Study Assessing the Efficacy, Safety and PK of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (EPIK-P2)

This is a Phase II multi-center study with an upfront 16-week, randomized, double-blind, placebo-controlled period, and extension periods, to assess the efficacy, safety and PK of alpelisib in pediatric and adult participants with PROS.

Study period 1 - Core Period: Double-blind treatment, with an upfront 16-week placebo-controlled period (From Randomization to the end of Week 24) - Groups 1 and 2 At study start, participants in Group 1 and Group 2 will be enrolled and randomized in a 2:1 ratio (104 participants in the active arms and 52 participants in the placebo arms) to alpelisib or matching placebo. The upfront placebo-controlled period will continue for the first 16 weeks. At the conclusion of week 16, those participants who were randomized to receive placebo will be switched to active treatment with alpelisib in a blinded fashion at the dose level received at the end of the placebo period. Those participants who were randomized to receive alpelisib, will continue their treatment at the same dose level.

During the initial 16 weeks of the Core period, study treatment will be given in a blinded fashion, starting from week 17 of the Core period in open label fashion. The randomized treatment assignment to the treatment arms will remain blinded to participants, Investigators and the study team until the time of the primary analysis, when the last participant reaches week 48 from randomization or discontinues earlier.

Study period 1 - Exploratory; Group 4, open label treatment with the alpelisib FCT formulation After the implementation of Global Protocol Amendment 01, approximately 6 participants 2 to 5 years of age will be enrolled in exploratory Group 4. These participants will receive alpelisib FCT in an open label setting.

Study period 2 - Extension 1: treatment with alpelisib (week 25 up to the end of week 48) - Groups 1 and 2 Participants (Group 1 and Group 2) will continue their treatment during this study period.

For Groups 1 and 2, dose escalation is NOT allowed during first 4 weeks of Extension 1 period (weeks 25-28).

Once a participant (Groups 1 and 2) has completed initial 24 weeks of study treatment and reached Week 29, dose escalation will be allowed (Refer to Section 6.5.1):

* Group 1: Alpelisib (125mg, or 200mg, or 250 mg QD) * Group 2: Alpelisib (50mg, or 125mg, or 200mg, or 250 mg QD)

Study period 2 - Exploratory: Group 4, open label treatment with the alpelisib FCT formulation

For Group 4 dose escalation is allowed once participant has reached the age of 6 years old, has completed the initial 24 weeks of study treatment, and has reached week 25:

• Group 4: Alpelisib (50 mg, or 125 mg, or 200 mg, or 250 mg QD)

Study period 3 - Extension 2: long-term treatment with alpelisib (Week 49 up to 5 years) - Groups 1 and 2 Groups 1 and 2 participants who continue the study until Week 48 and have clinical benefit from the study treatment, will enter a long-term extension period. Dose escalation and treatment beyond progression are allowed in both Group 1 and Group 2.

Study period 3 - Exploratory: Group 4, open label treatment with the alpelisib FCT formulation Group 4 participants who continue the study until Week 48 and have clinical benefit from the study treatment, will enter a long-term extension period. Dose escalation is allowed once a participant has reached the age of 6 years old, has completed the initial 24 weeks of study treatment, and has reached Week 25.

Exploratory study part: Group 3, open label treatment with the alpelisib granules formulation Group 3 will be an exploratory group of participants who are 0 to 5 years old and will receive the alpelisib granules formulation with an age-dependent starting dose and maximum dose levels ranging from 20 mg every other day to 50 mg once daily. Group 3 will be open to enrollment only after implementation of Global Protocol Amendment 05. Dose escalation is allowed once a participant has reached the age of 6 years, has completed the initial 24 weeks of study treatment, and has reached Week 25.

Group 5 open-label treatment with the alpelisib FCT formulation:

Participants of Group 5 will be enrolled after implementation of Global Protocol Amendment 02 and immediately after enrollment of Group 2 has been completed and will receive a starting dose of 125 mg alpelisib FCT formulation once daily in an open-label setting.

Dose escalation is allowed for those who did not derive sufficient clinical benefit at the Investigator's discretion and once participant has reached at least Week 25.

Study period 4 - Extension 3: treatment with alpelisib (from Week 264 until last patient enrolled completes 5 years of treatment) All participants from all groups will be followed until the last patient enrolled completes 5 years of treatment or discontinues early, to collect additional safety of alpelisib and in order to ensure patient access to treatment in the absence of global commercial supply in pediatric and adult participants with PROS. Visits will be performed every 24 weeks and additional safety assessments every 48 weeks.

It is planned to enroll approximately 192 participants in total, 78 adults and 114 children and adolescents. A total of approximately 156 male or female participants (of age ≥ 6 years) with PROS will be randomized in a 2:1 ratio in Groups 1 and 2 (approximately 78 participants per age group). Additional exploratory groups (Group 3, Group 4 and Group 5) will include approximately a total of 36 participants (approximately 15 in Group 3, 6 in Group 4 and 15 in Group 5).