Phase IIb Randomized Trial of Carboplatin-Cyclophosphamide vs. Paclitaxel ± Atezolizumab in Advanced Triple Negative Breast Cancer

The primary objective of this study is to validate the **BRCA1-like test** in predicting differential progression-free survival (PFS) according to RECIST v1.1 definitions for measurable and non-measurable disease. This is assessed with first-line alkylating and platinum agents, with or without antibody add-on, compared to paclitaxel, with or without antibody add-on, in patients with triple-negative breast cancer (TNBC). The clinical relevance of this objective lies in its potential to personalize treatment strategies for TNBC, a subtype of **metastatic breast cancer** known for its aggressive nature and limited treatment options.

Secondary objectives include: - Evaluating whether the addition of **atezolizumab** to paclitaxel is more favorable than adding it to carboplatin-cyclophosphamide, particularly in patients with PD-L1 positive tumors defined as CPS 10 or higher. - Testing whether the addition of atezolizumab to chemotherapy results in more objective responses and a higher proportion of patients who are free of progression at 6 and 12 months. - Analyzing whether PD-L1 in tumor-infiltrating immune cells predicts potential PFS benefit of atezolizumab added to first-line palliative chemotherapy in TNBC. - Evaluating the effectiveness of an alkylating-platinum regimen versus paclitaxel as first-line chemotherapy regarding PFS in BRCA1-like and non-BRCA1-like TNBC. - Defining whether different TNBC molecular subtypes predict the benefit of atezolizumab addition. - Evaluating the predictive potential of pretreatment LDH levels and other biomarkers for PFS advantage. - Assessing overall survival, overall response rate, clinical benefit rate, and duration of response for all atezolizumab-related questions. - Evaluating clinically relevant toxicity of all study regimens and preliminary efficacy by PFS and OS in subgroups treated before amendment 3.

The clinical trial focuses on individuals diagnosed with **metastatic breast cancer**, specifically targeting those with triple negative breast cancer. The study population includes both male and female participants, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants are required to have a WHO performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not involve a vulnerable population. The sponsor has not provided the total number of participants. Selection criteria emphasize histological confirmation of the disease, with specific requirements for tissue samples for BRCA1-like testing and translational research. Participants must not have received previous cytotoxic therapy for metastatic disease and should have a disease-free interval of at least 12 months after certain treatments. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of different chemotherapeutic regimens in patients with advanced **triple negative breast cancer**. The trial aims to validate the BRCA1-like test in predicting progression-free survival (PFS) when using alkylating and platinum agents, with or without the addition of **atezolizumab**, compared to **paclitaxel** with or without the same antibody. The study will involve multiple arms, including combinations of **carboplatin**, **cyclophosphamide**, and **paclitaxel**, with or without **atezolizumab** or **bevacizumab**. The trial is expected to run from October 2013 to April 2028, with participant involvement lasting up to 60 months, depending on the treatment arm.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed triple negative breast cancer and a WHO performance status of 0 or 1. Following randomization, participants will attend regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the final outcomes, including PFS and overall survival (OS). The trial will also explore secondary endpoints, such as the objective response rate (ORR) and the potential predictive value of biomarkers for treatment efficacy.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will adhere to rigorous ethical standards, ensuring that all procedures are conducted in accordance with regulatory guidelines. The study's findings are anticipated to contribute significantly to the understanding of treatment strategies for triple negative breast cancer, potentially leading to more personalized therapeutic approaches.

The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments**. The experimental medication **Avastin** (bevacizumab) is provided as a 25 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 10 mg/kg. The treatment period for Avastin is up to 60 days. Bevacizumab is a protein-based substance, and its role in the trial is as a test medication.

**Tecentriq** (atezolizumab) is another experimental medication used in the trial. It is available in two formulations: 840 mg and 1,200 mg concentrates for solution for infusion. Both formulations are administered intravenously. The maximum daily dose for the 840 mg formulation is 840 mg, while for the 1,200 mg formulation, it is 1,200 mg. The treatment period for both formulations is up to 60 days. Atezolizumab is a protein-based substance, and its role in the trial is as a test medication.

The trial also includes the use of **Carboplatin**, a non-experimental treatment, which is a chemotherapy agent. It is administered intravenously with a maximum daily dose of 750 mg. The treatment period for Carboplatin is up to 36 days. Carboplatin is a chemical-based substance and serves as a comparator treatment in the trial.

**Paclitaxel** is another chemotherapy agent used in the trial. It is administered intravenously with a maximum daily dose of 90 mg/m². The treatment period for Paclitaxel is up to 36 days. Paclitaxel is a chemical-based substance and serves as a comparator treatment in the trial.

**Cyclophosphamide** is also included as a chemotherapy agent in the trial. It is administered intravenously with a maximum daily dose of 600 mg/m². The treatment period for Cyclophosphamide is up to 36 days. Cyclophosphamide is a chemical-based substance and serves as a comparator treatment in the trial.

All medications are administered via the **intravenous route**. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to evaluate the efficacy of these treatments in advanced triple-negative breast cancer, with a focus on progression-free survival as the primary endpoint.

Efficacy in this clinical trial will be assessed primarily through the evaluation of **progression-free survival (PFS)** according to RECIST v1.1 definitions for both measurable and non-measurable disease. The primary endpoint involves an interaction test of BRCA1-like status versus treatment, comparing carboplatin-cyclophosphamide with paclitaxel, both with or without the addition of atezolizumab or bevacizumab. Secondary endpoints include the evaluation of the addition of atezolizumab to paclitaxel versus carboplatin-cyclophosphamide in patients with PD-L1 positive tumors, using PFS1 as a measure. The trial will also assess the objective response rate (ORR), the proportion of patients free of progression at 6 and 12 months, and overall survival (OS) from the day of randomization to death from any cause.

Additional analyses will determine the efficacy of the two different first-line chemotherapeutic regimens, regardless of antibody add-on, in the entire study group and in BRCA1-like and non-BRCA1-like triple-negative breast cancer (TNBC) subgroups. The trial will explore whether PD-L1 status, intratumoral CD8, tumor-infiltrating lymphocytes (TIL), and certain molecular TNBC subtypes predict the benefit of atezolizumab addition. Exploratory analyses will aim to identify biomarkers predicting PFS/OS advantages of specific chemotherapy regimens. Clinically relevant toxicity will be evaluated according to NCI CTCAE v4.03. The trial is estimated to conclude by April 2028.