A trial using blood tests to detect cancer cells after standard treatment to trigger additional treatment in early stage triple negative breast cancer patients

ISRCTN	ISRCTN12569958
DOI	https://doi.org/10.1186/ISRCTN12569958
EudraCT/CTIS number	2017-000508-92
ClinicalTrials.gov number	NCT03145961
Secondary identifying numbers	33825

Submission date: 08/05/2017
Registration date: 19/06/2017
Last edited: 10/10/2023

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-whether-ctdna-can-help-doctors-know-who-risk-breast-cancer-coming-back-pembroluzimab-reduces-ctdna-ctraktn

Study website

Contact information

Ms Katie Goddard
Public

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

Phone	+44 208 722 4614
Email	c-trak-tn-icrctsu@icr.ac.uk

Study information

Study design	Randomised; Both; Design type: Treatment, Screening, Immunotherapy, Active Monitoring, Cohort study
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details below to request a patient information sheet
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
Study 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(s)	South Central - Oxford C Research Ethics Committee, 05/04/2017, ref: 17/SC/0090
Condition	Breast cancer
Intervention	Current interventions as of 04/01/2023: Patients registered to c-TRAK TN underwent ctDNA blood tests every 3 months. If the patient had a positive ctDNA result during the ‘active’ ctDNA surveillance period, they were allocated centrally by the ICR-CTSU. Prior to the implementation of protocol v6.0; the randomised component of the trial; ctDNA surveillance was blinded and patients were randomised on a 2:1 basis via a minimisation algorithm to either pembrolizumab treatment or observation. Following the implementation of protocol version 6.0; the non-randomised component of the trial; all patients were then allocated to treatment intervention. 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 be blinded. For 12 months after the completion of pembrolizumab, patients will continue with ctDNA blood tests 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. Previous interventions: 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 on 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
Primary outcome measure	Current primary outcome measure as of 31/10/2019: 1. ctDNA positivity in blood by 12 months, as assessed by digital PCR on the blood sample taken at that time point 2. ctDNA positivity in blood by 24 months as assessed by digital PCR on the blood sample taken at that time point 3. Removal of ctDNA in the blood by 6 months (24 weeks) after starting pembrolizumab, measured by digital PCR on the blood sample collected 6 months (24 weeks) after commencing pembrolizumab 4. Absence of disease recurrence by 6 months (24 weeks) after starting pembrolizumab, measured by the recurrence assessment carried out 6 months (24 weeks) after commencing pembrolizumab Previous 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	Current secondary outcome measures as of 31/10/2019: 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. The time between randomisation to the therapeutic aspect of the trial (either to pembrolizumab treatment or observation group) and first confirmed detection of recurrent disease. 4. Proportion of patients without detectable ctDNA or disease recurrence 6 months after randomisation to observation group 5. Safety and tolerability of pembrolizumab treatment, assessed by NCI CTCAE v4.0 classification of adverse events and the proportion of patients reporting a dose reduction or delay 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. To explore predictors of sustained ctDNA clearance on pembrolizumab 3. To explore potential predictors of relapse and ctDNA detection, and alternative definitions of ctDNA clearance. Assess the relationship between lead time and clinical/biological factors using standard statistical techniques for time to event data. 4. Association between ctDNA clearance and time to recurrence in the pembrolizumab group, assessed using standard statistical techniques for time to event data Previous 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 study start date	01/07/2015
Overall study end date	31/03/2024

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 150; UK Sample Size: 150
Total final enrolment	208
Participant inclusion criteria	Current inclusion criteria as of 31/10/2019: 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: 6.1. Neoadjuvant chemotherapy (no adjuvant chemotherapy planned): 6.1.1. High-risk criteria - Residual microscopic or macroscopic invasive cancer in the axillary nodes after chemotherapy 6.1.2. Moderate risk criteria - Residual invasive cancer in the breast, and axillary lymph node negative after chemotherapy 6.2. Adjuvant chemotherapy: 6.2.1. High-risk criteria - Tumour size >50mm and node positive OR ≥4 nodes positive regardless of primary tumour size 6.2.2. Moderate risk criteria - Tumour size >20mm AND/OR involved axillary macroscopic lymph node 6.3 Both neoadjuvant and adjuvant chemotherapy: Patients who have received both neoadjuvant chemotherapy and further adjuvant chemotherapy must fulfil only the adjuvant chemotherapy risk criteria to be eligible. They can fulfil the criteria on either clinical staging prior to neoadjuvant chemotherapy or pathological staging at surgery 7. Patients must be registered according to the following criteria for timing of registration: 7.1. Neoadjuvant chemotherapy (no adjuvant chemotherapy planned): Patients must be registered within 6 weeks of surgery. Patients may be registered before or during radiotherapy and should be registered as early as possible 7.2. Adjuvant chemotherapy (no neoadjuvant chemotherapy received): Patients must be registered before, or on the day of, the 3rd cycle of adjuvant chemotherapy and should be registered as early as possible 7.3. Both neoadjuvant and adjuvant chemotherapy Patients must be registered within 6 weeks of surgery. Patients may be registered before or during radiotherapy. Patients must register before starting capecitabine 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 as of 26/10/2018: 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 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 6 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 6 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 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 exclusion criteria	Current exclusion criteria as of 26/10/2018: 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 or allogenic stem cell 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 16. A pathological complete response (pCR) to neoadjuvant chemotherapy (added 31/10/2019) Previous 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	06/12/2019

Locations

Countries of recruitment

England
Scotland
United Kingdom
Wales

Study participating centres

The Royal Marsden Hospital

Fulham Road
Chelsea
London
SW3 6JJ
United Kingdom

The Royal Marsden Hospital

Downs Road
Sutton
SM2 5PT
United Kingdom

Beatson West of Scotland Cancer Centre

1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

The Christie

550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom

Clatterbridge Cancer Centre

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

Western General Hospital

Crewe Road South
Edinburgh
EH4 2XU
United Kingdom

Nottingham University Hospital

City Campus Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Royal Bournemouth Hospital

Castle Lane East
Bournemouth
BH7 7DW
United Kingdom

Weston Park Hospital

Whitham Road
Sheffield
S10 2SJ
United Kingdom

University College Hospital

250 Euston Road
London
NW1 2PG
United Kingdom

Charing Cross Hospital

Fulham Palace Road
London
W6 8RF
United Kingdom

Churchill Hospital

Old Road
Headington
Oxford
OX3 7LE
United Kingdom

Velindre Hospital

Velindre Road
Whitchurch
Cardiff
CF14 2TL
United Kingdom

St Bartholomew’s Hospital

W Smithfield
London
EC1A 7BE
United Kingdom

Royal Cornwall Hospital

Treliske
Truro
TR1 3LJ
United Kingdom

Guy’s Hospital

London
SE1 9RT
United Kingdom

Maidstone Hospital

Maidstone
ME16 9QQ
United Kingdom

Sponsor information

Institute of Cancer Research
Research organisation

Royal Cancer Hospital
237 Fulham Road
London
SW3 6JB
United Kingdom

Phone	+44 208 722 4040
Email	c-trak-tn-icrctsu@icr.ac.uk
"ROR"	https://ror.org/043jzw605

Funders

Funder type

Industry

Merck Sharp and Dohme
Private sector organisation / For-profit companies (industry)

Alternative name(s): MSD United Kingdom, Merck Sharp & Dohme, Merck Sharp & Dohme Corp., MSD
Location: United Kingdom

National Institute for Health Research
Government organisation / National government

Alternative name(s): National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
Location: United Kingdom

Results and Publications

Intention to publish date	31/12/2022
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
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 plan	The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request (c-trak-tn-icrctsu@icr.ac.uk)

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol file	version 6.0	16/06/2020	04/01/2023	No	No
Results article		21/11/2022	04/01/2023	Yes	No
HRA research summary			28/06/2023	No	No
Plain English results			10/10/2023	No	Yes

Additional files

ISRCTN12569958_PROTOCOL_V6.0_16Jun20.pdf

Editorial Notes

10/10/2023: A link to the plain English results was added.
21/09/2023: The overall end date was changed from 31/12/2023 to 31/03/2024.
04/01/2023: The following changes have been made:
1. Protocol uploaded (not peer reviewed).
2. Publication reference and trial website added.
3. The overall trial end date was changed from 31/12/2022 to 31/12/2023.
4. The interventions were updated.
22/10/2021: Internal review.
20/09/2021: Internal review.
15/01/2020: The following changes have been made:
1. The recruitment end date has been changed from 31/12/2019 to 06/12/2019.
2. The overall trial end date has been changed from 31/12/2021 to 31/12/2022.
3. The total target enrolment has been changed from 150 to 200.
07/01/2020: The total final enrolment number has been added.
31/10/2019: The following changes were made to the trial record:
1. The primary outcome measure was changed.
2. The secondary outcome measures were changed.
3. The inclusion criteria were changed.
4. The exclusion criteria were changed.
5. The IPD sharing statement in the publication and dissemination plan was changed.
30/05/2019: The trial participating centres were updated.
03/04/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Breast Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasm of breast" to "Breast cancer" following a request from the NIHR.
01/02/2019: The recruitment end date has been changed from 31/10/2019 to 31/12/2019
26/10/2018: The following changes have been made:
1. The participant inclusion criteria have been changed.
2. The participant exclusion criteria have been changed.
3. Guy’s Hospital and Maidstone Hospital have been added as trial centres.
4. The public contact has been changed from Leona Batten to Sophie Perry.
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.