Evaluation of Long-Term Safety and Efficacy of Alpelisib in Patients with PIK3CA-Related Overgrowth Spectrum (PROS) Following Participation in Study CBYL719F12002

The primary objective of this phase II study is to assess the long-term **safety** and tolerability of **alpelisib** over time in patients with PIK3CA-Related Overgrowth Spectrum (PROS). This is clinically relevant as it aims to ensure that the therapeutic benefits of alpelisib are sustained without compromising patient safety over extended periods, which is crucial for chronic conditions like PROS.

Secondary objectives include: - Retrospective period only: To assess the safety and tolerability of alpelisib. - Prospective period only: To assess the safety and tolerability of alpelisib over time. - Retrospective and prospective periods: To evaluate the long-term efficacy of alpelisib, assess symptoms and complications/comorbidities associated with PROS over time, assess the frequency of healthcare visits/hospitalizations due to PROS over time, and assess the type of medications and non-drug therapies over time.

The clinical trial involves a total of **one participant** diagnosed with **PIK3CA-Related Overgrowth Spectrum (PROS)**. The study population includes both male and female subjects, encompassing a broad age range from children to adults. Participants were selected based on their previous involvement in the EPIK-P1 study and their ability to provide informed consent. The trial includes individuals who are considered part of a vulnerable population. Participants are required to have received at least one dose of alpelisib after the specified data cutoff date. The study aims to assess the long-term safety and tolerability of alpelisib over time. No specific lifestyle considerations such as diet or physical activity are highlighted in the trial data provided.

The clinical trial is designed to evaluate the long-term safety and efficacy of **alpelisib** in patients with PIK3CA-Related Overgrowth Spectrum (PROS) who have previously participated in a prior study. This is a phase II, prospective, randomized, double-blind, controlled trial. The trial is expected to run until September 2027, with recruitment having commenced in January 2022. Participants will be involved in the study for a maximum treatment period of 260 weeks, receiving a daily dose of 250 mg of alpelisib in the form of a film-coated tablet administered orally.

The study includes several key visits: an initial inclusion (screening) visit, regular follow-up visits, and an end-of-study visit. During the inclusion visit, eligibility criteria will be confirmed, including prior participation in the EPIK-P1 study and the provision of informed consent. Follow-up visits will be conducted to monitor the incidence of new or worsening grade ≥3 treatment-emergent adverse events (AEs), as well as to assess safety data such as changes in laboratory values, vital signs, and cardiac function. The end-of-study visit will conclude the participant's involvement, with a final assessment of safety and efficacy outcomes.

Participants may be withdrawn from the study early if they experience significant safety concerns or if the investigator deems it necessary for their well-being. Additionally, participants who discontinue treatment for reasons other than safety prior to the first visit of the prospective period may be eligible to restart treatment if considered beneficial by the investigator. The primary endpoint of the trial is the incidence of new or worsening grade ≥3 treatment-emergent AEs, while secondary endpoints include assessments of lesion response, PROS-related symptoms, and healthcare utilization. The trial aims to provide comprehensive data on the long-term safety and tolerability of alpelisib in this patient population.

The clinical trial involves the administration of the experimental medication **alpelisib**, marketed under the product name BYL719. This medication is provided in the form of a **film-coated tablet** and is intended for **oral use**. The maximum daily dose of alpelisib is 250 mg, with the same amount being the maximum total dose per day. The treatment period is set to a maximum of 260 days. Alpelisib is of chemical origin and is not formulated for pediatric use. The medication is designated as an orphan drug, with the designation number EU/3/21/2420, indicating its use for a rare condition. The active substance, alpelisib, is produced by Novartis Pharma AG.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the long-term safety and efficacy of alpelisib in patients with PIK3CA Related-Overgrowth Spectrum (PROS) who have previously participated in a related study. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the long-term safety and tolerability of alpelisib over time, providing valuable data on its use in the specified patient population.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the incidence of new or worsening grade ≥3 treatment-emergent adverse events (AEs), categorized by system organ class and preferred term. This will provide a comprehensive overview of the safety profile of **alpelisib** in patients with PIK3CA Related-Overgrowth Spectrum (PROS).

Secondary endpoints will include a detailed analysis of the incidence, type, and severity of AEs according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. This will involve causality assessments of AEs and other safety data, such as changes in laboratory values, vital signs, and cardiac function assessments. Additionally, the prospective period will evaluate growth, bone/dental development, and sexual maturation in applicable age groups. Investigator assessments of lesion response will be categorized as improved, stable, or worsened. The trial will also monitor the incidence of PROS-related symptoms and complications, the number of healthcare visits or hospitalizations due to PROS, and a description of medications and non-drug therapies received, including PROS-related treatments other than alpelisib, concomitant medications, and surgeries.