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

The primary objective of this study is 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. This is clinically relevant as achieving a higher pCR rate is associated with improved long-term outcomes in patients with early triple-negative breast cancer.

Secondary objectives include:

• Comparing invasive disease-free survival (IDFS), breast cancer-specific survival (BCSS), distant recurrence-free survival (DRFS), and overall survival (OS).
• Evaluating the tolerability defined by toxicity and dose intensity.
• Determining the pCR rates in different treatment arms stratified for **Homologous Repair Deficiency (HRD)** positive versus HRD-negative/HRD-intermediate.
• Characterizing different subsets of **triple-negative breast cancer (TNBC)** in terms of morphology, epigenetic alterations, as well as somatic and inherited genetic alterations.
• Determining the pCR rate and long-term outcome in subsets of TNBC with defined molecular genetic alterations, including **BRCA1**, **BRCA2**, and **PALB2** germline mutations and others, BRCA1, BRCA2, and PALB2 somatic mutations and others, and BRCA1 or **RAD51** promoter methylation.

The clinical trial focuses on participants diagnosed with **early triple negative breast cancer**. The study population includes both female and male subjects, with an age range of 18 to less than 76 years. Participants are required to have a histologically confirmed unilateral adenocarcinoma of the breast, with neoadjuvant chemotherapy followed by definitive surgery planned. The trial includes individuals with node-positive disease (N1-3) or clinically N0 tumors over 20 mm. Participants must have ER-negative tumors, defined by specific immunohistochemistry criteria, and HER2-normal tumors according to national guidelines. The trial population was selected based on these criteria, and participants must consent to germline mutation screening for BRCA1, BRCA2, and other inherited breast cancer-associated genes. The general health status of participants is indicated by a WHO performance status of 0 or 1. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data. The trial includes a vulnerable population, and both genders are represented in the study.

The clinical trial is a **randomized**, phase III study designed to evaluate the effect of adding **capecitabine** to a **carboplatin**-based chemotherapy regimen in patients with early **triple-negative breast cancer**. The trial employs a **double-blind** and **controlled** methodology to ensure unbiased results. The estimated duration of the trial is from September 2019 to August 2034, with participant involvement expected to last up to 23 weeks, depending on individual treatment response and adherence to protocol.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, tumor characteristics, and performance status. Following successful screening, participants will be randomized to receive either the investigational treatment or the control. The treatment phase includes regular follow-up visits to monitor safety, efficacy, and adherence to the treatment regimen. These visits will involve clinical assessments, laboratory tests, and imaging studies as required by the protocol. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be conducted to evaluate the primary endpoint of pathologic complete response (pCR) and secondary endpoints such as Invasive Disease-Free Survival (IDFS) and Overall Survival (OS).

Participants may be withdrawn from the study prematurely if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest. The trial aims to provide robust data on the potential benefits of adding capecitabine to the standard chemotherapy regimen, contributing to the optimization of treatment strategies for early triple-negative breast cancer.

The clinical trial involves the administration of several **experimental medications**. **Cyclophosphamide** is provided as a **powder for solution for infusion** and is administered via **intravenous use**. The dosage is calculated based on body surface area, with a maximum daily dose of 600 mg/m² and a total maximum dose of 1800 mg/m² over a treatment period of 23 weeks.

**Epirubicin** is supplied as a **concentrate for solution for infusion** and is also administered intravenously. The maximum daily dose is 90 mg/m², with a total maximum dose of 360 mg/m² over the same treatment period.

**Pembrolizumab**, marketed as **Keytruda 25 mg/mL concentrate for solution for infusion**, is administered intravenously. The maximum daily dose is 400 mg, with a total maximum dose of 1600 mg over 23 weeks. This medication is of protein origin, specifically classified as "Protein - Other".

**Paclitaxel** is provided as a **concentrate for solution for infusion** and administered intravenously. The maximum daily dose is 80 mg/m², with a total maximum dose of 960 mg/m² over the treatment period.

**Carboplatin** is also a **concentrate for solution for infusion** administered intravenously. The dosing is specified as "Other" with a maximum daily dose of 5 units and a total maximum dose of 20 units over 23 weeks.

**Capecitabine** is administered orally in the form of **film-coated tablets**. The maximum daily dose is 1800 mg/m², with a total maximum dose of 100800 mg/m² over the treatment period. This medication is used in combination with carboplatin-based chemotherapy to evaluate its effect on pathologic complete response rates in early-stage triple-negative breast cancer.

All medications are of chemical origin, except for pembrolizumab, which is protein-based. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to assess the efficacy of these treatments in achieving the main objective of improving pathologic complete response rates in the specified patient population.

The efficacy of the clinical trial will be assessed by evaluating the **pathologic complete response (pCR)** rate as the primary endpoint. This involves comparing the effect of adding capecitabine to carboplatin-based preoperative chemotherapy in patients with early ER-negative and HER2-negative breast cancer. The primary endpoint will be measured by determining the pCR with the addition of capecitabine compared to carboplatin-based chemotherapy alone.

Secondary endpoints include Invasive Disease-Free Survival (IDFS), Breast Cancer Specific Survival (BCSS), and Overall Survival (OS). These endpoints will also compare the outcomes of adding capecitabine to the standard carboplatin-based chemotherapy regimen. The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, which is estimated to conclude by August 2034. The trial will utilize standard clinical and laboratory assessments to measure these outcomes, ensuring a comprehensive evaluation of the treatment's efficacy.