| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early stage triple negative breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Primary triple negative breast cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| There are two mains purposes of the c-TRAK TN trial. Firstly, to assess in patients with moderate or high risk primary triple negative breast cancer that have completed standard treatment, whether ctDNA screening of serial blood samples can predict which patients are at highest risk of relapse (cancer coming back) and identify patients with microscopic or minimal residual disease (MRD) (indicated by a positive ctDNA blood test) that is not visible on a scan. Secondly, in patients that have MRD detected during ctDNA screening, to assess the potential effectiveness of adjuvant treatment with pembrolizumab, assessed as the ability to result in a sustained clearance of ctDNA (indicated by successive negative ctDNA blood tests). |
|
| E.2.2 | Secondary objectives of the trial |
•To assess time to first positive ctDNA detection from entry into the ctDNA screening.
•To assess the rate of detection of overt metastatic disease at the time of first ctDNA detection.
•To assess the median lead-time between ctDNA detection and relapse (observation group).
•To assess sustained clearance of ctDNA in the observation group.
•Safety and tolerability of pembrolizumab.
•To assess the proportion of patients allocated to receive pembrolizumab who start pembrolizumab.
NB. Secondary objectives relating to the observation group will be evaluated in the patients group randomised to the observation group prior to the implementation of protocol v6.0. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Tracking tumour evolution through adjuvant therapy in Triple Negative Breast Cancer
Application date: 07-APR-2020
Objectives:
1. To analyse the evolution of triple negative breast cancer from early to advanced incurable disease with a view to informing future therapeutic approaches and clinical trials.
2. To analyse the primary tumour to assess for features which may be predictive for metastatic relapse including heterogeneity, chromosomal instability, mutational signatures and tumour infilitrating lymphocytes (TILs).
3. To assess if the immune system plays a role in shaping the evolution of breast cancer in the adjuvant setting but performing sequencing of the T cell receptor repertoire.
4. To assess if adjuvant therapies, such as pembrolizumab play a role in shaping the evolution of triple negative breast cancer in the adjuvant setting. |
|
| E.3 | Principal inclusion criteria |
Inclusion criteria for all patients:
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 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:
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 (no neoadjuvant chemotherapy received):
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 receiving adjuvant capecitabine 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. 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 on ctDNA detection
13. No evidence of distant metastatic disease or local recurrence on staging scans conducted at any time since initial diagnosis
Additional inclusion criteria for pembrolizumab treatment:
1. Signed Informed Consent Form for pembrolizumab treatment
2. Adequate organ function as defined by bone marrow function, renal function and coagulation laboratory values as per protocol
3. Women of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of trial medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
4. Patients willing to receive a 12 month course of pembrolizumab and have frequent blood tests (every 3 weeks during treatment and every three months for a year following completion of pembrolizumuab treatment). |
|
| E.4 | Principal exclusion criteria |
Exclusion criteria for all patients:
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 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 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
Additional exclusion criteria for pembrolizumab treatment:
1. Diagnosis of an additional cancer since enrolment in the trial other than basal cell carcinoma of the skin or cervical carcinoma in situ
2. Prior chemotherapy, targeted small molecule therapy or radiation therapy within 4 weeks prior to first administration of pembrolizumab, with the exception of planned locoregional adjuvant radiotherapy.
3. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to first administration of pembrolizumab.
4. Has not recovered (≤ Grade 1 or patient’s baseline) from adverse events due to a previously administered therapy. Note: Patients with ≤ grade 2 neuropathy or alopecia of any grade are an exception to this criterion and may qualify for the trial. If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the surgery prior to randomisation.
5. Treatment with an unlicensed or investigational product within 4 weeks prior to first administration of pembrolizumab
6. Received a live vaccine within 30 days of planned start of pembrolizumab. (seasonal flu vaccines are generally inactivated and are permitted; however intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines and are not permitted.)
7. Presence of any systemic illness incompatible with participation in the clinical trial or inability to provide written informed consent. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for ctDNA screening is positive ctDNA detection by 12 and 24 months from start of ctDNA screening. This will be calculated as the proportion of patients with ctDNA positivity by each timepoint from those with assessment performed at that timepoint.
The primary endpoint for the therapeutic component is absence of detectable ctDNA or disease recurrence 6 months (24 weeks) after commencing pembrolizumab. This will be calculated as the proportion of patients without either detectable ctDNA or disease recurrence 6 months (24 weeks) after commencing pembrolizumab. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint for ctDNA screening will be evaluated at 12 and 24 months from start of ctDNA screening. The primary endpoint for the therapeutic component will be evaluated at 6 months (24 weeks) after commencing pembrolizumab.
|
|
| E.5.2 | Secondary end point(s) |
The secondary endpoint for ctDNA screening is time to ctDNA detection.
The secondary endpoints for the therapeutic component are:
1) Detection of overt metastatic disease at the time of first ctDNA detection in patients allocated to pembrolizumab..
2) Lead-time between ctDNA detection and recurrence in the pembrolizumab treatment and observation groups.
3) Absence of detectable ctDNA or disease recurrence after 6 months in the observation group.
4) Safety and tolerability of pembrolizumab in this patient group.
5) Commencement of treatment in patients allocated to receive pembrolizumab.
NB. Secondary endpoints relating to the observation group will be analysed in the patients group randomised to the observation group prior to the implementation of protocol v6.0. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoint for ctDNA surveillance will be calculated as the time from entry into the ctDNA surveillance to first positive ctDNA detection.
The secondary endpoints for the therapeutic component will be calculated as:
1) The proportion of patients with metastatic disease from CT scan at the same time point as first positive ctDNA detection
2) The time between therapeutic trial entry and first confirmed detection of recurrent disease
3) The proportion of patients without either detectable ctDNA or disease recurrence 6 months after randomisation to the observation group
4) Safety will be assessed throughout the treatment period
5) The proportion of patients allocated to receive pembrolizumab who start this therapy |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| The current component of the trial is a phase II, single-arm study. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The trial end date is deemed to be the date of last data capture. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 11 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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