Evaluation of Palbociclib, Olaparib, and Pertuzumab in Personalized Treatment of High-Risk Breast Cancer: A Molecular Marker-Based Clinical Trial

The primary objective of the PETREMAC trial is to identify **molecular markers** of therapy response/resistance and survival outcome in patients with high-risk breast cancer. This is clinically relevant as it aims to enhance personalized treatment strategies, potentially improving patient outcomes by tailoring therapies based on individual molecular profiles.

Secondary objectives include:

• Evaluating the objective response rate (ORR) compared to historical data.
• Assessing tumor Ki67 reduction after 2 and 6 weeks of treatment in Arm A.
• Comparing recurrence-free and overall survival to historical data.
• Determining the percentage of patients successfully completing neoadjuvant treatment and surgery.
• Measuring the breast conserving surgery rate, indicating the potential to avoid mastectomy.
• Assessing the safety and tolerability of the study treatment.

The clinical trial focuses on participants diagnosed with **breast cancer**, aiming to identify molecular markers of therapy response and survival outcomes. The study population includes both male and female subjects, aged 18 years and older, with a specific emphasis on those with previously untreated, histologically confirmed non-inflammatory breast cancer. Participants must have a tumor size greater than 4 cm, or greater than 2 cm for HER2 positive and triple-negative breast cancers, and the tumor must be accessible for repeated biopsies. The trial does not involve a vulnerable population. Participants are required to have a WHO performance status of 0-1 and must meet specific hematological and biochemical criteria. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified as part of the trial's considerations. Key inclusion criteria include the absence of psychological, familial, sociological, or geographical conditions that could impede compliance with the study protocol, and the requirement for written informed consent according to national and local regulations.

The clinical trial is designed to evaluate the predictive and prognostic value of pre-treatment assessment of a panel of 300 known potential driver mutations in **breast cancer** by next-generation sequencing of tumor DNA. This is a Phase II, therapeutic exploratory and confirmatory clinical trial, which is not classified as low intervention. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial extends until June 30, 2030, with recruitment anticipated to commence on December 2, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed non-inflammatory breast cancer, tumor size, and absence of distant metastasis. Following the screening, participants will be randomized into different arms of the study, where they will receive either the investigational product or a comparator. The investigational products include **palbociclib** in various dosages and forms, **olaparib**, and **pertuzumab**, administered orally or via infusion, depending on the specific arm of the trial.

Study visits will be scheduled at regular intervals to monitor the participants' response to treatment, assess safety and tolerability, and collect data on secondary endpoints such as genetic and epigenetic changes in tumor tissue, objective response rate, and tumor Ki67 reduction. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the overall outcomes of the treatment.

The expected length of participant involvement varies depending on the treatment arm, with a maximum treatment period ranging from 6 to 30 days. Conditions that may lead to early termination from the study include non-compliance with the study protocol, adverse events, or withdrawal of consent. Participants will be closely monitored throughout the trial to ensure their safety and the integrity of the study data.

The clinical trial involves the administration of several experimental medications, each with specific characteristics and administration protocols. **IBRANCE 125 mg hard capsules** contain the active substance **palbociclib**, a **CDK 4/6 inhibitor** with anti-neoplastic properties. These capsules are administered orally, with a maximum daily dose of 125 mg. The treatment period for this medication is up to 30 days. The pharmaceutical form is a hard capsule, and the medication is produced by Pfizer Europe MA EEIG.

Another formulation of the same active substance, **IBRANCE 75 mg hard capsules**, is also used in the trial. These capsules are similarly administered orally, with a maximum daily dose of 125 mg, and a treatment period of up to 30 days. The pharmaceutical form remains a hard capsule, and the manufacturer is Pfizer Europe MA EEIG.

**IBRANCE 100 mg hard capsules** are also included in the study, containing the same active substance, **palbociclib**. The administration route is oral, with a maximum daily dose of 125 mg, and a treatment period of up to 30 days. The pharmaceutical form is a hard capsule, produced by Pfizer Europe MA EEIG.

**Lynparza 150 mg film-coated tablets** contain the active substance **olaparib**, a **PARP-inhibitor**. These tablets are administered orally, with a maximum daily dose of 600 mg and a treatment period of up to 10 days. The pharmaceutical form is a film-coated tablet, and the manufacturer is AstraZeneca AB.

**Perjeta 420 mg concentrate for solution for infusion** contains the active substance **pertuzumab**, a protein-based therapeutic. This medication is administered via infusion, with a maximum total dose of 840 mg. The treatment period is up to 6 cycles. The pharmaceutical form is a solution for infusion, and the manufacturer is Roche Registration GmbH.

Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the prescribed treatment regimens. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data provided.

The efficacy of the clinical trial titled "PErsonalized TREatment of high-risk MAmmary Cancer - the PETREMAC trial" will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on evaluating the predictive and prognostic value of pre-treatment assessment of a panel of 300 known potential driver mutations in breast cancer using next-generation sequencing of tumor DNA. This will provide insights into the genetic landscape of the tumors and their potential response to treatment.

Secondary endpoints include assessing genetic and epigenetic changes in tumor tissue during therapy, measuring the objective response rate (ORR) of personalized medicine compared to historical data, and evaluating tumor **Ki67** reduction after 2 and 5 weeks of treatment in Arm A. Additionally, the trial aims to estimate recurrence-free and overall survival rates when patients receive optimal personalized treatment, again using historical data for comparison. Other secondary endpoints involve evaluating the percentage of patients completing neoadjuvant treatment and surgery, the rate of breast-conserving surgery, and the safety and tolerability of the study treatment.