Please be advised that due to the high volume of submissions, the ANZCTR is currently experiencing delays in processing submissions from those outside of Australia and New Zealand. As the ANZCTR is funded by Australia and New Zealand, we must prioritise submissions from these countries first. International submissions should allow additional time for registration. Apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12615000770561
Ethics application status
Approved
Date submitted
1/07/2015
Date registered
24/07/2015
Date last updated
4/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of RAS mutations in cell free deoxyribonucleic acid (cfDNA) in response to cetuximab anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer.
Scientific title
A study to evaluate the temporal dynamics of RAS Mutation Emergence in Cell Free DNA (cfDNA) in response to first-line cetuximab anti-EGFR therapy in Patients with Metastatic Colorectal Cancer
Secondary ID [1] 287001 0
None
Universal Trial Number (UTN)
U1111-1171-6722
Trial acronym
Emerging RAS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Patients with histologically confirmed metastatic colorectal cancer. 295468 0
Condition category
Condition code
Cancer 295722 295722 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This is a prospective multi-centre biomarker study involving the collection of plasma from patients with a Ras wild-type (according to the local standard of care) tumour planned for treatment with first-line cetuximab in combination with Irinotecan with fluorouracil (5FU) and folinic acid (FOLFIRI) or Oxaliplatin with fluorouracil (5FU) and folinic acid (FOLFOX) will be periodically assessed with the following minimum study procedures. Additional non-study assessments may occur at the discretion of the treating clinician.

Blood sampling at the following time points:
a) Baseline (within 7 days of starting anti-EGFR treatment)
b) Week 3 of anti-EGFR treatment (after 2 weeks of treatment)
c) Week 5 of anti-EGFR treatment (after 4 weeks of treatment)
d) Every 4 weeks thereafter until disease progression

Representative archival tumour sample (either primary or metastasis tissue) will be made available for next-generation sequencing (NGS) based Ras testing (unless already performed) and/or for repeat RAS mutation analysis by BEAMing (Beads, Emulsions, Amplification, and Magnetics) digital PCR (polymerase chain reaction) assay where there is any discordance between tumour tissue and cfDNA analysis.

Images from the following staging CT chest/abdomen/pelvis performed as part of routine care will be centrally reviewed by a radiologist:

a. Screening – within 4 weeks of starting anti-EGFR therapy
b. Every 8 weeks until disease progression using CEA and imaging.

Follow-up as per standard practice until disease progression, death or a maximum of 3 years, which ever occurs first.
Intervention code [1] 292207 0
Not applicable
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 295426 0
To explore the emergence of Ras mutations in cfDNA as an escape mechanism for first-line cetuximab anti-EGFR therapy.
To examine the emergence of Ras mutations during anti-EGFR therapy therapy, serial blood samples (30mls) will be collected and processed into plasma. The plasma will then be tested for Ras mutant status using BEAMing.
Timepoint [1] 295426 0
Patients will be examined for the period of time from therapy initiation to time when Ras mutations are first detected and followed by similar testing till disease progression.
In addition, the levels (quantities) of Ras mutations detected in circulating tumour DNA (ctDNA) in plasma will be examined and compared over time. This will occur at baseline, week 3, week 5 and every 4 weeks thereafter while patients remain on anti-EGFR treatment or until disease progression.
Patients recruited will be followed to documented disease progression; a mean time of follow up is estimated to be 11.4 months (estimated time from initiation of first-line cetuximab therapy to mean time progression free survival).
Please note that cfDNA and ctDNA are used interchangeably.
Secondary outcome [1] 315565 0
To explore the timing of the development of detectable molecular resistance assessed by ctDNA compared to detectable clinical progression.
To examine the emergence of Ras mutations during anti-EGFR therapy therapy, serial blood samples (30mls) will be collected and processed into plasma. The plasma will then be tested for Ras mutant status using BEAMing.
Clinical progression will be measured using tumour imaging with CT chest/abdomen/pelvis to assess for disease progression
Timepoint [1] 315565 0
Patients will be examined for the period of time from therapy initiation to time when Ras mutations are first detected and followed by similar testing till disease progression.
In addition, the levels (quantities) of Ras mutations detected in circulating tumour DNA in plasma will be examined and compared over time. This will occur at baseline, week 3, week 5 and every 4 weeks thereafter while patients remain on anti-EGFR treatment or until disease progression.
Patients recruited will be followed to documented disease progression; a mean time of follow up is estimated to be 11.4 months (estimated time from initiation of first-line cetuximab therapy to mean time progression free survival).
Secondary outcome [2] 315566 0
To explore the timing of the development of detectable molecular resistance assessed by cfDNA compared to serial carcinoembryonic antigen (CEA) levels.
To examine the emergence of Ras mutations during anti-EGFR therapy therapy, serial blood samples (30mls) will be collected and processed into plasma. The plasma will then be tested for Ras mutant status using BEAMing.
Each blood sample taken for the purpose of cfDNA analysis will also be analysed for CEA.
Timepoint [2] 315566 0
Patients will be examined for the period of time from therapy initiation to time when Ras mutations are first detected and followed by similar testing till disease progression.
In addition, the levels (quantities) of Ras mutations detected in circulating tumour DNA in plasma will be examined and compared over time. This will occur at baseline, week 3, week 5 and every 4 weeks thereafter while patients remain on anti-EGFR treatment or until disease progression.
Patients recruited will be followed to documented disease progression; a mean time of follow up is estimated to be 11.4 months (estimated time from initiation of first-line cetuximab therapy to mean time progression free survival).
Secondary outcome [3] 315567 0
To explore baseline total cfDNA levels as a predictive and prognostic marker in anti-EGFR treated patients.
To examine the emergence of Ras mutations during anti-EGFR therapy therapy, serial blood samples (30mls) will be collected and processed into plasma. The plasma will then be tested for Ras mutant status using BEAMing.
Timepoint [3] 315567 0
Patients will be examined for the period of time from therapy initiation to time when Ras mutations are first detected and followed by similar testing till disease progression.
In addition, the levels (quantities) of Ras mutations detected in circulating tumour DNA in plasma will be examined and compared over time. This will occur at baseline, week 3, week 5 and every 4 weeks thereafter while patients remain on anti-EGFR treatment or until disease progression.
Patients recruited will be followed to documented disease progression; a mean time of follow up is estimated to be 11.4 months (estimated time from initiation of first-line cetuximab therapy to mean time progression free survival).
Secondary outcome [4] 315568 0
To explore the correlation between changes in total cfDNA with tumour response as measured by RECIST criteria.
To examine the emergence of Ras mutations during anti-EGFR therapy therapy, serial blood samples (30mls) will be collected and processed into plasma. The plasma will then be tested for Ras mutant status using BEAMing.
Timepoint [4] 315568 0
Patients will be examined for the period of time from therapy initiation to time when Ras mutations are first detected and followed by similar testing till disease progression.
In addition, the levels (quantities) of Ras mutations detected in circulating tumour DNA in plasma will be examined and compared over time. This will occur at baseline, week 3, week 5 and every 4 weeks thereafter while patients remain on anti-EGFR treatment or until disease progression.
Patients recruited will be followed to documented disease progression; a mean time of follow up is estimated to be 11.4 months (estimated time from initiation of first-line cetuximab therapy to mean time progression free survival).
Secondary outcome [5] 315569 0
To determine if treatment responses can be seen in patients with tissue Ras wild-type status but with cfDNA Ras mutation at initial testing.
To examine the emergence of Ras mutations during anti-EGFR therapy therapy, serial blood samples (30mls) will be collected and processed into plasma. The plasma will then be tested for Ras mutant status using BEAMing.
Timepoint [5] 315569 0
Patients will be examined for the period of time from therapy initiation to time when Ras mutations are first detected and followed by similar testing till disease progression.
In addition, the levels (quantities) of Ras mutations detected in circulating tumour DNA in plasma will be examined and compared over time. This will occur at baseline, week 3, week 5 and every 4 weeks thereafter while patients remain on anti-EGFR treatment or until disease progression.
Patients recruited will be followed to documented disease progression; a mean time of follow up is estimated to be 11.4 months (estimated time from initiation of first-line cetuximab therapy to mean time progression free survival).

Eligibility
Key inclusion criteria
1. Subjects with histologically confirmed metastatic colorectal cancer
2. Systemic treatment will comprise (first line anti-EGFR antibody (cetuximab) therapy in combination with either irinotecan-based (FOLFIRI) or oxaliplatin-based (FOLFOX) chemotherapy
3. A representative tumour sample is available for molecular testing
4. Has measurable metastatic lesion(s), as defined by RECIST version 1.1.
5. ECOG performance status 0-2
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of another primary cancer within the last 3 years, with the exception of non-melanomatous skin cancer and carcinoma in situ of the cervix
2. Prior treatment with an anti-EGFR antibody

Study design
Purpose
Screening
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
The aim of this study is to understand how serial analysis of pre-established RAS as well as any emerging RAS mutations in plasma can predict tumour progression in comparison to established methods that rely on CEA level determination and imaging. Most of the analysis will be descriptive and a formal sample size calculation has not been performed.
Follow up will occur until disease progression or for a maximum of 3 years.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC

Funding & Sponsors
Funding source category [1] 291553 0
Commercial sector/Industry
Name [1] 291553 0
Sysmex Inostics, Inc.
Address [1] 291553 0
1 Sysmex Way, Mundelein, Illinois 60060
Country [1] 291553 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
The Walter and Eliza Hall Institute of Medical Research
Address
1G Royal Pde
Parkville
Vic 3052
Country
Australia
Secondary sponsor category [1] 290230 0
None
Name [1] 290230 0
Address [1] 290230 0
Country [1] 290230 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293095 0
Melbourne Health HREC
Ethics committee address [1] 293095 0
Post Office
Royal Melbourne Hospital
Parkville Victoria 3050
Ethics committee country [1] 293095 0
Australia
Date submitted for ethics approval [1] 293095 0
Approval date [1] 293095 0
01/06/2015
Ethics approval number [1] 293095 0
HREC/15/MH/88

Summary
Brief summary
This aim of this study is to explore the emergence of RAS mutations as an escape mechanism in patients receiving first-line cetuximab anti-EGFR therapy in combination with FOLFOX or FOLFIRI as well as to demonstrate the general utility of cfDNA RAS mutation monitoring as compared to standard care measurements of treatment resistance and disease progression using CEA and imaging.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above, and have been diagnosed with metastatic colorectal cancer.

Study details
All participants in this study will receive first line anti-EGFR antibody (cetuximab) therapy in combination with either irinotecan-based (FOLFIRI) or oxaliplatin-based (FOLFOX) chemotherapy, as chosen by their treating medical oncologist.

To examine the emergence of RAS mutations during anti-EGFR therapy, serial blood samples (30mls) will be collected from patients. The timing of emergence and genotype analysis of RAS mutations from cfDNA in patients undergoing 1st line treatment with cetuximab in combination with FOLFOX or FOLFIRI will then be examined. For all patients, disease progression will be examined by comparing RAS mutation levels to routine CEA assessment and imaging.

Patients having RAS WT tumours and receiving first-line cetuximab therapy in combination with FOLFOX or FOLFIRI will be monitored until documented tumour progression.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58458 0
Dr Jeanne Tie
Address 58458 0
Royal Melbourne Hospital Grattan Street Parkville VIC 3050
Country 58458 0
Australia
Phone 58458 0
+61 3 9342 7695
Fax 58458 0
Email 58458 0
jeanne.tie@mh.org.au
Contact person for public queries
Name 58459 0
Mr Siavash Foroughi
Address 58459 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville
VIC
3052
Country 58459 0
Australia
Phone 58459 0
+61 3 9345 2894
Fax 58459 0
Email 58459 0
siavash.foroughi@mh.org.au
Contact person for scientific queries
Name 58460 0
Dr Jeannie Tie
Address 58460 0
Royal Melbourne Hospital Grattan Street Parkville VIC 3050
Country 58460 0
Australia
Phone 58460 0
+61 3 9342 7695
Fax 58460 0
Email 58460 0
jeanne.tie@mh.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary