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
ACTRN12618001766202
Ethics application status
Approved
Date submitted
11/10/2018
Date registered
26/10/2018
Date last updated
26/10/2018
Date data sharing statement initially provided
26/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Tracking Residual Disease Using Circulating Tumour DNA In High-Risk Early Breast Cancer
Scientific title
Tracking Residual Disease Using Circulating Tumour DNA In High-Risk Early Breast Cancer
Secondary ID [1] 296254 0
None
Universal Trial Number (UTN)
Trial acronym
TRAIL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 309916 0
Condition category
Condition code
Cancer 308697 308697 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Tracking residual disease by circulating tumour DNA analysis at the patient's first ctDNA identifed Minimal Residual Disease (MRD) time point assessment following completion of standard of care surgery neo-/adjuvant chemotherapy (surgery and chemotherapy), who are nonetheless radiologically negative.

Pre-screening takes place when the patient is diagnosed with early breast cancer. Patient continues onto their normal treatment. If pre-screening has detected trackable somatic mutations from their breast cancer tumour tissue and if the patient is eligible, they will be consented for the main part of the study at approximately 6 months after pre-screening and continue to come in every 3 months for blood collection for 2 years.

During the main study, if MRD is detected, patient will be investigated with CT staging and whole body bone scan even if he/she is clinically asymptomatic to detect early breast cancer recurrence.
Intervention code [1] 312584 0
Early detection / Screening
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307672 0
1. Level of modified Disease Free Survival (mDFS) between the following groups of high-risk early breast cancer patients:
• Patients with MRD (minimal residual disease) identified through circulating tumour DNA analysis (‘ctDNA identified MRD positive’, or more simply ‘MRD+’)
• Patients who are ctDNA identified MRD negative (MRD-) at their first MRD assessment time point following standard of care therapy.
Timepoint [1] 307672 0
Time point between the day of main study registration and the day of modified disease recurrence.
Secondary outcome [1] 352686 0
Proportion of patients who are MRD+ on the day of main study registration
Timepoint [1] 352686 0
Day of main study registration
Secondary outcome [2] 352687 0
Amongst the subset of patients found to be plasma ctDNA detected MRD positive for the first time, the proportion of patients with positive CT or whole body bone scan findings of cancer recurrence at the same time.
Timepoint [2] 352687 0
At any given plasma serial ctDNA assessment time point
Secondary outcome [3] 352688 0
Serial ctDNA dynamics during and after completion of surgery and neo-/ adjuvant chemotherapy.
Timepoint [3] 352688 0
Serial plasma ctDNA assessment at baseline pre-treatment, during pre-screening phase and at every 3-months up till 2 years post main study registration.
Secondary outcome [4] 352689 0
mDFS12, a time to event measurement which is defined analogously to mDFS (Modified Disease free survival).
mDFS is defined as the time between six weeks after main study registration and first disease recurrence at any site (local, regional, distant) or death.
For mDFS12 the start date is the date at which results of all 12 month scans become available.
Timepoint [4] 352689 0
mDFS12 is defined as the the date at which results of all 12 months scans become available, expected to be 6 weeks after the date of the 12-month MRD test. It is defined only for the subset of patients who have not experienced a mDFS event of interest at this time point.
Secondary outcome [5] 352690 0
MRD12, a dichotomous variable which is defined as positive if any one or more of the MRD tests at 3, 6, 9, and 12 months are positive. In other words, MRD12 is negative if and only if MRD tests at 3, 6, 9 and 12 months are all negative.
Timepoint [5] 352690 0
mDFS12 is defined as the the date at which results of all 12 months scans become available, expected to be 6 weeks after the date of the 12-month MRD test. It is defined only for the subset of patients who have not experienced a mDFS event of interest at this time point.
Secondary outcome [6] 352691 0
Genomic variants of the primary cancer and genomic variants identified at the time of relapse through tumour tissue and MRD analysis.
Timepoint [6] 352691 0
At the time of primary diagnosis and relapse through tumour tissue and ctDNA analysis

Eligibility
Key inclusion criteria
Inclusion criteria for Pre-screening:
1. Provision of informed consent prior to any study specific procedures (pre-screening PICF)
2. Female or male patients >=18 years of age
3. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast that is one of the two following phenotypes:
• Triple negative breast cancer defined as:
Estrogen Receptor (ER) and Progesterone Receptor (PgR) negative defined as immunohistochemistry (IHC) nuclear staining <1%
AND
HER2 negative (not eligible for anti-HER2 therapy) defined as:
– IHC 0, 1+ without ISH OR
– IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells OR
– ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells (without IHC)
• ER and/or PgR positive, HER2 negative breast cancer defined as:
ER and/or PgR positive defined as IHC nuclear staining =1%.
AND
HER2 negative (not eligible for anti-HER2 therapy) defined as for TNBC above.
4. Patients have AJCC 8th edition Clinical Prognostic Stage 3 Grade 2 or 3 disease as detailed below:

Histology Grade TN
Triple negative breast cancer Grade 2-3 T3-4 Any N or T2-4N1 or Any T N2-3
Hormone positive (ER+PR+) Grade 2 T4 Any N or Any T N3
Grade 3 T4 Any N or T3-4N1 or Any T N2-3
Hormone positive (ER+PR-) or (ER-PR+) Grade 2 T4 Any N or T3-4N1 or Any T N2-3
Grade 3 T3-4 Any N or T2-4 N1 or Any T N2-3

5. Be willing to provide tissue from core biopsy or surgical resection sample for somatic mutation(s) testing. Patients for whom fresh samples cannot be provided may submit an archived specimen.
6. Patients with multifocal or multicentric invasive disease are eligible as long as all the lesions for which HER2 characterization is available are HER2 negative.
7. Patients with synchronous bilateral invasive disease are eligible as long as all the lesions assessed for HER2 on both sides are negative.
• In both the above cases the lesion considered at highest risk for recurrence based on the investigator’s discretion will be used for eligibility determination.
8. ECOG performance status 0-2

INCLUSION CRITERIA FOR MAIN STUDY
1. Provision of informed consent prior to any study specific procedures (main study PICF)
2. Patient has somatic mutation(s) in tissue for assessment of minimal residual disease.
3. Patient has received NAC or AC with curative intent. Please note patient must have received at least one cycle of chemotherapy to be eligible.
4. Patient is willing and able to comply with the protocol procedures for the duration of the study including undergoing blood collection, scheduled visits, examinations and completion of PROs

Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
EXCLUSION CRITERIA FOR PRE-SCREENING
1. Evidence of metastatic breast cancer
2. HER2 positive disease
3. Grade 1 primary disease
4. Patients with a second primary malignancy. EXCEPTIONS are:
• Adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, Ductal Carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial carcinoma.
• Other solid tumours and lymphomas (without bone marrow involvement) diagnosed >= 5 years prior to registration and treated with no evidence of disease recurrence and for whom no more than one line of chemotherapy was applied.
5. Patients considered at high medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
• Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, extensive bilateral lung disease on High Resolution Computed Tomography scan or any psychiatric disorder that prohibits obtaining informed consent.
6. Patients with known active Hepatitis B or C or HIV
7. Patients who are/will be enrolled in another clinical trial evaluating other drug intervention(s) that will conflict with or interrupt the assessments of this study.
EXCLUSION CRITERIA FOR MAIN STUDY
1. Patient has developed a secondary primary malignancy or metastatic disease since signing the pre-screening consent
2. HER2 positive disease on the surgical specimen.
3. Grade 1 disease on the surgical specimen.


Study design
Purpose of the study
Diagnosis
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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Type of endpoint(s)
Statistical methods / analysis
ANALYSIS PLAN
An interim analysis for excess efficacy will be conducted when over half of the anticipated 29 events have occurred (15 events). Given the anticipated accrual and event rates, this is expected to happen approximately two months after the end of the 3 year accrual period.

If the trial does not stop at the interim analysis, the final primary analysis will be triggered when the last recruited patient has been followed up for at least 24 months. The secondary endpoints will also be analysed at the same time.

Subgroup analyses will be conducted to assess the consistency of the effect of MRD positivity across potential or expected prognostic factors, as listed below (SUBGROUP ANALYSES).

If there are too few events available for a meaningful analysis of a particular subgroup, the relationship between that subgroup and mDFS will not be formally analysed. In this case, only descriptive summaries will be provided.

SUBGROUP ANALYSES
The following subgroups are of primary interest:
1. Hormone receptor status (ER and/or PgR positive and HER2 negative; TNBC)
2. Chemotherapy timing (Neoadjuvant chemotherapy; adjuvant chemotherapy)
3. Hormone receptor status by prior chemotherapy timing (if there are sufficient events to split into the four groups)
a. ER and/or PgR positive with neoadjuvant chemotherapy
b. ER and/or PgR positive with adjuvant chemotherapy
c. ER and PgR negative with neoadjuvant chemotherapy
d. ER and PgR negative with adjuvant chemotherapy
4. Pathological response in those who underwent neoadjuvant chemotherapy
a. Complete pathological response
b. Incomplete pathological response.

INTERIM ANALYSIS
A single interim analysis is planned after half the events have taken place (15 events), which is expected to occur after the trial has been running for 3 years and 2 months, i.e. approximately 2 months after the time of completion of accrual. If at this time point the test for superior mDFS in the MRD- arm yields a p-value of below 0.005 the trial will be stopped for clear efficacy and the null hypothesis will be rejected. Due to the conservative nature of the interim analysis, the type I error inflation is very small, and thus no adjustment to the final analysis is planned to account for alpha spending. Under the alternate hypothesis assumption of 3 year mDFS rates of 50% in the MRD+ group and 80% in the MRD- group, the probability of stopping at the interim analysis is ~30%.

Recruitment
Recruitment status
Not yet 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)
VIC
Recruitment hospital [1] 12137 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 12138 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 24307 0
3000 - Melbourne
Recruitment postcode(s) [2] 24308 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 300850 0
Charities/Societies/Foundations
Name [1] 300850 0
National Breast Cancer Foundation
Address [1] 300850 0
Level 9, 10 Barrack Street,
Sydney
NSW 2000
Country [1] 300850 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
305 Grattan Street
Melbourne VIC 3000
Australia
Country
Australia
Secondary sponsor category [1] 300458 0
None
Name [1] 300458 0
none
Address [1] 300458 0
none
Country [1] 300458 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301624 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 301624 0
305 Grattan Street
Melbourne
VIC, 3000
Australia
Ethics committee country [1] 301624 0
Australia
Date submitted for ethics approval [1] 301624 0
13/08/2018
Approval date [1] 301624 0
25/09/2018
Ethics approval number [1] 301624 0
HREC/43163/PMCC-2018

Summary
Brief summary
The purpose of this study is to determine if breast cancer genetic material (known as circulating tumour DNA (ctDNA)) can be detected in the bloodstream.

Who is it for?
You may be eligible for this study if you are aged 18 or over and have confirmed non-metastatic adenocarcinoma of the breast.

Study details
You will require a blood test every 3 months for two years from the time of registration to the main study. As part of this study, you will also need to complete questionnaires that ask about your feelings towards the regular blood tests and thoughts of cancer return. If the ctDNA levels are detected in your bloodstream during the 2 year period, you will be asked to return to have a CT and/or bone scan.

It is hoped that this research will demonstrate the utility of this circulating material as an early marker of breast cancer activity.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87574 0
A/Prof Sarah-Jane Dawson
Address 87574 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000Australia
Country 87574 0
Australia
Phone 87574 0
+61 3 855 97132
Fax 87574 0
+61 3 8559 7379
Email 87574 0
Sarah-Jane.Dawson@petermac.org
Contact person for public queries
Name 87575 0
A/Prof Sarah-Jane Dawson
Address 87575 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000Australia
Country 87575 0
Australia
Phone 87575 0
+61 3 855 97132
Fax 87575 0
+61 3 8559 7379
Email 87575 0
Sarah-Jane.Dawson@petermac.org
Contact person for scientific queries
Name 87576 0
A/Prof Sarah-Jane Dawson
Address 87576 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000Australia
Country 87576 0
Australia
Phone 87576 0
+61 3 855 97132
Fax 87576 0
+61 3 8559 7379
Email 87576 0
Sarah-Jane.Dawson@petermac.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Summary results
No Results