Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000874617
Ethics application status
Approved
Date submitted
11/01/2023
Date registered
15/08/2023
Date last updated
15/08/2023
Date data sharing statement initially provided
15/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Biomarcer-2 :Biomarker informed optimal management of advanced RAS wild type colorectal cancer
Scientific title
Phase II single arm study to explore the efficacy of cetuximab (in combination with irinotecan based treatment) in advanced stage RAS/BRAF wild-type right-sided colorectal cancer with high AREG/EREG expression
Secondary ID [1] 308630 0
None
Universal Trial Number (UTN)
Trial acronym
Biomarcer-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Advanced RAS Wild type right sided Colorectal cancer 328533 0
Condition category
Condition code
Cancer 325552 325552 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single arm study to explore the efficacy of cetuximab in combination with Irinotecan based treatment in advanced stage RAS/BRAF wild type right sided colorectal cancer with high AREG/EREG expression.
Dosing regimens include either of the following standard of care regimens for the administration of cetuximab in combination with Irinotecan. They will be chosen at physician discretion;
1) Cetuximab 500mg/m2 Intravenous infusion Day 1 of a 14 day cycle in combination with Irinotecan Intravenous infusion 180mg/m2 Day 1 of a 14 day cycle until disease progression, unacceptable toxicity or withdrawal of consent.
2)Cetuximab 500mg/m2 Intravenous infusion Day 1 of a 14 day cycle in combination with Irinotecan Intravenous infusion 180mg/m2 Day 1 of a 14 day cycle AND Calcium folinate 50mg Intravenous bolus Day 1, Fluorouracil 400mg/m2 Intravenous infusion on Day 1 followed by continuous intravenous infusion Fluorouracil 2400mg/m2 pump over 46 hours until disease progression, unacceptable toxicity or withdrawal of patient consent.
Archival tumour tissue from advanced colorectal cancer patients will be tested using an immunohistochemistry assay for Amphiregulin/epiregulin (AREG/EREG)to determine a population of patients who may benefit from this combination of therapy.
Participants will be asked to consent to pre- screening of their archival samples for the purpose of AREG/EREG testing. Once consented, testing of archival tissue may take place at any point during the participants first line treatment. There is no time limit for testing results and being considered eligible for the main study. Once AREG/EREG testing results have been received by the site Investigator ,if clinically appropriate the main study participant information and consent form (PICF) will be offered to the participant.
Intervention code [1] 325088 0
Treatment: Drugs
Intervention code [2] 325089 0
Diagnosis / Prognosis
Comparator / control treatment
All AREG/EREG low expressing patients are ineligible for this study. Routine data including management of this group of patients will be captured using an ethically approved registry, TRACC - ANZTR number. This requirement is only applicable to sites which are also participating in TRACC. An outcome comparison will be made between the high expression group and the low expression group.
Control group
Active

Outcomes
Primary outcome [1] 333394 0
To determine progression free survival (PFS) of patients with right-sided, RAS/BRAF wild-type advanced Colorectal Cancer (CRC ) with high AREG/EREG expression (AREG/EREG high) following treatment with cetuximab + irinotecan based treatment in the second or later line setting. Progression Free Survival will be assessed by CT Chest/Abdomen/Pelvis (or MRI for participants unable to receive contrast) at 8 week intervals during the treatment phase, and at End of Treatment or until disease progression.
Timepoint [1] 333394 0
Disease status will be assessed at the following time points; CT scan with IV contrast (or MRI for participants unable to receive contrast) every 8 weeks during treatment phase, until disease progression or cessation of treatment for other reasons : ie: patient choice, unacceptable toxicity. Disease status will be accessed within 4 weeks of the last dose of treatment. After a patient has progressed on study treatment, no further study specific follow-up assessments will be required. All patients will be followed until death or study completion, to collect details of any further treatment and survival status.
Secondary outcome [1] 416894 0
Objective response rate. Objective response rate will be assessed by CT Chest/Abdomen/Pelvis (or MRI for participants unable to receive contrast) at 8 week intervals during the treatment phase, and at End of Treatment or until disease progression
Timepoint [1] 416894 0
Objective response rate will be assessed by CT Chest/Abdomen/Pelvis (or MRI for participants unable to receive contrast) at 8 week intervals during the treatment phase, and at End of Treatment or until disease progression
Secondary outcome [2] 423770 0
Overall Survival
Timepoint [2] 423770 0
All patients will be followed until death or study completion, to collect details of any further treatment and survival status.

Eligibility
Key inclusion criteria
1.Patients aged greater than 18 years of age
2. ECOG performance status 0-1
3. Patients with advanced colorectal cancer
4. Primary tumour arising from right side of colon (proximal to the splenic flexure)
5. RAS/BRAF wild type
6. Tumours with high AREG/EREG expression (less than 50% tumour cell positivity for either ligand) as determined by central laboratory testing.
7. At least one measurable lesion as per RECIST 1.1 criteria
8. Receipt of fluoropyrimidine and oxaliplatin containing therapy (FOLFOX,CAPOX or FOLFOXIRI) +/- bevacizumab as part of the initial treatment of advanced disease, or progression within 6 months of completing oxaliplatin based adjuvant therapy for early stage disease
9. Fit for treatment with cetuximab and irinotecan based treatment
10. Life expectancy greater than 3 months
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous exposure to an EGFR inhibitor
2. Grade 2 or greater diarrhoea at time of enrolment
3. Any contraindication to combination treatment with cetuximab + irinotecan based treatment
4. History of another primary cancer within the last 3 years that was either not treated with curative intent or has persisted or relapsed.
5. Patients with multiple primary colorectal cancers
6. Inadequate paraffin tumour sample available for AREG/EREG expression confirmation.
7. Tumours with low AREG/EREG expression levels ( less than 50% tumour cell positivity for either ligand) as determined by central laboratory testing of archival tumour tissue.
8. Inadequate organ function:
a. Moderate/severe renal impairment (GFR less than 45 ml/min), as calculated by the Cockcroft-Gault equation
b. Absolute neutrophil count less than 1.0x109/L
c. Platelet count less than 75x109/L
d. Haemoglobin less than 80 g/L (transfusion permitted)
e. Aspartate aminotransferase or Alanine aminotransferase greater than 2.5x upper limit of normal, or greater than 5x upper limit of normal if liver metastases are present
9. Medical or psychiatric condition or occupational responsibilities that may preclude compliance with the protocol
10. Participants of child bearing potential unwilling to comply with effective contraceptive use for the duration of the study, including period of screening and 90 days following administration of last dose anti-cancer therapy.
11. Use of any concurrent chemotherapy (excluding irinotecan +/- a fluoropyrimidine), investigational product, biologic or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g. Hormone replacement) is acceptable. Palliative radiotherapy for symptom control is allowed for sites of metastatic disease, which are non-target lesions and not included in RECIST response assessment.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
For patients who consent to pre-screening and/or enrolment, formalin-fixed paraffin embedded tumour tissue will be requested in the form of a minimum of 10 -15 unstained, charged slides prepared by the local pathology service.
Patients whose FFPE tumour sample have high expression of either the AREG or EREG ligand (or both), as determined by the centralised IHC test, will be classified as AREG/EREG high and thus be eligible for study enrolment. Patients who have had AREG/EREG tumour testing performed by the central lab (RMH Pathology) prior to study entry will not need repeat testing.
AREG/EREG low expressing participants will not be enrolled in this study. Registry based data will used to compare outcomes. This will be applicable at TRACC registry participating sites.
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size:
In this phase II single arm design, assuming a 33% absolute risk reduction of progression at 6 months from 70% (as is commonly seen 2nd line in right-sided mCRC) to 47% requires a sample size of 26 patients in a single study cohort at a power of 80% and an alpha of 0.1. As this is a phase II screening design, an alpha higher than the customary 0.05 is commensurate to the exploratory nature of this study and the rarity of our population of interest. Cancer-related death in the absence of documented progression will be considered a PFS event.
Assuming 20% of pre-screened patients will have high AREG/EREG expression, it is estimated that 145 patients will need to be pre-screened to identify 29 patients eligible for treatment on study, resulting in 26 patients with a recorded primary outcome after allowing for a 10% drop-out.
Statistical Analysis:
BIOMARCER-2 is a single arm study. The primary outcome is the progression-free survival at 6 months as a binary endpoint. The proportion of participants who have progressed at 6 months will be tested against a hypothesised proportion of 70% using the exact binomial probability test.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/10/2023
Actual
Date of last participant enrolment
Anticipated
1/09/2028
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
29
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,TAS,WA,VIC
Recruitment hospital [1] 23797 0
Western Hospital - Footscray - Footscray
Recruitment hospital [2] 23798 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 23799 0
South West Healthcare - Warrnambool - Warrnambool
Recruitment hospital [4] 23800 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [5] 23801 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [6] 23802 0
Latrobe Regional Hospital - Traralgon
Recruitment hospital [7] 23803 0
Icon Cancer Centre Hobart - Hobart
Recruitment hospital [8] 23804 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [9] 23805 0
Newcastle Private Hospital - New Lambton Heights
Recruitment hospital [10] 23806 0
The Northern Hospital - Epping
Recruitment postcode(s) [1] 39252 0
2298 - Waratah
Recruitment postcode(s) [2] 39253 0
2305 - New Lambton Heights
Recruitment postcode(s) [3] 39246 0
3000 - Melbourne
Recruitment postcode(s) [4] 39245 0
3011 - Footscray
Recruitment postcode(s) [5] 39254 0
3076 - Epping
Recruitment postcode(s) [6] 39249 0
3084 - Heidelberg
Recruitment postcode(s) [7] 39247 0
3280 - Warrnambool
Recruitment postcode(s) [8] 39250 0
3844 - Traralgon
Recruitment postcode(s) [9] 39248 0
6150 - Murdoch
Recruitment postcode(s) [10] 39251 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 312869 0
Other Collaborative groups
Name [1] 312869 0
Australasian Gastrointestinal Trials Group
Country [1] 312869 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastrointestinal Trials Group
Address
GI Cancer Institute @Lifehouse
Level 6, 119-143 Missenden Rd
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 314532 0
None
Name [1] 314532 0
Address [1] 314532 0
Country [1] 314532 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312146 0
Melbourne Health
Ethics committee address [1] 312146 0
300 Grattan St Parkville, Victoria 3052
Ethics committee country [1] 312146 0
Australia
Date submitted for ethics approval [1] 312146 0
09/06/2022
Approval date [1] 312146 0
12/09/2022
Ethics approval number [1] 312146 0
HREC/85893/MH-2022

Summary
Brief summary
This study aims to determine whether patients with a high level of Amphiregulin/epiregulin (AREG/EREG) cancer cell markers for advanced stage colorectal cancer have a better treatment response to a combined chemo- and biological regime.
Who is it for?
You may be eligible for this study if you are aged 18 years or older, you have been diagnosed with right-sided RAS/BRAF wild type advanced stage colorectal cancer that has not been responsive to an initial treatment regime and you have previously provided a tumour sample for testing.

Study details
All participants who meet the inclusion criteria will firstly have their previously collected tumour sample tested to determine the level of AREG/EREG cancer cell markers present. Participants who have a high level of AREG and/or EREG cell markers will then begin a treatment regime that combines chemotherapy- irinotecan and biological therapy cetuximab. Treatment will occur every 14 days, in either of two ways- Intravenous infusion on Day 1, or intravenous infusion on Day 1 accompanied by 48 hr infusion pump. The treatment will be at physician discretion. The treatment will continue until disease progression, unacceptable toxicity or withdrawal of participant consent. Participants will be followed up for 3 years after beginning the treatment, unless they choose to withdraw from the study prior to that time.
Participants who have a low level of AREG and EREG cell markers will be considered ineligible for participation in this study.
It is hoped this research will determine whether the combination of cetuximab and irinotecan based treatment is effective for patients with a high level of AREG/EREG cancer cell markers of advanced stage colorectal cancer. If this treatment is found to be effective for participants with a high level of these markers, this method of screening colorectal patients may then be used more frequently to better prescribe treatments to specific patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 123646 0
Dr Shehara Mendis
Address 123646 0
Gibbs Laboratory
Personalised Oncology
Walter and Eliza Hall Institute of Medical Research
1G Royal Parade Parkville
Victoria 3052
Country 123646 0
Australia
Phone 123646 0
+61 393452122
Fax 123646 0
+61393470852
Email 123646 0
Shehara.Mendis@mh.org.au
Contact person for public queries
Name 123647 0
Ms Helen Brasier
Address 123647 0
Gibbs Laboratory
Personalised Oncology
Walter and Eliza Hall Institute of Medical Research
1G Royal Parade Parkville
Victoria 3052
Country 123647 0
Australia
Phone 123647 0
+61 0411031184
Fax 123647 0
+61393470852
Email 123647 0
helen.brasier@mh.org.au
Contact person for scientific queries
Name 123648 0
Dr Shehara Mendis
Address 123648 0
Gibbs Laboratory
Personalised Oncology
Walter and Eliza Hall Institute of Medical Research
1G Royal Parade Parkville
Victoria 3052
Country 123648 0
Australia
Phone 123648 0
+61 393452122
Fax 123648 0
+61393470852
Email 123648 0
Shehara.Mendis@mh.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be shared for this project


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
18016Ethical approval    385147-(Uploaded-11-01-2023-17-05-37)-Study-related document.pdf



Results publications and other study-related documents

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