c-TRAK TN is a multi-centre phase II study, consisting of a circulating tumour DNA (ctDNA)
screening component and a therapeutic component. c-TRAK TN aims to assess whether ctDNA
screening can be used to detect residual disease following patients standard primary
treatment for triple negative breast cancer, and will assess the safety and activity of the
investigational medicinal product pembrolizumab.
Patients will undergo blinded serial ctDNA screening every 3 months from the point of
registration and completion of primary treatment for their triple negative breast cancer. If
a ctDNA positive result occurs on or before their 12 month ctDNA screening assessment they
will be randomised by the Institute of Cancer Research Clinical Trials and Statistics Unit
(ICR-CTSU) in a 2:1 ratio to the pembrolizumab treatment arm or observation arm. The patient
and their treating team will only be informed of the randomisation if they are allocated
treatment.
Patients without a positive ctDNA result within 12 months of starting ctDNA screening, will
not be randomised but will continue to have blinded ctDNA screening every 3 months up to 2
years from starting ctDNA screening.
All patients will be followed up every 6 months until recurrence, specific withdrawal of
consent for follow up, or until sponsor advises no further follow up is required.
Inclusion Criteria:
1. Signed Informed Consent Form for Registration
2. Male or female patients ages 16 years or older
3. Eastern Cooperative Oncology Group (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 human epidermal growth factor receptor 2 (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
the designated Trial Management Group (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:
1. Neoadjuvant chemotherapy - residual invasive cancer in the axillary node after
chemotherapy, defined as at least microscopic residual disease (>0.2mm) by
histology, OR One Step Nucleic acid Amplification (OSNA) macroscopic, OR OSNA
microscopic with residual invasive cancer in the breast.
2. Adjuvant chemotherapy - tumour size >50mm and node positive AND/OR ≥4 nodes
positive regardless of primary tumour size.
Moderate risk criteria:
1. Neoadjuvant chemotherapy - residual invasive cancer in the breast and axillary
lymph node negative after chemotherapy
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. 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
NB: Additional eligibility criteria apply to confirm eligibility to commence pembrolizumab
treatment following randomisation.
Exclusion Criteria:
1. Any concurrent or planned treatment for the current diagnosis of breast cancer other
than surgery, locoregional adjuvant radiotherapy, standard neoadjuvant or adjuvant
chemotherapy, or a bisphosphonate/denosumab.
2. Prior treatment with a programmed death ligand 1(PDL1), programmed cell death protein
1 (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 Tuberculosis Bacillus (TB).
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.
NB. Additional exclusion criteria apply to confirm eligibility to commence pembrolizumab
treatment following randomisation.
