Phase III Randomized Double-Blind Study of Alpelisib and Fulvestrant in HR-Positive, HER2-Negative Advanced Breast Cancer with PIK3CA Mutation

The primary objective of this study is to determine whether treatment with **alpelisib** plus **fulvestrant** prolongs progression-free survival (PFS) compared to treatment with placebo plus fulvestrant in patients with hormone receptor-positive, HER2-negative advanced breast cancer. This is clinically relevant as it aims to improve the management of advanced breast cancer by potentially extending the time patients live without disease progression.

Secondary objectives include:

• To determine whether treatment with alpelisib plus fulvestrant prolongs overall survival (OS) compared to treatment with placebo plus fulvestrant.
• To evaluate alpelisib plus fulvestrant compared to placebo plus fulvestrant, with regards to objective response by RECIST 1.1 criteria.
• To evaluate the association between PIK3CA mutation status as measured in circulating tumor deoxyribonucleic acid (ctDNA) at baseline with PFS upon treatment with alpelisib.
• To assess safety and tolerability of alpelisib in combination with fulvestrant compared to placebo in combination with fulvestrant.
• To evaluate treatment with alpelisib plus fulvestrant compared to placebo plus fulvestrant, with respect to time to deterioration of Eastern Cooperative Oncology Group (ECOG) performance status.
• To evaluate patient-reported outcomes of alpelisib plus fulvestrant compared to placebo and fulvestrant.
• To explore the long-term benefit intermediate to PFS and OS.

The clinical trial involves a total of **9 participants** diagnosed with **hormone receptor positive, HER2-negative advanced breast cancer**. The study population includes both male and female adults aged 18 years and older, with a focus on individuals who have a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer. Participants are required to have HER2-negative breast cancer, as defined by specific laboratory tests, and must have at least one measurable lesion according to RECIST v1.1 criteria. The trial population was selected based on the recurrence or progression of disease during or after combined aromatase inhibitor and CDK4/6 inhibitor therapy, with a maximum of two prior lines of systemic therapies in the metastatic setting. Additionally, the presence of PIK3CA mutation(s) is a prerequisite, determined through specific diagnostic tests. The study does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase III**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of **alpelisib** in combination with **fulvestrant** for men and postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer with a PIK3CA mutation. The primary objective is to determine whether this combination prolongs progression-free survival compared to treatment with placebo plus fulvestrant. The trial is expected to run from October 2021 to December 2027, with participants involved for a maximum treatment period of 60 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, cancer diagnosis, and previous treatment history. Following randomization, participants will receive either the investigational treatment or placebo, administered orally and via intramuscular injection, respectively. Follow-up visits will be scheduled to monitor the participants' health, assess the progression of the disease, and evaluate any adverse events according to CTCAE v4.03 criteria. The end-of-study visit will conclude the trial for each participant, assessing the final outcomes and collecting data on overall survival and response rates.

Participant involvement is expected to last until the end of the treatment period or until disease progression, unacceptable toxicity, or withdrawal of consent occurs. Conditions that may lead to early termination from the study include significant adverse events or non-compliance with the study protocol. The trial will utilize BIRC assessments and RECIST v1.1 criteria to evaluate primary and secondary endpoints, including progression-free survival, overall survival, and quality of life measures. The study aims to provide valuable insights into the treatment of advanced breast cancer with a PIK3CA mutation, contributing to the development of more effective therapeutic strategies.

The clinical trial involves the administration of **Alpelisib**, a film-coated tablet, as the experimental medication. Alpelisib is chemically derived and is available in two dosages: 50 mg (light pink) and 200 mg (light red). The tablets are identical to the marketed Piqray tablets, with the modification that they are supplied in clinical HDPE bottles for the study, as opposed to the commercial blister packaging. The maximum daily dose of Alpelisib is 300 mg, with a total maximum dose of 547,500 mg over a treatment period of 60 days. The route of administration is oral, and participant compliance is monitored through the clinical trial protocol.

The study also includes a **Placebo** group, which consists of film-coated tablets that are visually identical to the Alpelisib tablets, available in 50 mg (light pink) and 200 mg (light red) dosages. The placebo is administered orally, following the same dosing schedule as the Alpelisib group, to maintain the double-blind nature of the trial.

Additionally, **Fulvestrant** is used as a non-experimental treatment in the study. Fulvestrant is a solution for injection, chemically derived, and administered via intramuscular injection. The maximum daily dose is 500 mg, with a total maximum dose of 33,000 mg over the 60-day treatment period. Fulvestrant is used in combination with either Alpelisib or placebo to evaluate the efficacy of the experimental treatment in prolonging progression-free survival in participants with HR-positive, HER2-negative advanced breast cancer with a PIK3CA mutation.

The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**, as determined by blinded independent review committee (BIRC) assessments using RECIST v1.1 criteria. This primary endpoint will evaluate the duration during which patients remain free from disease progression or death. Secondary endpoints include overall survival, overall response rate (ORR) with confirmed response, clinical benefit rate (CBR) with confirmed response, duration of response (DOR) with confirmed response, and time to response (TTR), all based on BIRC assessment and RECIST v1.1 criteria. Additionally, PFS will be assessed for participants by PIK3CA mutation status in circulating tumor DNA (ctDNA) at baseline.

Other secondary endpoints involve the incidence, type, and severity of adverse events as per CTCAE v4.03 criteria, time to definitive deterioration of ECOG performance status from baseline, and time to definitive (10%) deterioration in global health status/Quality of Life (QoL) and symptom scale scores of the EORTC QLQ-C30. The change from baseline in global health status/QoL and symptom scale scores of the EORTC QLQ-C30 will also be evaluated. Furthermore, the time from randomization to objective tumor progression on the next line of treatment or death from any cause (PFS2) will be measured. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration, ensuring a comprehensive evaluation of the treatment's impact on advanced breast cancer with a PIK3CA mutation.