Clinical trial NCT03145961: A Trial Using ctDNA Blood Tests to Detect Cancer Cells After Standard Treatment to Trigger Additional Treatment in Early Stage Triple Negative Breast Cancer Patients
Official 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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Triple Negative Breast Cancer
Keywords: Breast cancer early stage
circulating tumour DNA
pembrolizumab
targeted therapy
randomised clinical trial
phase II
mutation screening
intermediate endpoint
Lead sponsor: Institute of Cancer Research, United Kingdom
Sponsor class: OTHER
Collaborators: name: National Institute for Health Research Biomedical Research Centre at the Royal Marsden / Institute of Cancer Research UK
name: Merck Sharp & Dohme LLC
First posted: 2017-05-09
Enrollment: 208
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: c-TRAK TN is a multi-centre phase II study, consisting of a circulating tumour DNA (ctDNA) surveillance component and a therapeutic component. c-TRAK TN aims to assess whether ctDNA surveillance 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.

Detailed description: During the randomised component of the trial (prior to implementation of protocol v6.0 on 16 Sept 2020), patients would undergo serial ctDNA surveillance every 3 months from the point of registration and completion of primary treatment for their triple negative breast cancer. ctDNA surveillance was blinded and the detection of a ctDNA positive result on or before the 12 month ctDNA surveillance assessment triggered randomisation to treatment with pembrolizumab or observation (on a 2:1 ratio). The patient and their treating team were only informed of the randomisation if allocated treatment.

Patients without a positive ctDNA result within 12 months of starting ctDNA surveillance, continued to have blinded ctDNA surveillance every 3 months up to 2 years total.

Following the implementation of protocol v6.0 (16 Sept 2020), patients were asked to transfer to the non-randomised component of the trial, all patients who were previously randomised to observation and remain in active ctDNA surveillance would transition to the non-randomised component of the trial following re-consent, and allocated pembrolizumab at the next positive ctDNA result.

All patients will be followed up every 6 months until disease recurrence, specific withdrawal of consent for follow up, or until sponsor advises no further follow up is required.

Eligibility criteria: Inclusion Criteria:

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:

   Neoadjuvant chemotherapy (no adjuvant chemotherapy planned) High risk criteria - Residual microscopic or macroscopic invasive cancer in the axillary nodes after chemotherapy Moderate risk criteria - Residual invasive cancer in the breast, and axillary lymph node negative after chemotherapy Adjuvant chemotherapy High risk criteria - Tumour size \>50mm and node positive OR ≥4 nodes positive regardless of primary tumour size.

   Moderate risk criteria - Tumour size \>20mm AND/OR involved axillary macroscopic lymph node.

   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:

   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.

   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.

   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 allocated 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 surveillance and 3 weekly if subsequently allocated pembrolizumab) and receive a 12 month course of pembrolizumab on ctDNA detection.
13. No evidence of distant metastatic disease or local recurrence 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, loco regional adjuvant radiotherapy, standard neoadjuvant or 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 (see protocol section 15).
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 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

NB. Additional exclusion criteria apply to confirm eligibility to commence pembrolizumab treatment following randomisation.

Primary outcomes:
measure: Positive ctDNA detection by 12 months
timeFrame: 12 months
measure: Positive ctDNA detection by 24 months
timeFrame: 24 months
measure: Absence of detectable ctDNA or disease recurrence 6 months (24 weeks) after commencing pembrolizumab
timeFrame: 6 months (24 weeks) after commencing pembrolizumab
Secondary outcomes:
measure: Time to ctDNA detection
timeFrame: Baseline to first ctDNA positivity (up to a maximum of 12 months after starting ctDNA surveillance)
measure: Detection of overt metastatic disease at time of first ctDNA detection in patients allocated to pembrolizumab
timeFrame: Baseline to first ctDNA positivity (up to a maximum of 12 months after starting ctDNA surveillance)
measure: Lead time between ctDNA detection and disease recurrence in the pembrolizumab treatment and observation groups
timeFrame: From date of randomisation to recurrence detection, expected to occur up to 5 years
measure: Absence of detectable ctDNA or disease recurrence after 6 months in the observation group
timeFrame: 6 months after randomisation
measure: Safety and tolerability of pembrolizumab assessed using NCI CTCAE v4.0, and the proportion of patients reporting dose reductions or delays.
timeFrame: Throughout pembrolizumab treatment, up to 12 months of treatment
measure: Commencement of treatment in patients randomised to receive pembrolizumab
timeFrame: At point of commencement or non-commencement of treatment, up to 8 weeks following randomisation
Other outcomes:
measure: Descriptive differences in time between ctDNA detection and disease recurrence, and disease free survival, between patients in the pembrolizumab and the observation groups
timeFrame: Time between first ctDNA detection and documented recurrence or disease free survival event, whichever comes first, expected to occur up to 5 years
measure: To explore predictors of sustained ctDNA clearance on pembrolizumab.
timeFrame: 6-12 months after commencing pembrolizumab
measure: To explore potential predictors of relapse and ctDNA detection, and alternative definitions of ctDNA clearance
timeFrame: Baseline to point of disease recurrence, expected to occur up to 5 years
measure: Association between ctDNA clearance and time to recurrence in pembrolizumab group
timeFrame: Time of ctDNA clearance to time of recurrence, expected to occur up to 5 years
Locations:
city: Chelsea
country: United Kingdom
facility: Royal Marsden Hospital, Chelsea
state: London
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital, Sutton
state: Surrey
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: University College London Hopitals
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Wirral
country: United Kingdom
facility: Clatterbridge Cancer Centre
Study officials:
affiliation: Royal Marsden NHS Foundation Trust
name: Nick Turner
role: PRINCIPAL_INVESTIGATOR
References: