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

Triple Negative Breast Cancer Clinical Trial

— c-TRAK-TN  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03145961
• Other study ID #: ICR-CTSU/2016/10058
• Secondary ID: 2017-000508-92
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 21, 2017
• Est. completion date: March 31, 2024

Study information

• Verified date: February 2022
• Source: Institute of Cancer Research, United Kingdom
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 208
• Est. completion date: March 31, 2024
• Est. primary completion date: September 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

Intervention

Drug:
• Pembrolizumab
200mg intravenous infusion

Locations

Country	Name	City	State
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	Royal Marsden Hospital, Chelsea	Chelsea	London
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Charing Cross Hospital	London
United Kingdom	Guy's Hospital	London
United Kingdom	St Bartholomew's Hospital	London
United Kingdom	University College London Hopitals	London
United Kingdom	Maidstone Hospital	Maidstone
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Weston Park Hospital	Sheffield
United Kingdom	Royal Marsden Hospital, Sutton	Sutton	Surrey
United Kingdom	Royal Cornwall Hospital	Truro
United Kingdom	Clatterbridge Cancer Centre	Wirral

Sponsors (3)

Lead Sponsor	Collaborator
Institute of Cancer Research, United Kingdom	Merck Sharp & Dohme Corp., National Institute for Health Research Biomedical Research Centre at the Royal Marsden / Institute of Cancer Research UK

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Descriptive differences in time between ctDNA detection and disease recurrence, and disease free survival, between patients in the pembrolizumab and the observation groups	Time from first positive ctDNA detection to disease recurrence or disease-free survival event.	Time between first ctDNA detection and documented recurrence or disease free survival event, whichever comes first, expected to occur up to 5 years
Other	To explore predictors of sustained ctDNA clearance on pembrolizumab.	The relationship between sustained clearance of ctDNA on pembrolizumab and biological markers will be summarised and investigated using logistic regression.	6-12 months after commencing pembrolizumab
Other	To explore potential predictors of relapse and ctDNA detection, and alternative definitions of ctDNA clearance	Relationship between lead time and clinical/biological factors will be assessed using standard statistical techniques for time to event data.	Baseline to point of disease recurrence, expected to occur up to 5 years
Other	Association between ctDNA clearance and time to recurrence in pembrolizumab group	Relationship between ctDNA clearance and time to recurrence in the pembrolizumab group will be assessed using standard statistical techniques for time to event data.	Time of ctDNA clearance to time of recurrence, expected to occur up to 5 years
Primary	Positive ctDNA detection by 12 months	The proportion of patients with ctDNA positivity by 12 months as assessed by the blood sample taken at that timepoint	12 months
Primary	Positive ctDNA detection by 24 months	The proportion of patients with ctDNA positivity by 24 months as assessed by the blood sample taken at that timepoint	24 months
Primary	Absence of detectable ctDNA or disease recurrence 6 months (24 weeks) after commencing pembrolizumab	The proportion of patients without either detectable ctDNA or disease recurrence 6 months (24 weeks) after starting pembrolizumab	6 months (24 weeks) after commencing pembrolizumab
Secondary	Time to ctDNA detection	The time from entry into ctDNA surveillance to first positive ctDNA detection	Baseline to first ctDNA positivity (up to a maximum of 12 months after starting ctDNA surveillance)
Secondary	Detection of overt metastatic disease at time of first ctDNA detection in patients allocated to pembrolizumab	Proportion of patients with metastatic disease at the same time point as first positive ctDNA detection	Baseline to first ctDNA positivity (up to a maximum of 12 months after starting ctDNA surveillance)
Secondary	Lead time between ctDNA detection and disease recurrence in the pembrolizumab treatment and observation groups	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.	From date of randomisation to recurrence detection, expected to occur up to 5 years
Secondary	Absence of detectable ctDNA or disease recurrence after 6 months in the observation group	Proportion of patients without detectable ctDNA or disease recurrence 6 months after randomisation to observation group	6 months after randomisation
Secondary	Safety and tolerability of pembrolizumab assessed using NCI CTCAE v4.0, and the proportion of patients reporting dose reductions or delays.	Adverse events assessed throughout treatment period, using the NCI CTCAE v4.0. Proportion of patients reporting a dose reduction or delay will be presented.	Throughout pembrolizumab treatment, up to 12 months of treatment
Secondary	Commencement of treatment in patients randomised to receive pembrolizumab	Proportion of patients randomised to receive pembrolizumab who start the therapy.	At point of commencement or non-commencement of treatment, up to 8 weeks following randomisation