Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.

A Two-stage Double-blind, Randomized, Placebo-controlled Study to Assess the Efficacy, Safety and Pharmacokinetics of Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.

The main purpose of this study in participants with PIK3CA-mutated LyM is to assess the change in radiological response and symptom severity upon treatment with alpelisib film-coated tablets (FCT) as compared to placebo.

This is a phase II/III multi-center study with two stages:

• Stage 1 is designed to select the dose(s) for the confirmatory phase (DSCP) for alpelisib in Stage 2 and will comprise a 24-week open-label core phase in adult (≥18 years of age) and pediatric participants (6-17 years of age) with PIK3CA-mutated LyM, followed by an extension. After eligibility has been confirmed at screening, participants will be randomized in a 1:1 ratio to the different alpelisib doses according to their age. Depending on the results at the end of Stage 1 core phase, the Stage 2 will be opened to adult and/or pediatric participants or the study may be stopped.
• Stage 2 is designed to confirm the efficacy and assess safety of alpelisib at the DSCP in participants with PIK3CA-mutated LyM and will comprise a 24-week randomized, double blind, placebo-controlled confirmatory phase in adult (≥18 years of age) and pediatric participants 6-17 years of age followed by an open-label extension. After eligibility has been confirmed at screening participants will be randomized in a 2:1 ratio to alpelisib or placebo.

Additionally, in parallel, Stage 2 will include a 24-week open-label core phase in pediatric participants 0-5 years of age followed by an extension, if pediatric participants will be enrolling in Stage 2.

Based on the results of the 24-week open-label core phase of Stage 1, the dose(s) for Stage 2 will be selected by Novartis in consultation with the Steering Committee (SC). During the 24-week randomized, double blind, placebo-controlled core phase of Stage 2, an Independent Data Monitoring Committee (DMC) will conduct periodic safety and efficacy reviews to assess the risk benefit profile of the treatment.

Key inclusion criteria:

1. Signed informed consent and assent (when applicable) from the participant, parent, legal authorized representative or guardian.
2. Participant must be willing to remain at the clinical site as required by the protocol and be willing to adhere to study restrictions and examination schedules.
3. Participant has a physician confirmed and documented diagnosis of a symptomatic LyM at the time of informed consent (Note: the physician must confirm that the LyM cannot be included under the PROS diagnostic criteria).
4. Participant is not considered as a candidate for or is not willing to receive non-drug therapies including but not limited to sclerotherapy, embolization, and surgery until the completion of Week 24 in Stage 1 and 2.
5. Participant has evidence of a somatic mutation(s) in the PIK3CA gene prior to randomization.
6. Participant has at least one measurable LyM lesion confirmed by BIRC assessment prior to randomization.
7. Participants must be able to ingest study drug (either in tablet form or as a drinkable suspension [Groups 1 to 4] or granules or as an oral suspension [Group 5]) as assessed within 7 days before study treatment start. Drug administration via feeding tubes is allowed.

Key exclusion criteria:

1. Participant has a physician-confirmed and documented diagnosis of PROS at the time of informed consent.
2. Participant has a physician-confirmed and documented diagnosis of a Central Conducting Lymphatic Anomaly, General Lymphatic Anomaly, Gorham-Stout disease, Kaposiform lymphangiomatosis at the time of informed consent.
3. Participant has a known history of Stevens-Johnson syndrome, erythema multiforme, or toxic epidermal necrolysis at the time of informed consent.
4. Participant has an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at the time of informed consent.
5. Participant had previous treatment with alpelisib and/or any other PI3K inhibitors with treatment duration longer than 2 weeks at the time of informed consent.

Other inclusion/exclusion criteria may apply