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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 (c-TRAK-TN)

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ClinicalTrials.gov Identifier: NCT03145961
Recruitment Status : Recruiting
First Posted : May 9, 2017
Last Update Posted : January 29, 2018
Sponsor:
Collaborators:
National Institute for Health Research Biomedical Research Centre at the Royal Marsden / Institute of Cancer Research UK
Merck Sharp & Dohme Ltd
Information provided by (Responsible Party):
Institute of Cancer Research, United Kingdom

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Drug: Pembrolizumab Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Masking Description:

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 the patient will be randomised by the 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 to the treatment arm.

For patients allocated to the observation group, the treating team and patient will not be informed that randomisation has taken place in order to remain blinded to the positive ctDNA result. Such patients will continue to have blood samples collected for ctDNA analysis every 3 months up to 2 years from starting ctDNA screening.

Primary Purpose: Treatment
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
Actual Study Start Date : December 21, 2017
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : December 1, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
No Intervention: Observation
Patient will have blood samples collected for ctDNA analysis every 3 months for up to 2 years from starting ctDNA screening.
Experimental: Pembrolizumab Treatment
Patients will be given pembrolizumab every 3 weeks for up to a maximum of 12 months, with blood samples collected prior to each cycle for continued ctDNA analysis. Following treatment discontinuation, blood samples will be collected for ctDNA analysis every 3 months for a further 12 months.
Drug: Pembrolizumab
200mg intravenous infusion
Other Name: Keytruda




Primary Outcome Measures :
  1. Positive ctDNA detection by 12 months [ Time Frame: 12 months ]
    The proportion of patients with ctDNA positivity by 12 months as assessed by the blood sample taken at that timepoint

  2. Positive ctDNA detection by 24 months [ Time Frame: 24 months ]
    The proportion of patients with ctDNA positivity by 24 months as assessed by the blood sample taken at that timepoint

  3. Absence of detectable ctDNA or disease recurrence 12 months after commencing pembrolizumab [ Time Frame: 12 months after commencing pembrolizumab ]
    The proportion of patients without either detectable ctDNA or disease recurrence 12 months after starting pembrolizumab


Secondary Outcome Measures :
  1. Time to ctDNA detection [ Time Frame: Baseline to first ctDNA positivity (up to a maximum of 12 months after starting ctDNA screening) ]
    The time from entry into ctDNA screening to first positive ctDNA detection

  2. Detection of overt metastatic disease at time of first ctDNA detection in patients allocated to pembrolizumab [ Time Frame: Baseline to first ctDNA positivity (up to a maximum of 12 months after starting ctDNA screening) ]
    Proportion of patients with metastatic disease at the same time point as first positive ctDNA detection

  3. Lead time between ctDNA detection and disease recurrence in the pembrolizumab treatment and observation groups [ Time Frame: From date of randomisation to recurrence detection, expected to occur up to 5 years ]
    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. Absence of detectable ctDNA or disease recurrence after 12 months in the observation group [ Time Frame: 12 months after randomisation ]
    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. [ Time Frame: Throughout pembrolizumab treatment, up to 12 months of treatment ]
    Adverse events assessed throughout treatment period, using the NCI CTCAE v4.0. Proportion of patients reporting a dose reduction or delay will be presented.

  6. Commencement of treatment in patients randomised to receive pembrolizumab [ Time Frame: At point of commencement or non-commencement of treatment, up to 8 weeks following randomisation ]
    Proportion of patients randomised to receive pembrolizumab who start the therapy.


Other 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 [ Time Frame: Time between first ctDNA detection and documented recurrence or disease free survival event, whichever comes first, expected to occur up to 5 years ]
    Time from first positive ctDNA detection to disease recurrence or disease-free survival event.

  2. Absence of ctDNA 12 months after commencing pembrolizumab and measurement of potential predictive biomarkers [ Time Frame: 12 months after commencing pembrolizumab ]
    The relationship between sustained clearance of ctDNA on pembrolizumab and biological markers will be summarised and investigated using logistic regression.

  3. Detection of ctDNA and measurement of potential predictive clinical and biological factors [ Time Frame: Baseline to point of positive ctDNA result, up to 24 months ]
    Relationship between lead time and clinical/biological factors will be assessed using standard statistical techniques for time to event data.

  4. Detection of disease relapse and measurement of potential predictive clinical and biological factors [ Time Frame: Baseline to point of disease recurrence, expected to occur up to 5 years ]
    Relationship between lead time and clinical/biological factors will be assessed using standard statistical techniques for time to event data.



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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03145961


Contacts
Contact: Sophie Perry 0208 722 4614 c-TRAK-TN-icrctsu@icr.ac.uk
Contact: Leona Batten 0208 722 4040 c-TRAK-TN-icrctsu@icr.ac.uk

Locations
United Kingdom
Royal Marsden Hospital, Chelsea Recruiting
Chelsea, London, United Kingdom, SW3 6JJ
Principal Investigator: Nick Turner         
Royal Marsden Hospital, Sutton Recruiting
Sutton, Surrey, United Kingdom, SM2 5PT
Principal Investigator: Nick Turner         
Queen Elizabeth Hospital Not yet recruiting
Birmingham, United Kingdom
Principal Investigator: Dan Rea         
Royal Bournemouth Hospital Recruiting
Bournemouth, United Kingdom
Principal Investigator: Tamas Hickish         
University Hospitals Bristol NHS Foundation Trust Not yet recruiting
Bristol, United Kingdom
Principal Investigator: Vivek Mohan         
Velindre Cancer Centre Not yet recruiting
Cardiff, United Kingdom
Principal Investigator: Simon Waters         
Western General Hospital Not yet recruiting
Edinburgh, United Kingdom
Principal Investigator: Peter Hall         
Beatson West of Scotland Cancer Centre Recruiting
Glasgow, United Kingdom
Principal Investigator: Iain MacPherson         
Charing Cross Hospital Not yet recruiting
London, United Kingdom
Principal Investigator: Farah Rehman         
St Bartholomew's Hospital Not yet recruiting
London, United Kingdom
Principal Investigator: Peter Schmid         
University College London Hopitals Not yet recruiting
London, United Kingdom
Principal Investigator: Fharat Raja         
The Christie NHS Foundation Trust Not yet recruiting
Manchester, United Kingdom
Principal Investigator: Andrew Wardley         
Nottingham University Hospitals NHS Trust Not yet recruiting
Nottingham, United Kingdom
Principal Investigator: Steven Chan         
Churchill Hospital Not yet recruiting
Oxford, United Kingdom
Principal Investigator: Rene Roux         
Weston Park Hospital Not yet recruiting
Sheffield, United Kingdom
Principal Investigator: Matthew Winter         
Royal Cornwall Hospital Not yet recruiting
Truro, United Kingdom
Principal Investigator: Duncan Wheatley         
Clatterbridge Cancer Centre Not yet recruiting
Wirral, United Kingdom
Principal Investigator: Carlo Palmieri         
Sponsors and Collaborators
Institute of Cancer Research, United Kingdom
National Institute for Health Research Biomedical Research Centre at the Royal Marsden / Institute of Cancer Research UK
Merck Sharp & Dohme Ltd
Investigators
Principal Investigator: Nick Turner Royal Marsden NHS Foundation Trust

Responsible Party: Institute of Cancer Research, United Kingdom
ClinicalTrials.gov Identifier: NCT03145961     History of Changes
Other Study ID Numbers: ICR-CTSU/2016/10058
2017-000508-92 ( EudraCT Number )
First Posted: May 9, 2017    Key Record Dates
Last Update Posted: January 29, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Formal requests for data sharing will be considered in line with ICR-CTSU procedure with due regard given to funder and sponsor guidelines. Requests are via a standard pro forma describing the nature of the proposed research and extent of data requirements. Data recipients are required to sign a data release form which describes the conditions for release and requirements for data transfer, storage, archiving, publication and Intellectual Property.

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Institute of Cancer Research, United Kingdom:
Breast cancer early stage
circulating tumour DNA
pembrolizumab
targeted therapy
randomised clinical trial
phase II
mutation screening
intermediate endpoint

Additional relevant MeSH terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Pembrolizumab
Antineoplastic Agents