Efficacy and Safety of Fezolinetant in Treating Vasomotor Symptoms in Hormone Receptor-Positive Breast Cancer Patients on Adjuvant Endocrine Therapy

The primary objective of this study is to evaluate the **efficacy** of fezolinetant 45 mg administered once daily compared to placebo in reducing the frequency and severity of moderate to severe vasomotor symptoms (VMS) in women undergoing adjuvant endocrine therapy for stage 0-3 hormone receptor-positive (HR+) breast cancer. This is clinically relevant as VMS, commonly known as hot flashes, significantly impact the quality of life in this patient population, and effective management is crucial for improving patient outcomes.

Secondary objectives include:

• Evaluating the effect of fezolinetant on patient-reported quality of life and sleep disturbance.
• Assessing the persistence of fezolinetant's effect over 24 weeks.
• Determining the safety profile of fezolinetant in women experiencing VMS due to adjuvant endocrine therapy.
• Investigating the impact of fezolinetant on the frequency and severity of moderate to severe VMS.
• Evaluating responder rates based on specific reductions in VMS frequency.
• Analyzing the pharmacokinetics (PK) of fezolinetant.
• Assessing the effect of fezolinetant on the PK of adjuvant endocrine therapies.
• Evaluating the effect on patients' global assessments of VMS and sleep disturbance.

The clinical trial comprises **89 participants** who are exclusively female, with an age range of at least 18 years. The study population includes women experiencing **moderate to severe vasomotor symptoms (VMS)** due to adjuvant endocrine therapy for stage 0-3 hormone receptor-positive (HR+) breast cancer. Participants were selected based on their personal history of HR+ breast cancer and their current stable maintenance on adjuvant endocrine therapy, such as tamoxifen or aromatase inhibitors, with or without gonadotropin-releasing hormone agonists/antagonists. The trial excludes male subjects and does not involve a vulnerable population. Participants are required to have a minimum average of seven moderate to severe VMS episodes per day, as recorded in an electronic daily diary, and must have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, indicating a good general health status. Additionally, participants must have a negative serology panel for hepatitis B, hepatitis C, and HIV, and a life expectancy of at least 12 months. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled, Phase 3 study to evaluate the efficacy and safety of **fezolinetant** in treating moderate to severe vasomotor symptoms (VMS) in women with stage 0 to 3 hormone receptor-positive breast cancer undergoing adjuvant endocrine therapy. The trial will involve the administration of fezolinetant 45 mg once daily, compared to a placebo, over a maximum treatment period of 52 weeks. The primary objective is to assess changes in the frequency and severity of VMS from baseline to weeks 4 and 12. Secondary endpoints include changes in the Menopause-specific Quality of Life Questionnaire (MENQOL) and the Patient-reported Outcomes Measurement Information System Sleep Disturbance Short Form (PROMIS SD SF) scores, as well as the incidence of treatment-emergent adverse events.

Participants will be involved in the study for approximately 52 weeks, with the trial expected to conclude by September 2028. The study will commence with a screening visit to confirm eligibility based on criteria such as age, medical history, and current treatment regimen. Participants must have a minimum average of seven moderate to severe VMS episodes per day and meet other health criteria, including a negative serology panel. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and safety, with assessments conducted at weeks 4, 12, and 24. The end-of-study visit will occur at the conclusion of the treatment period to evaluate the overall outcomes and any long-term effects.

Participant involvement may be terminated early if they experience significant adverse events, fail to adhere to the study protocol, or choose to withdraw consent. The trial will ensure rigorous monitoring of safety and efficacy, with data collected through electronic diaries and clinical assessments. The study aims to provide comprehensive insights into the potential benefits of fezolinetant for managing VMS in the specified patient population.

The clinical trial involves the administration of **fezolinetant**, an experimental medication, in the form of film-coated tablets. Each tablet contains 45 mg of the active substance, fezolinetant, which is a chemical entity. The medication is administered orally once daily. The maximum daily dose is 45 mg, with a total maximum dose of 16,380 mg over a treatment period of up to 52 weeks. Fezolinetant is developed by Astellas Pharma Global Development, Inc. and is identified by the sponsor product code ESN364. The primary objective of the trial is to evaluate the efficacy of fezolinetant in reducing the frequency and severity of moderate to severe vasomotor symptoms (VMS) in women undergoing adjuvant endocrine therapy for stage 0-3 hormone receptor-positive breast cancer.

The study also includes a **placebo** group, which receives placebo tablets that are identical in appearance to the fezolinetant tablets. The placebo is administered orally once daily, with each tablet containing no active substance. The placebo serves as a comparator to assess the efficacy and safety of fezolinetant. The maximum daily dose and total dose for the placebo group are equivalent to those of the fezolinetant group, ensuring consistency in the treatment regimen. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The efficacy of fezolinetant in the clinical trial will be assessed through several co-primary and secondary endpoints. The co-primary endpoints focus on evaluating the change in frequency and severity of moderate to severe **vasomotor symptoms (VMS)** from baseline to week 4 and week 12. These parameters will be measured using patient-reported outcomes, specifically tracking the frequency and severity of VMS episodes.

Secondary endpoints include changes in the Menopause-specific Quality of Life Questionnaire (MENQOL) VMS domain score and the Patient-reported Outcomes Measurement Information System Sleep Disturbance Short Form (PROMIS SD SF) 8b Total Score from baseline to week 12. Additional secondary endpoints involve assessing the change in frequency and severity of VMS from baseline to week 24, as well as the incidence and severity of treatment-emergent adverse events (TEAEs), including adverse events of special interest (AESIs), clinical laboratory assessments, vital signs, and ECG results.

Further analysis will include the percent reduction of ≥ 50%, ≥ 75%, and 100% in the frequency of moderate to severe VMS from baseline to weeks 1, 4, 8, and 12. Pharmacokinetic parameters for fezolinetant and its interaction with tamoxifen or aromatase inhibitors will also be evaluated. The study will utilize validated scales and questionnaires to collect data at specified timepoints, ensuring a comprehensive assessment of the drug's efficacy in managing VMS in the target population.