Evaluation of Trastuzumab Deruxtecan in Combination with Anti-Cancer Agents in HER2-Positive Metastatic Breast Cancer with Brain Metastases

The primary objective of this study is to evaluate the **safety** and **tolerability** of **trastuzumab deruxtecan (T-DXd)** in combination with other anti-cancer agents in patients with **HER2-positive metastatic breast cancer**. This is crucial for determining the recommended Phase 2 dose (RP2D) for these combinations, which will be used in the dose-expansion phase. The study targets patients with HER2-positive advanced or metastatic breast cancer, as per ASCO/CAP 2018 guidelines, and includes those who have not received prior treatment for advanced/metastatic disease.

Secondary objectives include:

• Assessing the anti-tumor activity of T-DXd combinations and T-DXd monotherapy.
• Evaluating the pharmacokinetics (PK) of T-DXd, durvalumab, pertuzumab, paclitaxel, and tucatinib.
• Investigating the immunogenicity of T-DXd, durvalumab, and pertuzumab.

The clinical trial involves a total of **198 participants** diagnosed with **HER2-positive Metastatic Breast Cancer**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have been pathologically confirmed to have advanced or metastatic breast cancer. Participants are required to have an **ECOG Performance Status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on specific inclusion criteria, such as having a locally assessed HER2-positive status and adequate tumor samples for biomarker assessment. The study also considers lifestyle factors, such as the presence of brain metastases, with specific criteria for untreated or stable conditions. The trial includes a vulnerable population, ensuring comprehensive safety and efficacy assessments across diverse patient groups.

The clinical trial is designed as a **Phase 1b/2** multicenter, open-label, modular study to evaluate the safety, tolerability, and anti-tumor activity of **trastuzumab deruxtecan** in combination with other anti-cancer agents in patients with **HER2-positive metastatic breast cancer**. The trial consists of two parts: a dose-finding phase (Part 1) and a dose-expansion phase (Part 2). In Part 1, the primary objective is to assess the safety and tolerability of the drug combinations and determine the recommended Phase 2 dose (RP2D). Part 2 aims to further evaluate the safety and tolerability of the monotherapy and combinations using the RP2D established in Part 1.

The trial is expected to commence recruitment on April 24, 2024, and conclude by July 2, 2025. Participants will be involved in the study for the duration of their treatment cycles, with the possibility of early termination if they experience unacceptable adverse events, disease progression, or withdrawal of consent. The study includes several visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes.

Inclusion criteria require participants to be at least 18 years old with pathologically documented HER2-positive metastatic breast cancer. They must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and provide adequate tumor samples for biomarker assessment. Exclusion criteria are not specified in the provided data. The primary endpoints include the assessment of adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicities (DLTs), and laboratory findings. Secondary endpoints involve evaluating the overall response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).

The clinical trial involves the administration of **trastuzumab deruxtecan**, marketed as DS-8201a, which is an **antibody-drug conjugate**. This experimental medication is provided in the form of a **solution for infusion** and is administered via **intravenous use**. The dosing schedule and frequency are determined based on the study protocol, with careful monitoring of participant compliance to ensure accurate assessment of safety and efficacy.

**Infliximab**, marketed as Inflectra, is used as a comparator treatment in the study. It is supplied as a **powder for concentrate for solution for infusion** and is also administered intravenously. The dosing regimen follows standard clinical guidelines for its use, and participant adherence is monitored throughout the trial.

**Pertuzumab** is another agent used in the study, provided as a **concentrate for solution for infusion**. It is administered via **intravenous use**. The administration schedule is aligned with the study's objectives to evaluate its safety and tolerability in combination with other agents.

**Durvalumab**, marketed as IMFINZI, is included in the trial as a **concentrate for solution for infusion**. It is administered intravenously, with dosing schedules designed to assess its anti-tumor activity in combination with trastuzumab deruxtecan. Compliance with the dosing regimen is closely monitored.

**Mycophenolate mofetil**, marketed as Mycophenolate Mofetil Accord, is used as an auxiliary treatment in the study. It is provided in the form of **hard capsules** and administered orally. The dosing schedule is based on established therapeutic guidelines, and participant adherence is tracked to ensure consistent administration.

The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoints for Part 1 include the evaluation of adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicities (DLTs), and laboratory findings. For Part 2, the primary endpoints are AEs, SAEs, and laboratory findings. Secondary endpoints for both parts include the **Objective Response Rate (ORR)**, which is defined as the proportion of patients achieving a complete response (CR) or partial response (PR) as determined by the investigator at the local site per RECIST 1.1 criteria. Progression-Free Survival (PFS) is also assessed, defined as the time from randomization until disease progression or death from any cause.

Additional secondary endpoints for Part 2 include PFS2, which measures the time from randomization until progression on the next line of treatment or death, and Duration of Response (DoR), defined as the time from the first documented response until progression or death. Overall Survival (OS) is also evaluated, defined as the time from randomization until death from any cause. Pharmacokinetic parameters such as serum concentrations of T-DXd, total anti-HER2 antibody, MAAA-1181a, durvalumab, and pertuzumab, as well as plasma concentrations of paclitaxel and tucatinib, will be measured. Immunogenicity assessments for T-DXd, durvalumab, and pertuzumab are also included.