Condition category
Cancer
Date applied
08/05/2017
Date assigned
19/06/2017
Last edited
13/06/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Contact information

Type

Public

Primary contact

Ms Leona Batten

ORCID ID

Contact details

The Institute of Cancer Research
Royal Cancer Hospital
237 Fulham Road
London
SW3 6JB
United Kingdom

Additional identifiers

EudraCT number

2017-000508-92

ClinicalTrials.gov number

NCT03145961

Protocol/serial number

33825

Study information

Scientific title

c-TRAK TN: A randomised trial utilising ctDNA mutation tracking to detect minimal residual disease and trigger intervention in patients with moderate and high risk early stage triple negative breast cancer

Acronym

c-TRAK TN

Study hypothesis

Study aims:
1. To assess whether ctDNA screening can be used to predict which patients are at highest risk of relapse, and identify patients that have microscopic or minimal residual disease (MRD), that is not visible on imaging
2. In patients that have MRD (as detected by a positive ctDNA blood test) following completion of treatment, to assess the potential effectiveness of treatment with pembrolizumab, assessed as the sustained clearance of ctDNA

Ethics approval

South Central - Oxford C Research Ethics Committee, 05/04/2017, ref: 17/SC/0090

Study design

Randomised; Both; Design type: Treatment, Screening, Immunotherapy, Active Monitoring, Cohort study

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Cancer, Primary sub-specialty: Breast Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasm of breast

Intervention

Patients will be registered to c-TRAK TN, and undergo blinded ctDNA blood tests every 3 months. Neither the patient nor their treating team will be informed of the blood test results. If the patient has a positive ctDNA result within 12 months of commencing ctDNA screening, the patient will be randomised centrally by the ICR-CTSU in a 2:1 basis via a minimisation algorithm, to either pembrolizumab treatment or observation.

Pembrolizumab treatment group: Patients will be informed and asked to re-consent to confirm they want to receive treatment. They will then undergo eligibility assessments to ensure it is safe for them to start treatment. If the patient consents and is eligible to start treatment, they will receive 200mg pembrolizumab as a 30 minute intravenous infusion every 3 weeks for up to 12 months. A ctDNA blood test will be done at every cycle and will remain blinded. For 12 months after the completion of pembrolizumab, patients will have blinded ctDNA blood tests done every 3 months. After this, patients will be followed up every 6 months until disease recurrence, or until centres are informed no further follow up is required, unless the patient withdraws consent.

Observation group: Patients and their treating team will not be informed of the randomisation and will continue to have ctDNA blood tests every 3 months up to 24 months after commencing ctDNA screening. They will be followed up every 6 months until disease recurrence, or until centres are informed no further follow up is required, unless the patient withdraws consent.

Intervention type

Other

Phase

Drug names

Primary outcome measure

1. The proportion of patients with ctDNA positivity by 12 or 24 months as assessed by the blood sample taken at 12 months and 24 months
2. The proportion of patients without either detectable ctDNA or disease recurrence 12 months after starting pembrolizumab, measured by the blood sample and recurrence assessment carried out 12 months after commencing pembrolizumab

Secondary outcome measures

1. The time from entry into ctDNA screening to first positive ctDNA detection, assessed using ctDNA screening blood samples taken every 3 months from baseline up to a maximum of 12 months after starting ctDNA screening
2. The proportion of patients randomised to receive pembrolizumab that are found to have metastatic disease, visible and diagnosed via imaging, at the time of first ctDNA detection which is assessed using ctDNA blood samples taken every 3 months from baseline up to a maximum of 12 months after starting ctDNA screening
3. Review of the lead time between first detection of ctDNA and confirmed recurrent disease assessed by comparing the date of randomisation to recurrence detection, expected to occur up to 5 years
4. The proportion of patients without detectable ctDNA or disease recurrence 12 months after randomisation to observation group
5. Safety and tolerability of pembrolizumab assessed using NCI CTCAE v4.0, and the proportion of patients reporting dose reductions or delays, assessed throughout pembrolizumab treatment, up to 12 months
6. The proportion of patients randomised to receive pembrolizumab who start the therapy, assessed at the point of commencement or non-commencement of treatment, up to 8 weeks following randomisation

Exploratory Outcome Measures:
1. Descriptive differences in time between ctDNA detection and disease recurrence, and disease free survival, between patients in the pembrolizumab and the observation groups, assessed as the time between first ctDNA detection and documented recurrence or disease free survival event, whichever comes first, expected to occur up to 5 years
2. The relationship between sustained clearance of ctDNA on pembrolizumab and biological markers up to 12 months after commencing pembrolizumab
3. Relationship between lead time of detection of ctDNA and disease relapse and measurement of potential predictive clinical and biological factors will be assessed using standard statistical techniques for time to event data up to 5 years

Overall trial start date

01/07/2015

Overall trial end date

31/12/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 03/05/2018:
1. Signed Informed Consent Form for Registration
2. Male or female patients ages 16 years or older
3. ECOG performance status 0, 1 or 2
4. Histologically proven primary triple negative breast cancer as defined as oestrogen receptor (ER) negative, progesterone receptor (PgR) negative (if available, otherwise PgR unknown), (as defined by Allred score 0/8 or 2/8 or stain in <1% of cancer cells) and HER2 negative (immunohistochemistry 0/1+ or negative by in situ hybridization) as determined by local laboratory.
5. Availability of tissue from two archival tumour tissue samples (either from diagnostic biopsy, and/or primary surgery). If only one tumour sample is available, the site should inform the ICR-CTSU who will discuss eligibility with the Chief Investigator (or designated TMG member). Patients who have tumours previously sequenced outside the c-TRAK TN trial must provide one archival tumour tissue sample and the report that confirms the mutations detected
6. Patients with moderate or high risk early stage triple negative breast cancer according to the following risk of relapse criteria:
High risk criteria:
6.1.1. Neoadjuvant chemotherapy – residual invasive cancer in the axillary nodes after chemotherapy, defined as at least microscopic residual disease (>0.2mm) by histology, OR OSNA macroscopic, OR OSNA microscopic with residual invasive cancer in the breast.
6.1.2. Adjuvant chemotherapy – tumour size >50mm and node positive AND/OR ≥4 nodes positive regardless of primary tumour size.
Moderate risk criteria:
6.2.1. Neoadjuvant chemotherapy – residual invasive cancer in the breast and axillary lymph node negative after chemotherapy
6.2.2. Adjuvant chemotherapy – tumour size >20mm AND/OR involved axillary macroscopic lymph node defined as ≥2mm by histology or OSNA macroscopic.
Note: Patients who have received both neoadjuvant chemotherapy and further adjuvant chemotherapy must fulfill the adjuvant chemotherapy risk criteria to be eligible on either clinical staging prior to neoadjuvant chemotherapy or pathological staging at surgery.
7. Patients registered according to following criteria for timing of registration
Neoadjuvant chemotherapy:
Patients must be registered within 3 months of surgery or within 4 weeks of completing adjuvant radiotherapy if indicated, whichever occurs later. Patients may be registered before or during radiotherapy and should be registered as early as possible.
Adjuvant chemotherapy:
Patients must be registered within 3 months of the last cycle of adjuvant chemotherapy, or within 4 weeks of completing adjuvant radiotherapy, whichever occurs later. Patients may register during adjuvant chemotherapy or radiotherapy and should be registered as early as possible.
8. Consent to provide research blood samples
9. Patients with bilateral tumours can be included if both are triple negative and if two archival tissues samples can be provided per tumour.
10. Patients must have had surgery achieving clear margins (as per local guidelines).
11. Female and male patients of reproductive potential must be willing to use an adequate method of contraception, for the first year of the trial and if randomised to pembrolizumab, for the duration of treatment through to 120 days after the last dose of pembrolizumab (see appendix 2). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
12. Patients must be willing to have frequent blood tests (every 3 months for 2 years in ctDNA screening and 3 weekly if subsequently allocated pembrolizumab) and receive a 12 month course of pembrolizumab if randomised to pembrolizumab treatment on ctDNA detection.
13. No evidence of distant metastatic disease on staging scans conducted at any time since initial diagnosis

Previous inclusion criteria:
1. Signed Informed Consent Form for Registration
2. Male or female patients ages 16 years or older
3. ECOG performance status 0 or 1
4. Histologically proven primary triple negative breast cancer as defined as oestrogen receptor (ER) negative, progesterone receptor (PgR) negative (if available, otherwise PgR unknown), (as defined by Allred score 0/8 or 2/8 or stain in <1% of cancer cells) and HER2 negative (immunohistochemistry 0/1+ or negative by in situ hybridization) as determined by local laboratory.
5. Provision of tissue from two archival tumour tissue samples (either from diagnostic biopsy, and/or primary surgery, or where available residual disease post-neoadjvuant chemotherapy). If only one tumour sample is available, the site should inform the ICR-CTSU who will discuss eligibility with the Chief Investigator or if unavailable the designated TMG member. Patients who have tumours previously sequenced outside the c-TRAK TN trial must provide one archival tumour tissue sample and the report that confirms the mutations detected.
6. Patients with moderate or high risk early stage triple negative breast cancer according to the following risk of relapse criteria:
High risk criteria:
6.1.1. Neoadjuvant chemotherapy – residual invasive cancer in the axillary nodes after chemotherapy, defined as at least microscopic residual disease (>0.2mm) by histology, OR OSNA macroscopic, OR OSNA microscopic with residual invasive cancer in the breast.
6.1.2. Adjuvant chemotherapy – tumour size >50mm and node positive AND/OR ≥4 nodes positive regardless of primary tumour size.
Moderate risk criteria:
6.2.1. Neoadjuvant chemotherapy – residual invasive cancer in the breast and axillary lymph node negative after chemotherapy
6.2.2. Adjuvant chemotherapy – tumour size >20mm AND/OR involved axillary macroscopic lymph node defined as ≥2mm by histology or OSNA macroscopic.
Note: Patients who have received both neoadjuvant chemotherapy and further adjuvant chemotherapy must fulfill the adjuvant chemotherapy risk criteria to be eligible on either clinical staging prior to neoadjuvant chemotherapy or pathological staging at surgery.
7. Patients registered according to following criteria for timing of registration
Neoadjuvant chemotherapy:
Patients must be registered within 3 months of surgery or within 4 weeks of completing adjuvant radiotherapy if indicated, whichever occurs later. Patients may be registered before or during radiotherapy and should be registered as early as possible.
Adjuvant chemotherapy:
Patients must be registered within 3 months of the last cycle of adjuvant chemotherapy, or within 4 weeks of completing adjuvant radiotherapy, whichever occurs later. Patients may register during adjuvant chemotherapy or radiotherapy and should be registered as early as possible.
8. Provision of blood samples for germline DNA analysis and exploratory ctDNA analysis.
9. Patients with bilateral tumours can be included if both are triple negative and if two archival tissues samples can be provided per tumour.
10. Patients must have had surgery achieving clear margins (as per local guidelines).
11. Female and male patients of reproductive potential must be willing to use an adequate method of contraception, for the first year of the trial and if randomised to pembrolizumab, for the duration of treatment through to 120 days after the last dose of pembrolizumab (see appendix 2). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
12. Patients must be willing to have frequent blood tests (every 3 months for 2 years in ctDNA screening and 3 weekly if subsequently allocated pembrolizumab) and receive a 12 month course of pembrolizumab if randomised to pembrolizumab treatment on ctDNA detection.
13. No evidence of distant metastatic disease on staging scans conducted at any time since initial diagnosis

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 150; UK Sample Size: 150

Participant exclusion criteria

Current exclusion criteria as of 03/05/2018:
1. Any concurrent or planned treatment for the current diagnosis of breast cancer other than surgery, locoregional adjuvant radiotherapy, standard adjuvant chemotherapy, or a bisphosphonate/denosumab
2. Prior treatment with a PDL1, PD1, or other immunomodulatory therapy
3. Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous 5 years, other than for basal cell carcinoma of the skin or cervical carcinoma in situ
4. Patients previously entered into a therapeutic trial during or after neoadjuvant chemotherapy where experimental therapy is continued post-surgery
5. Treatment with an unlicensed or investigational product within 4 weeks of trial entry
6. Active autoimmune disease requiring systemic therapy in the last two years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of such systemic treatment
7. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab
8. Known history of active TB (Tuberculosis Bacillus)
9. Known history of Human Immunodeficiency Virus (HIV)
10. Known active Hepatitis B or Hepatitis C
11. Known history of, or any evidence of active, non-infectious pneumonitis
12. Active infection requiring systemic therapy
13. Previous solid organ transplantation
14. Females who are pregnant or breastfeeding
15. Presence of any systemic illness incompatible with participation in the clinical trial or inability to provide written informed consent

Previous exclusion criteria:
1. Any concurrent or planned treatment for the current diagnosis of breast cancer other than surgery, locoregional adjuvant radiotherapy, standard adjuvant chemotherapy, or a bisphosphonate/denosumab
2. Prior treatment with a PDL1, PD1, or other immunomodulatory therapy
3. Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous 5 years, other than for basal cell carcinoma of the skin or cervical carcinoma in situ
4. Patients previously entered into a therapeutic trial during or after neoadjuvant chemotherapy where experimental therapy is continued post-surgery. Patients involved in clinical trials involving experimental drugs prior to primary standard treatment (i.e. window of opportunity trials) can be considered for entry into c-TRAK TN
5. Treatment with an unlicensed or investigational product within 4 weeks of trial entry
6. Active autoimmune disease requiring systemic therapy in the last two years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of such systemic treatment
7. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab
8. Known history of active TB (Tuberculosis Bacillus)
9. Known history of Human Immunodeficiency Virus (HIV)
10. Known active Hepatitis B or Hepatitis C
11. Known history of, or any evidence of active, non-infectious pneumonitis
12. Active infection requiring systemic therapy
13. Females who are pregnant or breastfeeding
14. Presence of any systemic illness incompatible with participation in the clinical trial or inability to provide written informed consent

Recruitment start date

21/12/2018

Recruitment end date

31/10/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

The Royal Marsden Hospital
Fulham Road Chelsea
London
SW3 6JJ
United Kingdom

Trial participating centre

The Royal Marsden Hospital
Downs Road
Sutton
SM2 5PT
United Kingdom

Trial participating centre

Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Trial participating centre

The Christie
550 Wilmslow Road Withington
Manchester
M20 4BX
United Kingdom

Trial participating centre

Clatterbridge Cancer Centre
Clatterbridge Health Park Clatterbridge Road Birkenhead
Wirral
CH63 4JY
United Kingdom

Trial participating centre

Western General Hospital
Crewe Road South
Edinburgh
EH4 2XU
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
Mindelsohn Way
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Nottingham University Hospital
City Campus Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Trial participating centre

Royal Bournemouth Hospital
Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

Trial participating centre

Weston Park Hospital
Whitham Road
Sheffield
S10 2SJ
United Kingdom

Trial participating centre

University College Hospital
250 Euston Road
London
NW1 2PG
United Kingdom

Trial participating centre

Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom

Trial participating centre

Bristol Haematology and Oncology Centre
Horfield Road Avon
Bristol
BS2 8ED
United Kingdom

Trial participating centre

Churchill Hospital
Old Road Headington
Oxford
OX3 7LE
United Kingdom

Trial participating centre

St James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Velindre Hospital
Velindre Road Whitchurch
Cardiff
CF14 2TL
United Kingdom

Trial participating centre

St Bartholomew’s Hospital
W Smithfield
London
EC1A 7BE
United Kingdom

Trial participating centre

Royal Cornwall Hospital
Treliske
Truro
TR1 3LJ
United Kingdom

Sponsor information

Organisation

Institute of Cancer Research

Sponsor details

Royal Cancer Hospital
237 Fulham Road
London
SW3 6JB
United Kingdom
+44 208 722 4040
c-trak-tn-icrctsu@icr.ac.uk

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Industry

Funder name

Merck Sharp and Dohme

Alternative name(s)

Merck Sharp & Dohme, Merck Sharp & Dohme Corp., MSD

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The main trial results will be published in a peer‐reviewed journal, on behalf of all collaborators. It is the aim that this will be published around 1 year after the overall trial end date.

IPD Sharing statement:
The current data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/12/2022

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

13/06/2018: Cancer Research UK lay summary link added to plain English summary field 03/05/2018: The following changes have been made: 1. The Clinicaltrials.gov number NCT03145961 has been added. 2. The recruitment start date has been changed from 01/09/2017 to 21/12/2018. 3. The recruitment end date has been changed from 01/03/2019 to 31/10/2019. 4. The participant inclusion criteria have been changed. 5. The participant exclusion criteria have been changed. 6. Derriford Hospital has been removed from the trial centres and Royal Cornwall Hospital has been added.