radiologically stable disease or a response For the purpose of these analyses those without follow-up imaging will be assumed to have progressed
AREGEREGEGFR expression will be assessed as a continuous variable and using dichotomous classifiers high and low for each marker individually and in combination Subgroup analyses will be performed for BRAF mutation positive tumours primary tumour location right versus left colon and rectum and previous surgery primary excised versus in situ Within the retrospective cohort those who received single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria will be analysed separately
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None