NordicTrip

PROTOCOL SYNOPSIS

A translational randomized phase III study exploring the effect of the addition of capecitabine to carboplatin based chemotherapy in early “triple negative” breast cancer

Sponsor: Skåne University Hospital

Investigational Medical Product: Capecitabine, carboplatin, cyclophosphamide, epirubicin, paklitaxel, pembrolizumab.

Participating countries: Sweden, Denmark

Endpoints: Primary endpoint: pCR rate

Primary Translational Endpoint: pCR rate in the different study arms stratified for HRD status

Secondary endpoints: IDFS, OS, BCSS, DRFS, toxicity and outcome correlated with potential predictive biomarkers of response and toxicity.

Study Design:

Two armed, open label, multicenter.

Study treatment arms    

A: ddEC x 4à PK x 4, ie: (epirubicin 90 mg/m² + cyclophosphamide 600 mg/m²) every 2 weeks (q2w) x 4 followed by (paklitaxel 80 mg/m² day 1, 8, 15 + carboplatin AUC 5 day 1) every 3 weeks (q3w) x 4.

Pembrolizumab is given as the authority approved dose (e.g. a flat dose of 200 mg q3w or 400 mg q6w in Sweden or 2 mg/kg q3w or 4 mg/mg q6w to a maximum dose of 200 or 400 mg per cycle, respectively in Denmark) for the duration of preoperative chemotherapy.* 

B: CEX x 4à PK x 4, ie (epirubicin 75 mg/m² + cyclophosphamide 600 mg/m² + capecitabine 1800 mg/m² day 1-14) q3w x 4 followed by (paklitaxel 80 mg/m² day 1, 8, 15 + carboplatin AUC 5 day 1)      q3w x 4. Pembrolizumab is given as the authority approved dose for the duration of preoperative chemotherapy.*

*The addition of pembrolizumab is strongly recommended to all patients. However, patients with a documented contraindication, or unwilling to receive immunotherapy may be included in the study without the administration of pembrolizumab. 

Inclusion Criteria: 

Patients must meet all of the following criteria to be eligible:

1. Signed written informed consent approved by the  Ethical Review Board (IRB).
2. Age ≥ 18 to < 76 years.
3. Histologically confirmed unilateral                    adenocarcinoma of the breast where neoadjuvant  chemotherapy followed by definitive surgery is planned.

4. Node positive disease (N1-3) or if clinically N0 Tumor size ≥ 20 mm.

   When deciding T-stage the following hierarchy applies,

   1. MRI
   2. Ultrasound
   3. Mammography
   4. Clinical examination
5. ER negative tumor defined by at least one the following                                                                    a.       ER < 1% cells positive by                                          immunohistochemistry (IHC) or ER ≤ 10%                cells positive by IHC and basal-like subtype              using gene expression analysis
    b.       ER ≤ 10% cells positive by IHC and PgR ≤              10% cells positive by IHC
   
6. HER2-normal tumor defined according to applicable national guidelines.
7.  Consent for germline mutation screening for BRCA1, BRCA2 and other inherited breast cancer associated genes.
8. WHO performance status 0 or 1.
9. Negative pregnancy test in women of childbearing potential (premenopausal or <12 months of amenorrhea post-menopause and who have not undergone surgical sterilization).
10. Willingness of female patients of childbearing potential, male patients and their sexual partners to use an effective means of contraception during the treatment period and at least 6 months thereafter.
11. Willingness by the patient to undergo treatment and study related procedures according to the protocol.    

Exclusion Criteria:

Patients meeting any of the following criteria are not eligible:

1. Clinical or radiological signs of metastatic disease.
2. History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or non-melanoma skin cancer.
3. Previous chemotherapy for cancer or other malignant disease.
4. Charlson comorbidity index, excluding score for malignancy: (CCI) > 2, Comment: In patients 70-75 a CCI = 3 is allowed, see appendix B.
5. Inadequate organ function, suggested by the following laboratory results:                              a.     Absolute neutrophil count < 1,5 x 10⁹/L      b.     Platelet count < 100 x 10⁹/L                        c.     Haemoglobin < 90 g/L                              d.     Total bilirubin greater than the upper limit          of normal (ULN) unless the patient has              documented Gilbert´s syndrome                e.     ASAT (SGOT) and/or ALAT (SGPT)                    > 2,5 x ULN                                                f .     ASAT (SGOT) and/or ALAT (SGPT)                    > 1,5 x ULN with concurrent serum                    alkaline phosphatase (ALP)                                > 2,5 x ULN                                              g.     Serum creatinine clearance < 50 ml/min
   
6. Concurrent peripheral neuropathy of grade 3 or greater (NCI-CTCAE, Version 5.0).
7. Patient who is actively breast feeding.
8.  Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.

9. Patients with known deficiency of the DPD-enzyme who completely lack DPD.