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


Trial ID
ACTRN12612000345886
Ethics application status
Approved
Date submitted
21/03/2012
Date registered
26/03/2012
Date last updated
26/03/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
Circulating Tumour DNA as a Sensitive and Specific Marker of Response to Therapy and of Occult Disease in Colorectal Cancer
Scientific title
Circulating Tumour DNA as a Sensitive and Specific Marker of Response to Therapy and of Occult Disease in Colorectal Cancer
Secondary ID [1] 280176 0
Nil
Universal Trial Number (UTN)
U1111-1129-2961
Trial acronym
Liver Metastasis study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Patients with resectable colorectal cancer liver metastases 286110 0
Condition category
Condition code
Cancer 286303 286303 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Observational
Patient registry
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This is a prospective study involving the collection of blood samples for the purposes of measuring circulating DNA from patients with resectable colorectal cancer liver metastases. Two distinct cohorts of patients, those undergoing initial liver resection followed by 12 cycles of FOLFOX and those given pre and postoperative chemotherapy will be treated and followed according to standard protocols.
60 mls of blood will be collected at specified timpoints. - 60 mls will be collected at each timepoint.
COHORT 1 - Initial Surgery the timepoints are:
Timepoint 1 - Screening
Timepoint 2 - 4 weeks post surgery
Timepoint 3 Post cycle 6 adjuvant chemotherapy (Day 1 Cycle 7)
Timepoint 4 - Post cycle 12 (Days 3 at CADD disconnect)
Timepoint 5 - 10 every 3 months (3 mth follow up; 6mth follow up; 12 mth follow up; 18 mth follow up and 24 mth follow up)
COHORT 2 - Pre-op Chemo timpoints are:
Timepoint 1 - Screening
Timepoint 2 - Post cycle 1 (day 1 cycle 2)
Timepoint 3 - Post cycle 2 (day 1 cycle 3)
Timepoint 4 - post cycle 4 (day 1 cycle 5)
Timepoint 5 - 4 weeks post surgery
Timepoint 6 - Post cycle 12 (day 3 at CADD disconnect)
Timepoint 7 -10 - 3 monthly follow - ups ( 3 mths; 6 mths; 9 mths; 12 mnths)
Timepoint 11 & 12 - 6 monthly follow - ups (18 mths and 24 mths)
Intervention code [1] 284505 0
Not applicable
Comparator / control treatment
This is an exploratory, prospective study enrolling patients diagnosed with colorectal cancer liver metastases to investigate the potential use of a novel blood-based biomarker (circulating tumour DNA) as a sensitive and specific marker of disease response or resistance to chemotherapy and as a marker of residual disease that predicts later recurrence.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 286774 0
To demonstrate that the persistence of tumour DNA in peripheral blood immediately following clinically and radiologically complete resection of liver metastases is a sensitive and specific predictor of subsequent disease recurrence.
Timepoint [1] 286774 0
Final analysis of blood, plasma and tissue specimens.
COHORT 1 - Initial Surgery the timepoints are:
Timepoint 1 - Screening
Timepoint 2 - 4 weeks post surgery
Timepoint 3 Post cycle 6 adjuvant chemotherapy (Day 1 Cycle 7)
Timepoint 4 - Post cycle 12 (Days 3 at CADD disconnect)
Timepoint 5 - 10 every 3 months (3 mth follow up; 6mth follow up; 12 mth follow up; 18 mth follow up and 24 mth follow up)
COHORT 2 - Pre-op Chemo timpoints are:
Timepoint 1 - Screening
Timepoint 2 - Post cycle 1 (day 1 cycle 2)
Timepoint 3 - Post cycle 2 (day 1 cycle 3)
Timepoint 4 - post cycle 4 (day 1 cycle 5)
Timepoint 5 - 4 weeks post surgery
Timepoint 6 - Post cycle 12 (day 3 at CADD disconnect)
Timepoint 7 -10 - 3 monthly follow - ups ( 3 mths; 6 mths; 9 mths; 12 mnths)
Timepoint 11 & 12 - 6 monthly follow - ups (18 mths and 24 mths)
Secondary outcome [1] 296631 0
To demonstrate that early changes in circulating tumour DNA levels in patients with measurable disease are a sensitive and specific predictor of response or resistance to systemic chemotherapy compared to CT imaging (cohort 2 only).
Timepoint [1] 296631 0
Final analysis of blood, plasma and tissue specimens. Central review of CT scan by a radioligist post cycle 1 and cycle 4 completion of chemotherapy.
Secondary outcome [2] 296632 0
To demonstrate that the persistence of circulating tumour DNA levels (where present after complete surgical resection of all known disease) despite peri-operative or adjuvant therapy predicts subsequent radiologic recurrence.
Timepoint [2] 296632 0
Final analysis of blood, plasma and tissue specimens. Central review of CT scan by a radioligist post cycle 1 and cycle 4 completion of chemotherapy.
Secondary outcome [3] 296633 0
To demonstrate that the persistence of circulating tumour DNA levels (where present after complete surgical resection of all known disease) despite peri-operative or adjuvant therapy predicts for worse overall survival.
Timepoint [3] 296633 0
Final analysis of blood, plasma and tissue specimens. Central review of CT scan by a radioligist post cycle 1 and cycle 4 completion of chemotherapy.
Secondary outcome [4] 296634 0
To demonstrate that the appearance of circulating tumour DNA when patients are undergoing routine follow-up, where DNA has previously been eradicated by surgery +/- chemotherapy, predicts disease recurrence.
Timepoint [4] 296634 0
Final analysis of blood, plasma and tissue specimens.
COHORT 1 - Initial Surgery the timepoints are:
Timepoint 1 - Screening
Timepoint 2 - 4 weeks post surgery
Timepoint 3 Post cycle 6 adjuvant chemotherapy (Day 1 Cycle 7)
Timepoint 4 - Post cycle 12 (Days 3 at CADD disconnect)
Timepoint 5 - 10 every 3 months (3 mth follow up; 6mth follow up; 12 mth follow up; 18 mth follow up and 24 mth follow up)
COHORT 2 - Pre-op Chemo timpoints are:
Timepoint 1 - Screening
Timepoint 2 - Post cycle 1 (day 1 cycle 2)
Timepoint 3 - Post cycle 2 (day 1 cycle 3)
Timepoint 4 - post cycle 4 (day 1 cycle 5)
Timepoint 5 - 4 weeks post surgery
Timepoint 6 - Post cycle 12 (day 3 at CADD disconnect)
Timepoint 7 -10 - 3 monthly follow - ups ( 3 mths; 6 mths; 9 mths; 12 mnths)
Timepoint 11 & 12 - 6 monthly follow - ups (18 mths and 24 mths)
Secondary outcome [5] 296635 0
To demonstrate that the appearance of circulating tumour DNA in patients undergoing routine follow-up in patients where DNA has previously been eradicated by surgery +/- chemotherapy is a more specific and sensitive marker of early recurrence than CEA or imaging.
Timepoint [5] 296635 0
Final analysis of blood, plasma and tissue specimens. Central review of CT scan by a radioligist post cycle 1 and cycle 4 completion of chemotherapy.
Secondary outcome [6] 296636 0
To demonstrate that mutations detected in circulating tumour DNA are consistent with those detected in primary and/or metastatic deposits from these patients.
Timepoint [6] 296636 0
Final analysis of blood, plasma and tissue specimens.
COHORT 1 - Initial Surgery the timepoints are:
Timepoint 1 - Screening
Timepoint 2 - 4 weeks post surgery
Timepoint 3 Post cycle 6 adjuvant chemotherapy (Day 1 Cycle 7)
Timepoint 4 - Post cycle 12 (Days 3 at CADD disconnect)
Timepoint 5 - 10 every 3 months (3 mth follow up; 6mth follow up; 12 mth follow up; 18 mth follow up and 24 mth follow up)
COHORT 2 - Pre-op Chemo timpoints are:
Timepoint 1 - Screening
Timepoint 2 - Post cycle 1 (day 1 cycle 2)
Timepoint 3 - Post cycle 2 (day 1 cycle 3)
Timepoint 4 - post cycle 4 (day 1 cycle 5)
Timepoint 5 - 4 weeks post surgery
Timepoint 6 - Post cycle 12 (day 3 at CADD disconnect)
Timepoint 7 -10 - 3 monthly follow - ups ( 3 mths; 6 mths; 9 mths; 12 mnths)
Timepoint 11 & 12 - 6 monthly follow - ups (18 mths and 24 mths)
Secondary outcome [7] 296637 0
To demonstrate that where mutations are detected in circulating tumour DNA and recurrent disease is not found that alternative explanations for this finding will include the development of new adenomas or primary colorectal cancers or malignancy at another site.
Timepoint [7] 296637 0
Final analysis of blood, plasma and tissue specimens.
COHORT 1 - Initial Surgery the timepoints are:
Timepoint 1 - Screening
Timepoint 2 - 4 weeks post surgery
Timepoint 3 Post cycle 6 adjuvant chemotherapy (Day 1 Cycle 7)
Timepoint 4 - Post cycle 12 (Days 3 at CADD disconnect)
Timepoint 5 - 10 every 3 months (3 mth follow up; 6mth follow up; 12 mth follow up; 18 mth follow up and 24 mth follow up)
COHORT 2 - Pre-op Chemo timpoints are:
Timepoint 1 - Screening
Timepoint 2 - Post cycle 1 (day 1 cycle 2)
Timepoint 3 - Post cycle 2 (day 1 cycle 3)
Timepoint 4 - post cycle 4 (day 1 cycle 5)
Timepoint 5 - 4 weeks post surgery
Timepoint 6 - Post cycle 12 (day 3 at CADD disconnect)
Timepoint 7 -10 - 3 monthly follow - ups ( 3 mths; 6 mths; 9 mths; 12 mnths)
Timepoint 11 & 12 - 6 monthly follow - ups (18 mths and 24 mths)

Eligibility
Key inclusion criteria
1. Patients with histologically confirmed primary colorectal cancer
2. Patients with resected primary tumours or planned for curative primary tumour resection.
3. Patients with resectable liver metastases following workup including CT scans of chest, abdomen and pelvis (or MRI if unable to undertake CT scan) and whole body PET scan.
4. Patients fit for surgery
5. Patients fit for combination chemotherapy (5-FU and oxaliplatin)
6. Patients willing to provide written informed consent
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 5 years, with the exception of non-melanomatous skin cancer and carcinoma in situ of the cervix.
2. Medical or psychiatric condition or occupational responsibilities that may preclude compliance with the protocol
3. Patients that are not accessible for follow-up

Study design
Purpose
Duration
Selection
Timing
Statistical methods / analysis

Recruitment
Recruitment status
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)

Funding & Sponsors
Funding source category [1] 284929 0
Other Collaborative groups
Name [1] 284929 0
Ludwig Institute for Cancer Research
Address [1] 284929 0
PO Box 2008, RMH Post Office Parkville, VIC 3050
Country [1] 284929 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Ludwig Institute for Cancer Research
Address
PO Box 2008, RMH Post Office Parkville, VIC 3050
Country
Australia
Secondary sponsor category [1] 283802 0
None
Name [1] 283802 0
Address [1] 283802 0
Country [1] 283802 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286933 0
Melbourne Health HREC
Ethics committee address [1] 286933 0
PO
Royal Melbourne Hospital
Parkville Victoria 3050
Ethics committee country [1] 286933 0
Australia
Date submitted for ethics approval [1] 286933 0
Approval date [1] 286933 0
20/04/2011
Ethics approval number [1] 286933 0
2011.032

Summary
Brief summary
The purpose of this study is to measure cancer specific gene changes in the blood as a biomarker in monitoring
disease status in colorectal cancer. Biomarkers are substances that can be found in blood and/or tumour tissue
and may be used to measure the effects or progress of a disease or condition.
Genes are substances in the body which contain information about characteristics us as individuals. Previous
studies have found that the majority of colorectal cancers contain mutations in several genes (the gene is changed
or different from the common form) and that these cancerrelated
mutations can be detected in the blood.
Identifying biomarkers are important because they may be linked with disease progression, they may help to identify people who are most likely to benefit from a certain treatment such as chemotherapy, or they may be used to track the status of cancer without the need for invasive procedures, such as biopsies.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33947 0
Address 33947 0
Country 33947 0
Phone 33947 0
Fax 33947 0
Email 33947 0
Contact person for public queries
Name 17194 0
Philippa Robertson
Address 17194 0
PO Box 2008
RMH Post Office
Parkville VIC 3050
Country 17194 0
Australia
Phone 17194 0
+61(3)9342 4584
Fax 17194 0
Email 17194 0
philippa.robertson@ludwig.edu.au
Contact person for scientific queries
Name 8122 0
Dr Jeanne Tie
Address 8122 0
PO Box 2008
RMH Post Office
Parkville VIC 3050
Country 8122 0
Australia
Phone 8122 0
+61(3) 9342 3037
Fax 8122 0
Email 8122 0
jeanne.tie@ludwig.edu.au