Phase II Randomized Trial of Neoadjuvant Chemotherapy and Stereotactic Body Radiotherapy with Durvalumab and Oleclumab in Luminal B Breast Cancer

The primary objective of this phase II randomized trial is to demonstrate improved **tumour** response of the primary tumour and nodal metastases in arms 2 or 3 compared to arm 1 in patients with **Luminal B Breast Cancer**. This is clinically relevant as it aims to enhance treatment efficacy and potentially improve patient outcomes by optimizing therapeutic strategies.

Secondary objectives include:

• Evaluating the complete pathological response rate at surgery, defined as ypT0/Tis ypN0 and ypT0 ypN0, indicating the absence of residual invasive disease.
• Assessing the response to the primary tumour irrespective of the response to the pathological lymph nodes, and vice versa.
• Evaluating the feasibility of performing breast-sparing surgery in arms 2 and 3 versus arm 1.
• Demonstrating an increase in TIL levels of the primary breast cancer between baseline and the week 6 biopsy.
• In the follow-up phase, evaluating the ability to control invasive disease and survival in arms 2 and 3 versus arm 1 at 3 and 5 years post-surgery.
• Assessing the severity and duration of adverse events in arms 2 and 3 compared to arm 1.
• Evaluating cosmetic changes to the breast in arms 2 and 3 versus arm 1.

The clinical trial focuses on **Luminal B Breast Cancer** and involves a study population exclusively composed of **female** participants aged **18 years and older**. The sponsor has not provided the total number of participants. The trial population was selected based on specific inclusion criteria, including adequate bone marrow, liver, renal, and coagulant function, as well as a histological diagnosis of invasive breast adenocarcinoma that is estrogen receptor-positive and HER2-negative. Participants are required to have a MammaPrint genomic high-risk score and meet specific tumor size criteria. Lifestyle considerations such as diet and physical activity are not specified. The trial does not include a vulnerable population, and participants must have an ECOG performance status of 0 or 1. The study does not include male subjects, and all participants must provide informed consent and agree to provide tissue and blood samples for research purposes.

The clinical trial is designed to evaluate the efficacy of **neo-adjuvant chemotherapy** combined with stereotactic body radiotherapy, with or without the addition of **durvalumab** and **oleclumab**, in patients with luminal B breast cancer. This is a phase II randomized trial, structured as a double-blind, controlled study. The trial is expected to run from December 2019 to September 2029, with the primary objective of demonstrating improved tumor response in the treatment arms compared to the control arm.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, adequate organ function, and histological diagnosis of **estrogen receptor-positive** and **HER2-negative** breast cancer. The screening procedures must be completed within 28 days prior to randomization. Following randomization, participants will receive treatment according to their assigned study arm, with regular follow-up visits to monitor treatment response and safety. The end-of-study visit will occur after the completion of the treatment regimen, with additional follow-up assessments at 3 and 5 years post-surgery to evaluate long-term efficacy endpoints such as event-free survival and overall survival.

The expected length of participant involvement in the study is approximately 12 months, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will utilize intravenous administration of the investigational products, including **paclitaxel**, **cyclophosphamide**, **doxorubicin hydrochloride**, **durvalumab**, and **oleclumab**, with specific dosing regimens tailored to each treatment arm. The study aims to provide valuable insights into the potential benefits of combining chemotherapy with immunotherapy and radiotherapy in this patient population.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Paclitaxel** is provided as a 6 mg/mL concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 80 mg/m² and a total maximum dose of 960 mg/m² over a treatment period of up to 12 weeks. The active substance, paclitaxel, is of chemical origin and is marketed by Hospira UK Limited.

**Cyclophosphamide** is used in the form of a powder and solvent for solution for injection. It is also administered intravenously, with a maximum daily dose of 600 mg/m² and a total maximum dose of 2400 mg/m² over a 7-week treatment period. The active substance, cyclophosphamide, is chemically derived.

**Doxorubicin Hydrochloride** is provided as a 2 mg/mL concentrate for solution for infusion. This medication is administered intravenously, with a maximum daily dose of 60 mg/m² and a total maximum dose of 240 mg/m² over a 7-week treatment period. The active substance, doxorubicin hydrochloride, is of chemical origin and is produced by Accord Healthcare Limited.

**Durvalumab** is administered as a concentrate for solution for infusion. It is given intravenously with a maximum daily dose of 1500 mg. The treatment period is up to 5 weeks. The active substance, durvalumab, is a protein of other origin.

**Oleclumab** is also administered as a concentrate for solution for infusion. It is given intravenously with a maximum daily dose of 3000 mg over a 7-week treatment period. The active substance, oleclumab, is a protein of other origin and is produced by Institut Jules Bordet.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the treatment protocols. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is on evaluating the efficacy and safety of the experimental medications in the context of the study objectives.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **Residual Cancer Burden (RCB)**, which will be evaluated at the time of surgery. RCB is calculated as a continuous index that combines pathologic measurements of the primary tumor, including size and cellularity, and nodal metastases, such as number and size. This index is defined by Symmans et al. and categorizes RCB into RCB 0, indicating pathological complete response (pCR), and RCB 1, indicating minimal residual disease.

Secondary endpoints include several measures of pathological complete response (pCR) at surgery. These include the rate of pCR defined as the absence of residual invasive cancer (ypT0/Tis ypN0) and the rate of pCR with no ductal carcinoma in situ (DCIS) (ypT0 ypN0). Additionally, the complete pathologic response rate of the primary tumor and resected nodal metastases will be assessed independently. The percentage of breast conservation surgeries in different treatment arms will also be compared. Changes in tumor-infiltrating lymphocyte (TIL) levels between baseline and the week 6 biopsy will be measured.

Long-term efficacy will be evaluated during the follow-up phase at 3 and 5 years post-surgery. This will include assessments of event-free survival (EFS), breast cancer event-free survival (BC-EFS), overall survival (OS), and distant recurrence-free survival (DRFS), as defined by the Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials (NeoSTEEP). The occurrence of ipsilateral locoregional recurrence will also be monitored.