NordicTrip, a Translational Study of Preoperative Chemotherapy in TNBC

Study Overview
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Brief Summary
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Primary aim: To compare the effect on pathologic complete response (pCR) rate of adding capecitabine to carboplatin based preoperative chemotherapy in early ER-negative and HER2-negative breast cancer. Pembrolizumab is allowed in both arms after approval for TNBC 2022.

Detailed Description
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Primary aim: Pathological complete response rate after preoperative chemotherapy is the primary end-point of the study, which will be evaluated by comparing the effects of neoadjuvant administration of a carboplatin-based treatment and treatment adding capecitabine on pCR. After the approval of pembrolizumab in the preoperative treatment of early TNBC in 2022 the study will consist of two cohorts, one (cohort 1) without the addition of pembrolizumab, and one (cohort 2) with the addition of pembrolizumab to both study arms. The primary evaluation will be performed on the entire study population including both cohorts. Primary translational aim: To investigate if the effects of the treatments depend on homologous repair deficiency (HRD)-status. More specifically, the aim is to test for differential effect of the two treatments on pCR for HRD-negative (HRD low and intermediate by oncoscan) and HRD-positive (HRD high by oncoscan) patients.

Official Title
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A Translational Randomized Phase III Study Exploring the Effect of the Addition of Capecitabine to Carboplatine Based Chemotherapy in Early Triple Negative Breast Cancer

Conditions
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Breast Cancer, Triple Negative Breast Neoplasms

Intervention / Treatment
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* Drug: epirubicin, cyclophosphamide, paclitaxel, carboplatin, pembrolizumab
* Drug: epirubicin, cyclophosphamide, capecitabine, paclitaxel, carboplatin, pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent approved by the Ethical Review Board (IRB). Age ≥ 18 to < 76 years. Histologically confirmed unilateral adenocarcinoma of the breast where neoadjuvant chemotherapy followed by definitive surgery is planned. Node positive disease (N1-3) or if clinically N0 Tumor size >20 mm. When deciding T-stage the following hierarchy applies, MRI Ultrasound Mammography Clinical examination ER negative tumor defined by at least one the following: ER < 1% cells positive by immunohistochemistry (IHC) or ER ≤ 10% cells positive by IHC and basal-like subtype using gene expression analysis ER < 10% cells positive by IHC and PgR < 10% cells positive by IHC HER2-normal tumor defined according to applicable national guidelines Consent for germline mutation screening for BRCA1, BRCA2 and other inherited breast cancer associated genes. WHO performance status 0 or 1. Negative pregnancy test in women of childbearing potential (premenopausal or <12 months of amenorrhea post-menopause and who have not undergone surgical sterilization). 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. Willingness by the patient to undergo treatment and study related procedures according to the protocol. Exclusion Criteria: Clinical or radiological signs of metastatic disease. History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or non-melanoma skin cancer. Previous chemotherapy for cancer or other malignant disease. Charlson comorbidity index, excluding score for malignancy: (CCI) > 2, Comment: In patients 70-75 a CCI = 3 is allowed, see appendix B. 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 Hemoglobin < 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 Concurrent peripheral neuropathy of grade 3 or greater (NCI-CTCAE, Version 5.0). Patient who is actively breast feeding. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol. Patients with known deficiency of the DPD-enzyme who completely lack DPD.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (Platinum-based dose dense EC):<br>ddEC x 4 + pembrolizumab→ PK x 4 + pembrolizumab, Two-weekly epirubicin/cyclophosphamide (EC) x 4 (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2), followed after a three-week interval by three-weekly carboplatin x 4 (AUC = 5) together with weekly paclitaxel x 12 (80 mg/m2). Pembrolizumab is given as a 400 mg iv dosis every 6 weeks for the duration of preoperative chemotherapy.* | Drug: epirubicin, cyclophosphamide, paclitaxel, carboplatin, pembrolizumab<br>* Cytotoxic agents.<br>* Other names: anthracycline, taxane, platinum;|
| Experimental: Arm B (Platinum-based with capecitabine):<br>CEX x 4→ PK x 4, Three-weekly cyclophosphamide/epirubicin/capecitabine (CEX) (epirubicin 75 mg/m2, cyclophosphamide 600 mg/m2 and capecitabine 900 mg/m2) x 4, followed after a three-week interval by three-weekly carboplatin x 4 (AUC = 5) together with weekly paclitaxel x 12 (80 mg/m2).Pembrolizumab is given as a 400 mg iv dosis every 6 weeks for the duration of preoperative chemotherapy.* *The addition of pembrolizumab is strongly recommended to all participating patients. However, patients with a documented contraindication, or unwilling to receive immunotherapy may be included in the study without the administration of pembrolizumab. | Drug: epirubicin, cyclophosphamide, capecitabine, paclitaxel, carboplatin, pembrolizumab<br>* Cytotoxic agents.<br>* Other names: anthracycline, taxane, antimetabolite, platinum;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response rate. | Rate of pathological complete response, allowing residual dcis, at surgery after preoperative chemotherapy. | Immediately after surgery | 
| Primary translational outcome. | Pathological complete response rate, allowing residual dcis, stratified for homologous repair deficiency. | Immediately after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease Free Survival (IDFS) | Invasive disease-free survival | Throughout the study, an average of 3 years | 
| Overall Survival (OS) | Overall survival | Throughout the study, an average of 5 years | 
| Breast Cancer Specific Survival (BCSS) | Breast cancer specific survival | Throughout the study, an average of 3 years | 
| Distant Recurrence Free Survival (DRFS) | Distant recurrence free survival. | Throughout the study, an average of 3 years | 
| Dose intensity | Actual dosis/dosis per protocol | Immediately after surgery | 
| Toxicity according to CTCAE version 5.0 | Rate of included patients with toxicity grade 3 or greater during study treatment | Immediately after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast neoplasms, Triple negative breast neoplasms, Neoadjuvant treatment, Translational research, Pathologic response, Pathologic complete response, epirubicin, cyclophosphamide, paclitaxel, carboplatin, capecitabine, Survival outcomes, Homologous repair deficiency, pembrolizumab