Efficacy and Safety of Alpelisib in Pediatric and Adult Patients with PIK3CA-Mutated Lymphatic Malformations: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to demonstrate the efficacy of **alpelisib** in patients with lymphatic malformations associated with a PIK3CA mutation. This is measured by the proportion of participants randomized to alpelisib who exhibit a radiological response at Week 24 of Stage 2, compared to those randomized to placebo. This objective is clinically relevant as it aims to establish the potential of alpelisib as a therapeutic option for this condition, which is characterized by abnormal lymphatic vessel formation due to PIK3CA mutations.

Secondary objectives include:

• To demonstrate the efficacy of alpelisib in improving patient-reported severity of symptoms at Week 24 of Stage 2, compared to placebo, in participants aged 18 years and older (Group 3) and those aged 6 to 17 years (Group 4).
• To assess the efficacy of alpelisib in pediatric participants aged 2 to 5 years, as measured by the proportion of evaluable participants with a response at Week 24 of Stage 2.

The clinical trial involves a total of **40 participants** diagnosed with **lymphatic malformations** associated with a PIK3CA mutation. The study population includes both male and female subjects, with an age range spanning from 6 years to adults aged 18 years and older. Participants were selected based on their confirmed diagnosis and evidence of a somatic mutation in the PIK3CA gene. The trial includes individuals who are not candidates for or unwilling to undergo non-drug therapies such as sclerotherapy, embolization, and surgery until the completion of Week 24. The trial population is characterized by a willingness to adhere to study restrictions and examination schedules, and participants must be able to ingest the study drug in various forms. The study also includes a vulnerable population, ensuring a comprehensive assessment of the drug's efficacy across different demographic groups.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy, safety, and pharmacokinetics of **alpelisib** in patients with lymphatic malformations associated with a PIK3CA mutation. The trial is structured in two stages, with the primary objective of Stage 2 being to demonstrate the efficacy of alpelisib by assessing the proportion of participants with a radiological response at Week 24. The study will involve both pediatric and adult participants, divided into groups based on age, with specific inclusion criteria such as a confirmed diagnosis of lymphatic malformations and evidence of a PIK3CA mutation.

The trial will commence with a screening visit to confirm eligibility, during which informed consent will be obtained, and baseline assessments will be conducted. Participants will then be randomized to receive either alpelisib or a placebo, administered orally in the form of granules or film-coated tablets. The maximum daily dose of alpelisib is set at 250 mg, with a treatment period extending up to 260 days. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the protocol. The primary endpoint will be evaluated at the Week 24 visit, where a reduction in target lesion volumes will be assessed via MRI by a blinded independent review committee.

Participants are expected to remain involved in the study for the entire duration of the treatment period, with the possibility of early termination if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial is anticipated to conclude by October 2030, with recruitment starting in December 2023. The study's design ensures rigorous assessment of alpelisib's therapeutic potential while maintaining participant safety and data integrity.

The clinical trial involves the administration of **alpelisib**, marketed under the product name BYL719, which is provided in two pharmaceutical forms: **granules** and **film-coated tablets**. The granules form of BYL719 is administered orally with a maximum daily dose of 50 mg, and the treatment period can extend up to 260 days. The film-coated tablet form is also administered orally, with a maximum daily dose of 250 mg, and similarly, the treatment period can last up to 260 days. Both forms of BYL719 are of chemical origin and are not formulated for pediatric use. The active substance, alpelisib, is a chemical compound with the synonym (2S)-N1-(4-METHYL-5-(1-(1,1,1-TRIFLUORO-2-METHYLPROPAN-2-YL)PYRIDIN-4-YL)-1,3-THIAZOL-2-YL)PYRROLIDINE-1,2-DICARBOXAMIDE. The product is developed by Novartis Pharma AG and holds an orphan drug designation under the number EU/3/23/2841.

The study also includes the use of a **placebo** as a comparator treatment. The placebo is designed to match the film-coated tablets of BYL719 in appearance but does not contain the active substance, alpelisib. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is available in formulations corresponding to 50 mg, 125 mg, and 200 mg film-coated tablets, although specific details regarding the pharmaceutical form and active substance are not applicable.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess the efficacy, safety, and pharmacokinetics of alpelisib in patients with lymphatic malformations associated with a PIK3CA mutation, comparing outcomes between those receiving the active treatment and those receiving the placebo.

The efficacy of **alpelisib** in the clinical trial will be assessed primarily by evaluating the radiological response at Week 24 of Stage 2. This will be determined by the proportion of participants randomized to alpelisib who achieve a response, defined as at least a 20% reduction in the sum of target lesion volumes (1 to 3 lesions), as assessed by MRI. The assessment will be conducted by a blinded independent review committee (BIRC) at Week 24. It is crucial that none of the individual target lesions exhibit a 20% or greater increase from baseline, and there should be no progression of non-target lesions or the appearance of new lesions.

Secondary efficacy endpoints include a response at Week 24, defined by at least a 1-point improvement on the patient global impression of severity (PGI-S) scale compared to baseline. Additionally, the secondary endpoint mirrors the primary endpoint in terms of lesion volume reduction, assessed by MRI at Week 24 by the BIRC. These assessments will provide comprehensive data on the efficacy of alpelisib in treating lymphatic malformations associated with a PIK3CA mutation.