Phase III Trial of Intensified Alkylating Chemotherapy with Stem Cell Rescue and Olaparib in Stage III HER2-Negative HR-Deficient Breast Cancer

The primary objective of this study is to evaluate whether **neoadjuvant systemic treatment** with intensified alkylating chemotherapy and peripheral stem cell rescue (mCTC), followed by adjuvant capecitabine for patients without a (near) pathologic complete response, and subsequent 1-year olaparib monotherapy, significantly improves overall survival (OS) in patients with stage III, HER2-negative, HR impaired or HR deficient breast cancer. This is clinically relevant as it aims to enhance survival outcomes in a high-risk patient population lacking known germline BRCA1/2 mutations.

Secondary objectives include:

• Investigating whether mCTC treatment compared to AC-CP chemotherapy improves OS in patients with stage III, HER2-negative, HR-impaired (BRCA1-like and/or BRCA1pm) breast cancer without known germline BRCA1/2 mutations.
• Comparing the toxicity profiles between mCTC and standard dosed AC-CP chemotherapy followed by olaparib monotherapy.
• Assessing the improvement in pathological complete remission (pCR) rates with mCTC treatment compared to the AC-CP regimen.
• Evaluating the impact of mCTC treatment on recurrence-free survival (RFS) in specific patient subgroups.
• Exploring potential heterogeneity in efficacy, safety, quality of life, cost-effectiveness, and neurocognitive functioning across various patient factors.
• Determining the cost-effectiveness of mCTC compared to the AC-CP-olaparib regimen in targeted patient groups.
• Investigating patient-reported outcomes, including quality of life and neuro-cognitive functioning, in patients treated with mCTC versus the AC-CP-olaparib regimen.
• Examining the difference in OS between patients treated in the SUBITO trial and those treated outside the trial in the Netherlands.

The clinical trial involves participants diagnosed with **Stage III breast cancer**, specifically targeting those with HER2-negative and hormone receptor impaired or deficient profiles. The study population includes both males and females aged between 18 and 65 years, who are fit to undergo autologous stem cell transplantation. Participants must have a histologically confirmed adenocarcinoma of the breast and exhibit features of homologous recombination deficiency (HRD), such as being a BRCA1 or BRCA2 mutation carrier or having a BRCA1-like DNA copy number profile. The trial does not include a vulnerable population, and participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 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 clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of personalized therapy in patients with stage III, HER2-negative, hormone receptor impaired or deficient **breast cancer**. The trial aims to compare the overall survival of patients receiving neoadjuvant systemic treatment with intensified alkylating chemotherapy and peripheral stem cell rescue, followed by adjuvant **capecitabine** and one-year **olaparib** monotherapy, against those receiving AC-CP chemotherapy with similar adjuvant treatment. The trial is expected to run from January 2017 to September 2034, with participant involvement lasting up to 12 months, depending on the treatment arm and response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of adenocarcinoma, and performance status. Following randomization, participants will attend regular follow-up visits to monitor treatment response, manage any adverse effects, and ensure compliance with the study protocol. The end-of-study visit will assess the primary endpoint of overall survival and secondary endpoints, including recurrence-free interval and patient-reported outcomes. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Paclitaxel Aurobindo** 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 dose of 960 mg/m² over a treatment period of up to 12 weeks. The active substance, **paclitaxel**, is of chemical origin.

**Carboplatin Accord** is another experimental medication, available as a 10 mg/ml concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 400 mg/m² and a total dose of 800 mg/m² over a treatment period of up to 2 weeks. The active substance, **carboplatin**, is also of chemical origin.

**Cyclofosfamide Sandoz** is provided as a 1000 mg powder for solution for injection/infusion. It is administered intravenously with a maximum daily dose of 3000 mg/m² and a total dose of 3000 mg/m² over a treatment period of up to 2 weeks. The active substance, **cyclophosphamide**, is of chemical origin.

**Lynparza** is available in two formulations: 150 mg and 100 mg film-coated tablets. Both are administered orally with a maximum daily dose of 600 mg and a total dose of 219,000 mg over a treatment period of up to 12 months. The active substance, **olaparib**, is of chemical origin.

**Thiotepa Fresenius Kabi** is provided as a 15 mg powder for concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 250 mg/m² and a total dose of 500 mg/m² over a treatment period of up to 2 weeks. The active substance, **thiotepa**, is of chemical origin.

**DOXORUBICINE TEVA** is available as a 50 mg/25 ml injectable solution. It is administered intravenously with a maximum daily dose of 60 mg/m² and a total dose of 240 mg/m² over a treatment period of up to 8 weeks. The active substance, **doxorubicin**, is of chemical origin.

**Capecitabine Sandoz** is provided as 150 mg film-coated tablets. It is administered orally with a maximum daily dose of 2500 mg and a total dose of 280,000 mg over a treatment period of up to 24 weeks. The active substance, **capecitabine**, is of chemical origin.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. No additional non-experimental treatments, such as standard-of-care therapy or placebo, are specified in the trial protocol.

Efficacy in this clinical trial will be assessed primarily through the measurement of **overall survival**. This is defined as the time from randomization to death from any cause in all patients. Secondary endpoints include overall survival in patients without a germline BRCA1/2 mutation, recurrence-free interval, and several other parameters. The recurrence-free interval is defined as the time from randomization to invasive ipsilateral breast tumor recurrence, locoregional or distant recurrence, or death from breast cancer, whichever occurs first. This will be evaluated in all patients, as well as specifically in those with an HR impaired tumor. Additional secondary endpoints include the assessment of (non-)hematological toxicity according to CTCAE v4.03, cost-effectiveness measured by costs per quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER), and patient-reported outcomes such as quality of life and cognitive function. Several potential biomarkers will also be evaluated. The difference in overall survival between patients treated in the SUBITO trial and those with similar characteristics treated outside of the trial in the Netherlands will be analyzed using data from the Netherlands Cancer Registry (NCR). The trial is designed to investigate whether neoadjuvant systemic treatment with intensified alkylating chemotherapy and peripheral stem cell rescue, followed by adjuvant capecitabine and 1-year olaparib monotherapy, improves overall survival in patients with stage III, HER2-negative, HR impaired or HR deficient breast cancer.