Efficacy and Safety of Alpelisib in Pediatric and Adult Patients with PIK3CA-Related Overgrowth Spectrum: A Phase II Randomized, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of **alpelisib** in patients with PIK3CA-Related Overgrowth Spectrum (PROS). This is measured by the proportion of participants randomized to alpelisib who achieve a confirmed objective response by BIRC in either Group 1 (adults aged ≥18 years) or Group 2 (children/adolescents aged 6-17 years). This objective is clinically relevant as it aims to determine the therapeutic benefit of alpelisib in managing PROS, a condition characterized by overgrowth and complex vascular malformations, which can significantly impact quality of life.

Secondary objectives include:

• Demonstrating the efficacy of alpelisib versus placebo based on the proportion of participants with a response at Week 16 in Group 1 or Group 2.
• Assessing the efficacy of alpelisib by the proportion of participants with a response at Week 24 (by BIRC) in Groups 1 and 2.
• Evaluating the safety and tolerability of alpelisib compared to placebo in Groups 1 and 2 up to Week 16, and overall safety and tolerability in participants with PROS over time.
• Assessing changes in patient-reported pain intensity and overall severity of symptoms at Week 16 with alpelisib compared to placebo in pediatric and adult populations.
• Evaluating changes in target and non-target lesions over time and the appearance of new lesions from baseline.
• Assessing the pharmacokinetics (PK) of alpelisib in adult and pediatric patients with PROS.
• Evaluating changes in patient-reported pain, health-related quality of life, and overall impression of symptoms in pediatric and adult populations over time.
• Assessing the duration of response and time to treatment failure in participants receiving alpelisib.
• Evaluating the rate of overall clinical response as assessed by the Investigator at scheduled protocol visits for disease evaluation.
• Assessing the proportion of participants with a response at scheduled protocol visits during extension periods.
• Evaluating changes in symptoms and complications/comorbidities up to Week 16 with alpelisib compared to placebo, and over time in association with PROS.
• Assessing the frequency of healthcare visits/hospitalizations due to PROS and rescue surgeries for PROS over time.

The clinical trial involves a total of **150 participants** diagnosed with **PIK3CA-Related Overgrowth Spectrum (PROS)**. The study population includes both male and female subjects, categorized into two age groups: children and adolescents aged 6 to 17 years, and adults aged 18 years and older. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of PROS with symptomatic and/or progressive overgrowth, and the presence of at least one measurable PROS-related lesion. The trial population also includes individuals with documented evidence of a somatic mutation in the PIK3CA gene. Participants are required to have adequate bone marrow and organ function, as well as a performance status index of 50 or higher. The study considers vulnerable populations, and informed consent was obtained from all participants or their legal representatives. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and pharmacokinetics of **alpelisib** in pediatric and adult patients diagnosed with **PIK3CA-related overgrowth spectrum (PROS)**. The trial consists of an initial 16-week period where participants are randomly assigned to receive either alpelisib or a placebo. The primary objective is to assess the efficacy of alpelisib by measuring the proportion of participants with a confirmed objective response, as determined by a blinded independent review committee (BIRC). The trial is expected to conclude by June 2030, with recruitment having commenced in April 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including the presence of a measurable PROS-related lesion and documented evidence of a somatic mutation in the **PIK3CA** gene. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. The end-of-study visit will occur after the 16-week treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints.

The expected duration of participant involvement is approximately 16 weeks, with the possibility of early termination if certain conditions arise, such as significant adverse events or withdrawal of consent. Participants who discontinue treatment prior to confirmation of response or require surgery as rescue therapy for PROS lesions will be considered non-responders. The trial aims to provide valuable insights into the potential benefits of alpelisib for individuals affected by PROS, contributing to the broader understanding of treatment options for this rare condition.

The clinical trial involves the administration of **alpelisib**, marketed under the product name BYL719, which is being evaluated for its efficacy, safety, and pharmacokinetics in patients with PIK3CA-related overgrowth spectrum (PROS). The experimental medication is available in two pharmaceutical forms: film-coated tablets and granules. The film-coated tablets are administered orally with a maximum daily dose of 250 mg, and the treatment period extends up to 60 days. The granules, also administered orally, are specifically formulated for pediatric use, with a maximum daily dose of 50 mg over the same treatment duration. Both formulations are of chemical origin and are produced by Novartis Pharma AG.

In addition to the active treatment, a placebo is utilized in the study to maintain the double-blind design. The placebo is designed to match the appearance of the BYL719 film-coated tablets, available in light yellow for the 50 mg dosage and dark yellow for the 125 mg dosage. The placebo is administered orally, following the same dosing schedule as the active treatment, to ensure blinding and unbiased assessment of the treatment's efficacy.

Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the prescribed treatment schedule. The trial's primary objective is to assess the proportion of participants achieving a confirmed objective response, as evaluated by a blinded independent review committee (BIRC), in both adult and pediatric cohorts. The study is designed to provide robust data on the therapeutic potential of alpelisib in managing PROS, with careful consideration of participant safety and treatment efficacy.

The efficacy of **alpelisib** in the clinical trial will be assessed primarily by measuring the proportion of participants who achieve a confirmed objective response. This response is defined by a reduction of at least 20% from baseline in the sum of target lesion volumes, as assessed by MRI and evaluated by a blinded independent review committee (BIRC). The assessment will ensure that none of the individual target lesions have increased by 20% or more from baseline, and there is no progression of non-target lesions or appearance of new lesions.

Secondary efficacy endpoints include the comparison of the proportion of participants achieving a response at Week 16 between those receiving **alpelisib** and those receiving a placebo. The trial involves a double-blind, randomized, placebo-controlled period lasting 16 weeks, during which efficacy will be evaluated. The study targets pediatric and adult patients with PIK3CA-related overgrowth spectrum (PROS), and the efficacy assessments will be conducted at specified intervals to ensure accurate and reliable data collection.