Evaluation of Efficacy and Safety of Abemaciclib, Inavolisib, and Ribociclib in Combination Therapies for Metastatic Breast Cancer Subtypes

The primary objective of this study is to evaluate the **efficacy** and **safety** of multiple treatment combinations in patients with metastatic breast cancer during Stage 1. The efficacy will be assessed based on the objective response rate (ORR), while safety will be evaluated through the incidence, nature, and severity of adverse events and laboratory abnormalities, with severity determined according to NCI CTCAE v4.0, as well as changes from baseline in vital signs, ECG parameters, and targeted clinical laboratory test results. This is clinically relevant as it aims to identify effective and safe treatment options for metastatic breast cancer, a condition with significant morbidity and mortality.

Secondary objectives include:

• Stage 1: To evaluate the efficacy of treatment combinations based on progression-free survival (PFS), disease control rate (DCR), overall survival (OS), OS at specific timepoints, and duration of response (DOR).
• Stage 2: To evaluate the safety of treatment combinations during Stage 2.

The clinical trial involves a total of **135 participants** diagnosed with **metastatic breast cancer**, including subtypes such as triple negative breast cancer (TNBC), hormone receptor positive breast cancer (HR+ BC), and HER2 positive and HER2 low breast cancer (HER2+/HER2-low BC). The study population comprises both male and female subjects, aged 18 years and older, with an **ECOG Performance Status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on their diagnosis of metastatic or inoperable locally advanced breast cancer, with measurable disease as per RECIST v1.1 criteria, and a life expectancy of at least 3 months. The trial includes individuals with adequate hematologic and end-organ function, as determined by specific laboratory test results. The study population also includes vulnerable groups, although specific lifestyle considerations such as diet or physical activity are not detailed in the provided data.

The clinical trial is designed to evaluate the efficacy and safety of multiple treatment combinations in patients with **metastatic breast cancer**, including subtypes such as triple-negative breast cancer (TNBC), hormone receptor-positive breast cancer (HR+ BC), and HER2 positive and HER2 low breast cancer (HER2+/HER2-low BC). This is a Phase Ib/II, open-label, multicenter, randomized umbrella study. The trial is structured to include two stages, with the primary objective of Stage 1 being to assess the objective response rate (ORR) and the safety of the treatment combinations. Safety evaluations will be based on the incidence, nature, and severity of adverse events, as well as changes from baseline in vital signs, electrocardiogram (ECG) parameters, and targeted clinical laboratory test results, following the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

The trial is expected to run from June 1, 2018, to July 26, 2026. Participants will be involved in the study for the duration of their treatment cycles, with the possibility of early termination if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The study visits will include an initial screening visit to confirm eligibility based on criteria such as age, performance status, and measurable disease according to RECIST v1.1. Follow-up visits will be scheduled to monitor treatment response and safety, with an end-of-study visit to assess final outcomes and any long-term effects.

Participants must be at least 18 years old, have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, and a life expectancy of at least three months. Adequate hematologic and end-organ function are required, as defined by specific laboratory test results obtained within 14 days prior to the initiation of study treatment. The trial will include various investigational products, such as Verzenios, INAVOLISIB, Kisqali, Tecentriq, ACTEMRA, Faslodex, and Abraxane, administered through oral, intravenous infusion, or intramuscular injection routes, depending on the specific treatment combination being evaluated.

The clinical trial involves multiple treatment combinations for patients with metastatic breast cancer. The experimental medication **Verzenios** is administered in the form of film-coated tablets, available in dosages of 50 mg, 100 mg, and 150 mg. The active substance in Verzenios is **abemaciclib**, a chemical compound. The tablets are administered orally, and the frequency of administration is determined by the study protocol. Participant compliance is monitored through regular assessments and pill counts.

**INAVOLISIB** is another experimental medication used in the trial, provided as film-coated tablets. The active substance is inavolisib, also known by its synonyms such as GDC-0077. This medication is administered orally, with the dosage and frequency specified in the study protocol. Compliance is ensured through participant monitoring and adherence checks.

**Kisqali**, containing the active substance **ribociclib**, is administered as 200 mg film-coated tablets. This chemical compound is taken orally, with the dosing schedule outlined in the trial protocol. Participant adherence is monitored through regular follow-ups and pill counts.

**Tecentriq**, with the active substance **atezolizumab**, is provided as a solution for infusion. This protein-based medication is administered via intravenous infusion, with the dosing schedule specified in the study protocol. Compliance is monitored through infusion records and participant assessments.

**ACTEMRA**, containing **tocilizumab**, is also administered as a solution for infusion. This protein-based medication is given intravenously, with the frequency and dosage determined by the trial protocol. Participant adherence is tracked through infusion logs and regular assessments.

**Faslodex** is administered as a 250 mg solution for injection, with the active substance **fulvestrant**. This chemical compound is given via intramuscular injection, with the dosing schedule outlined in the study protocol. Compliance is monitored through injection records and participant follow-ups.

**Abraxane**, containing **paclitaxel albumin-bound**, is provided as a powder for dispersion for infusion. This specified substance group 1 compound is administered via intravenous infusion, with the dosing schedule specified in the trial protocol. Participant adherence is tracked through infusion records and regular assessments.

**SACITUZUMAB GOVITECAN** is administered as a PHF00230MIG formulation via intravenous infusion. The dosing schedule and frequency are determined by the study protocol, with compliance monitored through infusion logs and participant assessments.

Non-experimental treatments in the study may include standard-of-care therapies, placebos, or comparator treatments, as specified in the trial protocol. The administration and monitoring of these treatments follow the same rigorous standards to ensure participant safety and data integrity.

The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)** during Stage 1. This endpoint will evaluate the proportion of patients with a measurable reduction in tumor size, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary efficacy endpoints include **Progression-Free Survival (PFS)**, **Disease Control Rate (DCR)**, **Overall Survival (OS)**, **Duration of Response (DOR)**, and OS at specific timepoints. These parameters will provide a comprehensive evaluation of the treatment's impact on disease progression and patient survival.

The collection and analysis of efficacy data will be conducted at various stages of the trial. The ORR will be assessed during Stage 1, while PFS, DCR, OS, DOR, and OS at specific timepoints will be evaluated throughout the trial. The trial will utilize validated scales and criteria, such as RECIST v1.1, to ensure consistent and reliable measurement of tumor response. The data will be analyzed to determine the efficacy of the treatment combinations in patients with metastatic breast cancer.