Combining capecitabine with pembrolizumab for triple negative breast cancer after surgery

• CRITERIA FOR EXPERIMENTAL ARM :

Inclusion criteria (for experimental arm):

Patients eligible for this study must meet ALL of the following criteria:

1. Patient must have signed a written informed consent prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent;
2. Subject ≥18 years of age on day of signing informed consent form (ICF);
3. Histologically proven TNBC defined as follows:

   1. HER2 negativity (ASCO/CAP criteria)
   2. AND less than 10% of cells stained by immunohistochemistry (IHC) for ER and PgR;
4. TNBC patients previously treated by standard neoadjuvant chemotherapy with a minimum of 6 cycles of immunochemotherapy containing pembrolizumab, per standard of care (and pembrolizumab label) and anthracyclines and/or taxanes (with/without carboplatin). Other drugs may be acceptable following discussion with the sponsor (with the exclusion of capecitabine);
5. Complete resection of the breast tumor(s) (and of any invaded lymph node);
6. No complete pathological response, defined as RCB Class I, II or III (per local assessment);
7. Available representative formalin-fixed paraffin-embedded (FFPE) tumor block from surgery specimen with its histological report;
8. Eastern Cooperative Oncology Group (ECOG) Performance Status \<2;
9. Adequate organ and bone marrow function. All screening lab tests should be performed within 28 days before inclusion;
10. Resolution to at least grade 1 of all acute toxicities from previous therapies including immune-related toxicity due to pembrolizumab, except alopecia and grade 2 immune-related endocrinopathies controlled by hormone replacement which are allowed;
11. Minimal/maximal period for prior treatments (i.e. minimal delay from last dose of prior treatment to C1D1): breast surgery (the wound must have healed prior to C1D1) ≥2 weeks (maximum 10 weeks); last pembrolizumab injection ≥3 weeks;
12. Women of child-bearing potential must have a negative serum pregnancy test within 7 days before C1D1;
13. Women of child-bearing potential and male patients must agree to use 1 effective form of contraception from the time of the negative pregnancy test up to 6 months after the last dose of study drugs;
14. Patient should be able and willing to comply with study visits and procedures as per protocol;
15. Patients must be affiliated to a Social Security System (or equivalent).

Non-inclusion criteria (for experimental arm):

Patients eligible for this study must not meet ANY of the following criteria:

1. Radiological or clinical evidence of metastatic disease documented by imaging or clinical examination performed during screening period;
2. Has received capecitabine or other ICI than pembrolizumab in the NAC regimen;
3. Has a known additional malignancy, excepted skin basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer or previously treated malignancy with no evidence of disease for ≥2 years;
4. Presents a contraindication to continue pembrolizumab treatment as per respective SmPC including known hypersensitivity;
5. Previous immune-related adverse event of any grade due to pembrolizumab that led to permanent discontinuation of pembrolizumab;
6. Presents a contraindication to capecitabine treatment as per SmPC (See EMA website for most recent edition of SmPC);
7. Complete DPD (Dihydropyrimidine Dehydrogenase) deficiency (a systematic screening of DPD deficiency must be performed);
8. Patient with active infection ;
9. Patients with history of uncontrolled or symptomatic cardiac disease ;
10. Patients having received brivudine within 4 weeks prior to inclusion;
11. Require the use of one of the following forbidden treatments during the study treatment period:

    * Any investigational anticancer therapy other than the protocol specified treatment;
    * Any concurrent chemotherapy, immunotherapy, biologic for cancer treatment, other than the ones stated in the protocol;
12. Pregnant women or women who are breast-feeding;
13. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons;
14. Persons deprived of their liberty or under protective custody or guardianship;
15. Participation in another therapeutic trial within the 30 days prior to randomization.

    * CRITERIA FOR STANDARD OF CARE TREATED EXTERNAL COHORT

Inclusion criteria (for standard of care treated external cohort) :

Patients eligible for this cohort must meet ALL of the following criteria:

1. Patient information prior to study entry and non-opposition to data collection
2. Subject ≥18 years of age ;
3. Histologically proven TNBC defined as follows:

   1. HER2 negativity (ASCO/CAP criteria)
   2. AND less than 10% of cells stained by immunohistochemistry (IHC) for ER and PgR;
4. TNBC patients previously treated by standard neoadjuvant chemotherapy with a minimum of 6 cycles of immunochemotherapy containing pembrolizumab, per standard of care (and pembrolizumab label) and anthracyclines and/or taxanes (with/without carboplatin). Other drugs may be acceptable following discussion with the sponsor (with the exclusion of capecitabine);
5. Complete resection of the breast tumor(s) (and of any invaded lymph node);
6. No complete pathological response, defined as RCB Class I, II or III (per local assessment);
7. Patient should have received at least one injection of pembrolizumab as post-surgery treatment (concomitantly or after radiotherapy).

Non-exclusion criteria (for standard of care treated external cohort) :

Patients eligible for this study must not meet ANY of the following criteria:

1. Radiological or clinical evidence of metastatic disease documented by imaging or clinical examination after surgery.
2. Has received capecitabine or other ICI than pembrolizumab in the NAC regimen;
3. Has a known additional malignancy, excepted skin basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer or previously treated malignancy with no evidence of disease for ≥2 years;
4. Any investigational anticancer therapy (chemotherapy, immunotherapy, biologic for cancer treatment) other than pembrolizumab only as adjuvant treatment.