Phase II Evaluation of Alpelisib Efficacy, Safety, and Pharmacokinetics in Pediatric and Adult Patients with PIK3CA-Related Overgrowth Spectrum (PROS)

The primary objective is to demonstrate the efficacy of alpelisib in pediatric and adult patients with PIK3CA-related overgrowth spectrum (PROS), specifically within two age-based cohorts: individuals aged 18 years or older and those aged 2 to less than 18 years. Secondary objectives include:

• Evaluation of changes in target lesions, nontarget lesions, and the occurrence of new lesions over time.
• Assessment of clinical response rates, duration of response, and time to treatment failure.
• Characterization of the pharmacokinetics of the study drug.
• Monitoring changes in patient-reported pain, health-related quality of life, and overall symptom impression.
• Evaluation of changes in symptoms, comorbidities, and the frequency of hospitalizations or rescue surgeries.
• Assessment of the overall safety and tolerability of the treatment.

This study involves 32 participants diagnosed with PIK3CA-Related Overgrowth Spectrum (PROS). The study population includes both male and female individuals, categorized into two distinct age groups: those aged 2 to less than 18 years and those aged 18 years or older. Eligibility requires symptomatic and progressive overgrowth, characterized by syndromic disease or specific isolated features, excluding isolated macrodactyly, macrocephaly, or epidermal nevus. Participants must possess documented somatic mutations in the PIK3CA gene confirmed via DNA-based testing. Required clinical parameters include a Lansky performance status or Karnofsky performance status index of at least 50, a specific PGI-S score, and adequate bone marrow and organ function. Additionally, there must be at least one PROS-related measurable lesion with a diameter of 2 cm or greater that is associated with functional limitations or clinical symptoms.

This Phase II, single-arm study is designed to evaluate the efficacy, safety, and pharmacokinetics of alpelisib in pediatric and adult patients diagnosed with PIK3CA-related overgrowth spectrum (PROS). The research methodology involves assessing the proportion of participants achieving a confirmed objective response as the primary endpoint. The study includes two distinct cohorts based on age: individuals aged 18 years or older and those aged between 2 and less than 18 years. Participants must demonstrate evidence of a somatic mutation in the PIK3CA gene and present with symptomatic, progressive overgrowth. The clinical investigation includes a screening visit to confirm eligibility via DNA-based testing, assessment of performance status, and measurement of PROS-related lesions. Following screening, participants receive 250 mg of alpelisib administered via oral use in the form of granules or film-coated tablets. Secondary endpoints involve monitoring changes in lesion volumes, plasma concentration, and symptom severity through various clinical assessments. The study is scheduled to take place between December 2025 and November 2030. Early termination of an individual's involvement may occur due to disease progression, death, or the requirement for rescue surgery.

The investigational medicinal product is alpelisib, also identified as BYL719. This orphan drug is administered via oral use. The available pharmaceutical forms for this substance include granules and film-coated tablets. The specified dosage is 250 mg.

The primary efficacy endpoint is the proportion of participants achieving a confirmed objective response at any time. This is defined as a radiological response confirmed by a subsequent assessment performed at least 4 weeks later. Secondary efficacy assessments include changes from baseline in PIK3CA-related overgrowth spectrum (PROS) lesion volumes, specifically the sum of target lesion volume, the sum of MRI-measurable non-target lesion volume, and the sum of all MRI-measurable lesion volume. Additional evaluations include changes in other non-target lesions, the appearance of new lesions, and the proportion of participants with a radiological response at scheduled protocol timepoints, all as assessed by Blinded Independent Central Review (BIRC).

Further secondary parameters include:

• Duration of response, measured from the first documented confirmed objective response until disease progression, death, or rescue surgery.
• Time to treatment failure (TTF), defined as the interval from the start of alpelisib treatment until confirmed disease progression, death, rescue surgery, or treatment discontinuation.
• Changes in scores from the Brief Pain Inventory (BPI), the Wong-Baker Faces Scale, and the Patient Global Impression of Symptom Severity (PGI-S).
• Overall clinical response as assessed by the Investigator.
• Changes in PROS-related symptoms and the frequency of complications or comorbidities.
• The number and percentage of healthcare visits, hospitalizations, or surgeries required to manage the condition.