EPIK-P4: A Phase II Single-arm Study to Assess the Efficacy, Safety and Pharmacokinetics of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (PROS)

The study consists of a core period of 48 weeks and an extension period of up to 2 years to assess the efficacy, safety and pharmacokinetic (PK) of alpelisib in pediatric and adult participants with PROS.

Screening Period: Potential participants will be assessed for eligibility and undergo a whole body MRI scan to evaluate PROS-related lesions. Only those who meet all inclusion criteria will be eligible for randomization.

Core Period: Baseline is defined as the last available evaluation prior to the first dose of study treatment. Participants in Group 1 and Group 2 will be enrolled and treated with alpelisib in an open-label fashion.

• Group 1 (adults): will start with 250 mg once daily, with no dose escalation allowed.
• Group 2 (children and adolescents): will start with 50 mg once daily for participants aged 2 to \<6 years, and 125 mg once daily for participants aged 6 to \<18 years.

Extension 1 Period: Participants in both groups will continue their treatment under the same rules as the core period. This period will last until Week 168 following the completion of the core period for each participant. Those who complete this period before the end of the study will transition to the Extension 2 period.

Extension 2 Period: Participants will continue their treatment under the same rules as the core and Extension 1 periods until the last participant completes the Extension 2 period. Participants still deriving clinical benefit from alpelisib at the end of the study may receive post-trial access (PTA) to alpelisib.

Adult participants ≥18 years of age.

Drug: Alpelisib

Children and adolescents 2 to \<18 years of age.

Drug: Alpelisib

Oral Film-Coated Tablet (FCT):

• Group 1: 250 mg once daily
• Group 2, 6 to \<18 years: 125 mg once daily (starting dose)

Granules:

• Group 2, 2 to \<6 years: 50 mg once daily (starting dose)

Time frame: Up to Week 48

Confirmed objective response is defined as achieving radiological response, confirmed by a subsequent assessment performed at least after 4 weeks. The achievement of radiological response requires ≥20% reduction from baseline in the sum of target lesion volumes (1 to 3 target lesions, assessed by Magnetic Resonance Imaging (MRI) by a blinded independent review committee (BIRC)), provided that none of the individual target lesions has ≥20% increase from nadir, and in absence of progression of non-target lesions and without new lesions.

Time frame: Up to Week 48

Confirmed objective response is defined as achieving radiological response, confirmed by a subsequent assessment performed at least after 4 weeks. The achievement of radiological response requires ≥20% reduction from baseline in the sum of target lesion volumes (1 to 3 target lesions, assessed by Magnetic Resonance Imaging (MRI) by a blinded independent review committee (BIRC)), provided that none of the individual target lesions has ≥20% increase from nadir, and in absence of progression of non-target lesions and without new lesions.

Time frame: Baseline, Week 12, Week 24, Week 48, Week 96, Week 144, Week 168, End of Treatment (last dose +< 14 day - Only for participants discontinuing on or prior to week 168)

Change from baseline (as assessed by BIRC) in target lesion volume will be summarized descriptively

Time frame: Baseline, Week 12, Week 24, Week 48, Week 96, Week 144, Week 168, End of Treatment (last dose +< 14 day - Only for participants discontinuing on or prior to week 168)

Change from baseline (as assessed by BIRC) in MRI-measurable non-target lesion volume will be summarized descriptively

Time frame: Baseline, Week 12, Week 24, Week 48, Week 96, Week 144, Week 168, End of Treatment (last dose +< 14 day - Only for participants discontinuing on or prior to week 168)

Change from baseline (as assessed by BIRC) in all MRI-measurable (target and non-target) lesion volume will be summarized descriptively

Time frame: Baseline, Week 12, Week 24, Week 48, Week 96, Week 144, Week 168, End of Treatment (last dose +< 14 day - Only for participants discontinuing on or prior to week 168)

Change from baseline (as assessed by BIRC) in other non-target lesion will be summarized descriptively

Time frame: Week 12, Week 24, Week 48, Week 96, Week 144, Week 168, End of Treatment (last dose +< 14 day - Only for participants discontinuing on or prior to week 168)

Appearance of new lesions (as assessed by BIRC) will be summarized descriptively

Time frame: Week 12, Week 24, Week 48, Week 96, Week 144, Week 168, End of Treatment (last dose +< 14 day - Only for participants discontinuing on or prior to week 168)

Not reported in this registry record.

Time frame: From first documented response until progression of PROS lesions or death, assessed up to approximately 3 years

Duration of response (DOR) is defined as the time from the first documented confirmed objective response until progression of any PROS lesion by BIRC or death or rescue surgery for any PROS lesion.

Time frame: Week 1 Day 1 (Post-dose 3 hour), Week 4 Day 1 (Pre-dose and Post-dose 3 hour), Week 12 Day 1 (Pre-dose and Post-dose 3 hour)

Not reported in this registry record.

Time frame: Baseline, Week 4, Week 8, Week 12, Week 16, Week 24, Week 48, Week 72, Week 96, Week 120, Week 144, Week 168, End of Treatment (last dose +< 14 days)

Two items from the Brief Pain Inventory (BPI) will be used for adult and pediatric participants aged 12 years and older. The first item assesses the worst pain intensity in the past 24 hours, with responses on an 11-point scale from 0 (no pain) to 10 (pain as bad as you can imagine). The second item evaluates pain interference with general activity in the past 24 hours, also on an 11-point scale from 0 (does not interfere) to 10 (completely interferes).

Time frame: Baseline, Week 4, Week 8, Week 12, Week 16, Week 24, Week 48, Week 72, Week 96, Week 120, Week 144, Week 168, End of Treatment (last dose +< 14 days)

For children aged 3-11 years, the Wong-Baker FACES® Pain Rating Scale will be used instead of the BPI worst pain intensity question. This scale features six faces showing increasing levels of pain, each with a numeric rating and a descriptor (from 0 'no hurt' to 10 'hurts worst'). Children will select the face that best represents their pain level. There is no pain intensity scale for children under 3 years.

Time frame: Baseline, Week 4, Week 8, Week 12, Week 16, Week 24, Week 48, Week 72, Week 96, Week 120, Week 144, Week 168, End of Treatment (last dose +< 14 days)

A Patient Global Impression of Symptom Severity (PGI-S) item will be used to understand the overall severity of symptoms experienced and clinical meaningfulness of treatment effects experienced during this study. This item includes 5 response options: no symptoms, mild, moderate, severe, and very severe. This scale can be completed by the parent/caregiver for pediatric participants aged \<12 years.

Time frame: From Baseline up to approximately 3 years

Time to Treatment Failure (TTF) is defined as the time from alpelisib treatment start date until disease progression supported by radiological assessment performed by BIRC, death, rescue surgery for any PROS lesion or discontinuation of alpelisib due to any reason other than technical problems or study termination by the sponsor. Participants who complete the study, are ongoing treatment or discontinue alpelisib due to technical problems (e.g. drug supply issues, site prematurely ends study participation) or study termination by the sponsor will be censored at the date of last study treatment received.

Time frame: From Baseline up to approximately 3 years

The proportion of participants with overall clinical response reported as improvement, stable or worsening of clinical condition, as assessed by the Investigator will be summarized descriptively.

Time frame: From Baseline up to approximately 3 years

Changes in symptoms and complications/comorbidities (i.e., walking impairment, cardiac/pulmonary/renal function, pain, Karnofsky/Lansky performance status) will be summarized descriptively. For each complication/comorbidity, only participants who have this reported as being present at baseline will be included in the analysis. When new symptoms/complications/comorbidities appear at any time of study therapy, they will be assessed for clinical significance and reported as adverse events when applicable.

Time frame: Up to at least 3 years

Percentage of participants with healthcare visit/hospitalized due to PROS will be assessed for Group 1 and Group 2.

Time frame: Up to at least 3 years

Percentage of participants requiring rescue surgery due to PROS will be assessed for Group 1 and Group 2.

Time frame: Up to at least 3 years

Treatment emergent Adverse Event (TEAEs) in this study were events that started after the first dose of study treatment and until 30 days after the last dose of study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 30 days after the last study treatment.

Study Assessing the Efficacy, Safety and Pharmacokinetics of Alpelisib in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum (PROS)