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Trial registered on ANZCTR


Trial ID
ACTRN12612000326897
Ethics application status
Approved
Date submitted
21/03/2012
Date registered
21/03/2012
Date last updated
21/03/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
Circulating Tumour DNA as a Marker of Occult Disease in Stage II Colorectal Cancer and Response to Therapy in Metastatic Colorectal Cancer
Scientific title
Circulating Tumour DNA as a Marker of Occult Disease in Stage II Colorectal Cancer and Response to Therapy in Metastatic Colorectal Cancer
Secondary ID [1] 280173 0
Nil
Universal Trial Number (UTN)
U1111-1129-2841
Trial acronym
ctDNA stage II and IV
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Measuring cancer specific gene changes in the blood as a biomarker in monitoring disease status in stage II and IV colorectal cancer. 286106 0
Condition category
Condition code
Cancer 286298 286298 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 tumour DNA from two distinct cohorts of patients:
COHORT A: Patients with curatively resected stage II colon cancer- subgroups will be enrolled according to whether adjuvant chemotherapy is recommended by patient’s treating oncologist. Group A - Chemotherpay; Group B - No Chemo (serial blood collection) and Group C - No chemotherapy (baseline sample). Timepoints for each group in COHORT A are as follows:
Group A - 60mls of blood will be collected at 11 timepoints-
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint 2 - Post 3 month of chemotherapy
Timepoint 3 - Completion of chemotherapy
Timepoint (4 - 11) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group B - 60mls of blood will be collected at 9 timepoints -
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint (2 - 9) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group C - 60mls of blood will be collected at 1 timepoint -
Timepoint 1 Baseline (4-8 weeks post operation)

COHORT B - Patients with metastatic (stage IV) colorectal cancer undergoing first line chemotherapy.
60 mls of blood will be collected at 3 timepoints -
Timepoint 1 - Priot to Cycle 1 Day 1 chemotherapy
Timepoint 2 - Cycle 1 Day 3 chemotherapy
Timepoint 3 - Cycle 2 Day 1 cemotherapy
Intervention code [1] 284501 0
Not applicable
Comparator / control treatment
This is an exploratory, prospective study enrolling patients diagnosed with stage II (Cohort A) or metastatic colorectal cancer (Cohort B) to investigate the potential use of a novel blood-based biomarker (circulating tumour DNA) as a
marker of residual disease that predicts later recurrence in stage II colorectal cancer, and a sensitive and specific marker of disease response or resistance to chemotherapy in metastatic colorectal cancer.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 286770 0
COHORT A Stage II Colrectal Cancer - to demonstrate that persistence of tumour derived DNA in peripheral blood following complete resection of the primary tumour is a sensitive and specific arker of subsequent disease recurrence.
Timepoint [1] 286770 0
COHORT A - At the completion of the analysis of blood, plasma and tissue samples.

COHORT A are as follows:
Group A - 60mls of blood will be collected at 11 timepoints-
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint 2 - Post 3 month of chemotherapy
Timepoint 3 - Completion of chemotherapy
Timepoint (4 - 11) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group B - 60mls of blood will be collected at 9 timepoints -
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint (2 - 9) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group C - 60mls of blood will be collected at 1 timepoint -
Timepoint 1 Baseline (4-8 weeks post operation)
Primary outcome [2] 286771 0
COHORT B Stage IV Colorectal Cancer - To confirm that early changes in the level of circulating tumour DNA are a
sensitive and specific marker of treatment response or resistance.
Timepoint [2] 286771 0
COHORT B - At the completion of the analysis of blood, plasma and tissue samples.
COHORT B - Patients with metastatic (stage IV) colorectal cancer undergoing first line chemotherapy.
60 mls of blood will be collected at 3 timepoints -
Timepoint 1 - Priot to Cycle 1 Day 1 chemotherapy
Timepoint 2 - Cycle 1 Day 3 chemotherapy
Timepoint 3 - Cycle 2 Day 1 cemotherapy
Secondary outcome [1] 296611 0
COHORT A - To demonstrate that the disappearance of tumour DNA in peripheral blood is a sensitive and specific marker of benefit from adjuvant chemotherapy.
Timepoint [1] 296611 0
COHORT A - At the completion of the analysis of blood, plasma and tissue samples.
COHORT A are as follows:
Group A - 60mls of blood will be collected at 11 timepoints-
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint 2 - Post 3 month of chemotherapy
Timepoint 3 - Completion of chemotherapy
Timepoint (4 - 11) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group B - 60mls of blood will be collected at 9 timepoints -
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint (2 - 9) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group C - 60mls of blood will be collected at 1 timepoint -
Timepoint 1 Baseline (4-8 weeks post operation)
Secondary outcome [2] 296612 0
COHORT A - To explore the potential of the appearance or re-appearance of ctDNA of tumour DNA in peripheral blood as a specific and sensitive marker of disease recurrence
Timepoint [2] 296612 0
COHORT A - At the completion of the analysis of blood, plasma and tissue samples.

COHORT A are as follows:
Group A - 60mls of blood will be collected at 11 timepoints-
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint 2 - Post 3 month of chemotherapy
Timepoint 3 - Completion of chemotherapy
Timepoint (4 - 11) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group B - 60mls of blood will be collected at 9 timepoints -
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint (2 - 9) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group C - 60mls of blood will be collected at 1 timepoint -
Timepoint 1 Baseline (4-8 weeks post operation)
Secondary outcome [3] 296613 0
COHORT A - To explore the potential of the appearance or re-appearance of ctDNA of tumour DNA in peripheral blood as a specific and sensitive marker of new disease, either a metachronous CRC or other primary tumour.
Timepoint [3] 296613 0
COHORT A - At the completion of the analysis of blood, plasma and tissue samples.
COHORT A are as follows:
Group A - 60mls of blood will be collected at 11 timepoints-
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint 2 - Post 3 month of chemotherapy
Timepoint 3 - Completion of chemotherapy
Timepoint (4 - 11) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group B - 60mls of blood will be collected at 9 timepoints -
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint (2 - 9) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group C - 60mls of blood will be collected at 1 timepoint -
Timepoint 1 Baseline (4-8 weeks post operation)
Secondary outcome [4] 296614 0
COHORT B - To examine the time course of changes in circulating tumour DNA following treatment with chemotherapy.
Timepoint [4] 296614 0
COHORT B - At the completion of the analysis of blood, plasma and tissue samples.

COHORT B - Patients with metastatic (stage IV) colorectal cancer undergoing first line chemotherapy.
60 mls of blood will be collected at 3 timepoints -
Timepoint 1 - Priot to Cycle 1 Day 1 chemotherapy
Timepoint 2 - Cycle 1 Day 3 chemotherapy
Timepoint 3 - Cycle 2 Day 1 cemotherapy
Secondary outcome [5] 296615 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 [5] 296615 0
COHORT B - At the completion of the analysis of blood, plasma and tissue samples.
COHORT A are as follows:
Group A - 60mls of blood will be collected at 11 timepoints-
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint 2 - Post 3 month of chemotherapy
Timepoint 3 - Completion of chemotherapy
Timepoint (4 - 11) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group B - 60mls of blood will be collected at 9 timepoints -
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint (2 - 9) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group C - 60mls of blood will be collected at 1 timepoint -
Timepoint 1 Baseline (4-8 weeks post operation)

COHORT B - Patients with metastatic (stage IV) colorectal cancer undergoing first line chemotherapy.
60 mls of blood will be collected at 3 timepoints -
Timepoint 1 - Priot to Cycle 1 Day 1 chemotherapy
Timepoint 2 - Cycle 1 Day 3 chemotherapy
Timepoint 3 - Cycle 2 Day 1 cemotherapy
Secondary outcome [6] 296617 0
COHORT B - To explore the predictive (likelihood of response) and prognostic significance (overall survival) of the level of ctDNA prior to first line treatment.
Timepoint [6] 296617 0
COHORT B - At the completion of the analysis of blood, plasma and tissue samples.

COHORT B - Patients with metastatic (stage IV) colorectal cancer undergoing first line chemotherapy.
60 mls of blood will be collected at 3 timepoints -
Timepoint 1 - Priot to Cycle 1 Day 1 chemotherapy
Timepoint 2 - Cycle 1 Day 3 chemotherapy
Timepoint 3 - Cycle 2 Day 1 cemotherapy

At the completion of analysis of blood/plasma and tissue statistician will analyze the sample data (occur during year three of study).

The calculation of progression-free survival is only relevant for the metastatic
cohort for assessment of response duration to first line chemotherapy. PFS is
defined as the time interval between the date of study entry and the date of
tumour progression. PFS will be measured for tumour progression at any site.
Diagnosis of tumour progression should be made by using RECIST Criteria.
Secondary outcome [7] 296659 0
COHORT B - To determine the feasibility of a prospective clinical trial study where early changes in circulating tumour DNA are used to determine the further management of patients.
Timepoint [7] 296659 0
COHORT A are as follows:
Group A - 60mls of blood will be collected at 11 timepoints-
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint 2 - Post 3 month of chemotherapy
Timepoint 3 - Completion of chemotherapy
Timepoint (4 - 11) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group B - 60mls of blood will be collected at 9 timepoints -
Timepoint 1 - Baseline (4-8 weeks post operation)
Timepoint (2 - 9) -3 monthly follow ups post completion of treatment (3mths; 6mths; 9mths; 12mths; 15mths; 18 mths; 21 mnths and 24mths)
Group C - 60mls of blood will be collected at 1 timepoint -
Timepoint 1 Baseline (4-8 weeks post operation)

COHORT B - Patients with metastatic (stage IV) colorectal cancer undergoing first line chemotherapy.
60 mls of blood will be collected at 3 timepoints -
Timepoint 1 - Priot to Cycle 1 Day 1 chemotherapy
Timepoint 2 - Cycle 1 Day 3 chemotherapy
Timepoint 3 - Cycle 2 Day 1 cemotherapy

Cohort B (metastatic colorectal cancer undergoing chemotherapy) is a small exploratory pilot study that aims to identify how best to apply the ctDNA test and whether or not it has potential promise for use in practice. As such, a formal sample size calculation has not been performed for this subgroup. Forty patients with metastatic disease will be enrolled as a pilot study, to confirm the value of
ctDNA as a marker of disease response in this setting and to demonstrate our capability in this area.

Eligibility
Key inclusion criteria
Patients with histologically confirmed primary colorectal cancer
For the stage II colon cancer (cohort A)
-Patients with curatively resected stage II primary colon cancer
-Patients must be registered for study within 10 weeks of surgery
For the metastastic (stage IV) colorectal cancer (cohort B)
-Patients with measurable disease by RECIST criteria version 1.1
-Patients fit to receive standard first line combination chemotherapy, with cytotoxic agents and any biological therapy given at standard doses.
ECOG performance status 0 - 2
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 with major organ impairment.
4. Patients that are not accessible for follow-up.

Study design
Purpose
Duration
Selection
Timing
Prospective
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] 284925 0
Other Collaborative groups
Name [1] 284925 0
Ludwig Institute for Cancer Research
Address [1] 284925 0
PO Box 2008, RMH Post Office, Parkville, VIC 3050
Country [1] 284925 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] 283798 0
None
Name [1] 283798 0
Address [1] 283798 0
Country [1] 283798 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286923 0
Melbourne Health HREC
Ethics committee address [1] 286923 0
Post Office
Royal Melbourne Hospital
Parkville, Victoria, 3050
Ethics committee country [1] 286923 0
Australia
Date submitted for ethics approval [1] 286923 0
Approval date [1] 286923 0
20/04/2012
Ethics approval number [1] 286923 0
2011.033

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 stage II and IV 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 33945 0
Address 33945 0
Country 33945 0
Phone 33945 0
Fax 33945 0
Email 33945 0
Contact person for public queries
Name 17192 0
Philippa Robertson
Address 17192 0
PO Box 2008, RMH Post Office, Parkville, VIC 3050
Country 17192 0
Australia
Phone 17192 0
+61(3)9342 4584
Fax 17192 0
Email 17192 0
philippa.robertson@ludwig.edu.au
Contact person for scientific queries
Name 8120 0
Dr Jeanne Tie
Address 8120 0
PO Box 2008, RMH Post Office, Parkville, VIC 3050
Country 8120 0
Australia
Phone 8120 0
+61(3)9342 3037
Fax 8120 0
Email 8120 0
jeanne.tie@ludwig.edu.au