Safety, Tolerability, and Anti-tumor Activity of HER3-DXd Monotherapy and Combinations in Advanced Breast Cancer Post-Trastuzumab Deruxtecan Progression

The primary objective of this Phase 1b/2, multicenter, open-label, dose-expansion study is to evaluate the **safety**, **tolerability**, and anti-tumor activity of HER3-DXd monotherapy and its combinations in patients with inoperable advanced breast cancer (ABC) who have experienced disease progression following treatment with trastuzumab deruxtecan (T-DXd). This study is clinically relevant as it addresses the need for effective treatment options in patients with limited therapeutic alternatives due to progression on T-DXd. The study includes patients with HER2-positive (HER2-pos) or HER2-low ABC, with any hormone receptor (HR) status. Patients with HER2-pos tumors must have previously received trastuzumab (with or without pertuzumab) and taxanes, and may have received T-DM1. Those with HER2-low tumors must have been treated with taxanes, and patients with HR-positive and HER2-low tumors must have received endocrine therapy and CDK4/6 inhibitors.

The clinical trial involves a study population comprising both **male** and **female** participants, with an age range that includes adults and older adults. The trial focuses on individuals diagnosed with HER2-positive or HER2-low advanced breast cancer (ABC), who have shown progression after treatment with trastuzumab deruxtecan (T-DXd). Participants with HER2-positive tumors must have previously received trastuzumab, with or without pertuzumab, and taxanes, and may have been treated with T-DM1. Those with HER2-low tumors must have undergone prior treatment with taxanes. Additionally, patients with hormone receptor-positive and HER2-low tumors are required to have received endocrine therapy and CDK4/6 inhibitors. The trial includes a vulnerable population, although specific lifestyle considerations such as diet or physical activity are not detailed. The total number of participants is not provided, as the sponsor has not disclosed this information.

The clinical trial is a **Phase 1b/2**, multicenter, open-label, dose-expansion modular study designed to evaluate the safety, tolerability, and anti-tumor activity of HER3-DXd monotherapy and combinations in patients with inoperable advanced breast cancer (ABC) who have progressed on trastuzumab deruxtecan (T-DXd). The study targets patients with **HER2-positive** or HER2-low ABC, with any hormone receptor status. The trial is expected to commence recruitment on November 30, 2023, and is estimated to conclude by March 1, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific medical criteria, including prior treatments with trastuzumab, taxanes, and other therapies as applicable. Following successful screening, participants will enter the treatment phase, where they will receive HER3-DXd monotherapy or combination therapy. Regular follow-up visits will be scheduled to monitor safety, tolerability, and treatment efficacy. These visits will include 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 phase or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The expected duration of participant involvement will vary depending on individual response to treatment and the occurrence of any adverse events. The study is designed to ensure rigorous monitoring and data collection to achieve its objectives while maintaining participant safety.

In this clinical trial, the experimental medication and non-experimental treatments have not been specified in the provided data. Therefore, a detailed description of the **experimental medication**, including its name, pharmaceutical form, dosage, route, and frequency of administration, cannot be provided. Similarly, information regarding any non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatment, is not available. Consequently, additional relevant information about drug administration, dosing schedules, and participant compliance monitoring is also not included. The absence of this data precludes a comprehensive description of the treatments used in this clinical trial.

The clinical trial is scheduled to commence recruitment on November 30, 2023, with an estimated completion date of March 1, 2029. The trial is categorized under phase 7, indicating a specific stage in the clinical research process. Efficacy assessments will be conducted throughout the trial to evaluate the therapeutic impact of the intervention. The parameters or endpoints used to assess efficacy have not been specified in the provided data. The methods and schedule for measuring, collecting, and analyzing these efficacy parameters are also not detailed. The trial will adhere to standard clinical trial protocols to ensure the reliability and validity of the efficacy assessments. The trial's design and execution will be aligned with regulatory requirements and scientific standards to accurately determine the intervention's efficacy.