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 screening period of up to 42 days, 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.

Key Inclusion Criteria:

• Male or female participants aged ≥2 years at the time of informed consent/assent.
• Participants with diagnosis of PROS (according to Clinical Diagnostic Criteria for PROS proposed by Keppler Noreuil et al 2014) with symptomatic AND progressive overgrowth, who have syndromic disease or isolated features (with the exception of isolated macrodactyly, macrocephaly or epidermal nevus) at the time of informed consent/assent.
• Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories using a DNA-based test AND available archival tissue (if archival tissue sample is not available, a fresh biopsy should be performed, if it is not clinically contraindicated) at the time of informed consent/assent.
• Karnofsky (in participants >16 years of age at study entry) or Lansky (≤16 years of age at study entry) performance status index ≥50.
• PGI-S score of mild, moderate, severe, or very severe at screening.
• Adequate bone marrow and organ function.
• Presence of at least 1 PROS-related measurable lesion (longest diameter ≥2 cm) confirmed by BIRC assessment and associated with complaints, clinical symptoms or functional limitations affecting the participant's everyday life.

Key Exclusion Criteria:

• Participant with only isolated macrodactyly, epidermal nevus/nevi and macroencephaly (the only clinical feature or a combination of any of three of them), in absence of other PROS-related lesions at the time of informed consent/assent.
• Previous treatment with alpelisib and/or any other phosphatidylinositol 3-kinase (PI3K) inhibitor(s) (except treatment attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with treatment duration less than 2 weeks and stopped at least 4 weeks prior to the first dose of study medication with alpelisib).
• Debulking or other major surgery performed within 3 months at the time of informed consent/assent.
• Radiation exposure for PROS treatment purpose within 12 months prior to informed consent/assent.
• Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE v4.03) within 30 days before informed consent/assent, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent/assent.
• Clinically meaningful bleeding from PROS-related lesion (Grade 2 and more as per CTCAE v4.03) within 30 days before study treatment initiation.
• Participants with clinically significant worsening of PROS-related laboratory abnormalities, physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening of underlying pain, newly occurring swelling or redness) indicating an uncontrolled condition during the screening phase.

Other inclusion/exclusion criteria may apply