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

Key Inclusion Criteria:

• Signed informed consent and assent (when applicable) from the patient, parent, legalauthorized representative, or guardian prior to any study-related screeningprocedures were performed.

• Male or female patients age above 0 day at the time of informed consent: Group 1: ≥ 18 years old, Group 2: 6-17 years old, Group 3: ≥ 0-5 years old, Group 4: ≥ 2-5years old, Group 5: 6-17 years old.

• Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth andat least one measurable PROS-related lesion confirmed by BIRC assessment who hadsyndromic disease or isolated features at the time of informed consent. Patients,who previously had been receiving systemic treatment for PROS, could enter thestudy.

• Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in locallaboratories using a DNA-based test validated according to the local regulations atthe time of informed consent.

• A tissue sample (fresh or archival) was to be sent to a Novartis-designated centrallaboratory.

• Karnofsky (in patients > 16 years old at study entry)/Lansky (≤ 16 years of age atstudy entry) performance status index ≥ 50.

• Adequate bone marrow and organ function as assessed by central laboratory foreligibility.

• Presence of at least one PROS-related measurable lesion defined as a lesion withlongest diameter ≥ 2 cm, when the volume could be accurately and reproduciblymeasured by MRI, and associated with complaints, clinical symptoms or functionallimitations affecting the patient's everyday life. Measurability was confirmed byBIRC before randomization.

• Able to swallow study drug (as assessed within 7 days before study treatment start):

• Groups 1, 2, 4, and 5: FCT, or as drinkable suspension when applicable.

• Group 3: granules. Drug administration via feeding tube is allowed.

Key Exclusion Criteria:

• Patient with only isolated macrodactyly, epidermal nevus/nevi and macroencephaly (the only clinical feature or a combination of any three of them), in absence ofother PROS-related lesions at the time of informed consent.

• Previous treatment with alpelisib and/or any other PI3K inhibitor(s).

• Radiation exposure for PROS treatment purpose within the previous 12 months on thosePROS areas, which were expected to qualify for target lesions (except lesion(s)progressing after completion of radiotherapy) at time of informed consent.

• Debulking or other major surgery performed within 3 months at time of informedconsent.

• Clinically meaningful bleeding related to PROS: Grade 2 within 14 days or grade 3and more within 28 days before study treatment start as per CTCAE v4.03.

• Clinically meaningful PROS-related thrombotic event (grade 2 and more as per CTCAEv4.03) within 30 days before informed consent, and/or sclerotherapy/embolization forvascular complications performed within 6 weeks before informed consent.

• History of prior and or ongoing malignancy or ongoing investigations or treatmentfor malignancy at time of informed consent.

• Clinically significant heart disease at time of informed consent.

• Patients in Groups 1, 2, and 5 with documented pneumonitis or interstitial lungdisease at time of informed consent and with impaired lung function (e.g., FEV1 orDLCO ≤ 70% of predicted) that was not related to PROS. Patients in Groups 3 and 4with documented or suspicious pneumonitis or interstitial lung disease based on MRIimages at time of informed consent.

• History of acute pancreatitis within 1 year before informed consent or past medicalhistory of chronic pancreatitis at time of informed consent.

• Patients with an established diagnosis of type I diabetes mellitus or uncontrolledtype II diabetes mellitus at time of informed consent.

• Known impairment of gastrointestinal (GI) function due to concomitant GI diseasethat may significantly alter the absorption of the study drug at time of informedconsent.

• History of hypersensitivity to any drugs or metabolites of PI3K inhibitor or any ofthe excipients of alpelisib at time of informed consent.

• Known history of Steven Johnson's syndrome, erythema multiforme or toxic epidermalnecrolysis at time of informed consent.

• Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum attime of informed consent, when epilepsy was not controlled and/or the patient maynot be switched to non-enzyme inducing antiepileptic drug(s) at time of informedconsent.

• Patient with other concurrent severe and/or uncontrolled medical conditions thatcould, in the Treating Physician's judgment, contraindicate administration ofalpelisib at time of informed consent. Patient with an active documented COVID-19infection at time of informed consent could be included only when completelyrecovered and had no symptoms for at least 28 days before first dose of studymedication.

• Pregnant or breastfeeding female patients at time of informed consent.

• Female patients of child-bearing potential who did not consent to use a highlyeffective method of contraception and male patients who did not consent to use acondom and/or a highly effective method of contraception for the duration of thestudy and for one week following discontinuation of alpelisib.

• Patient was receiving any of the following medications and could not discontinue 7days prior to the start of the treatment: strong inducers of CYP3A4 or inhibitors ofbreast cancer resistance protein (BCRP).

• Not able to understand and to comply with study instructions and requirements attime of informed consent.

• Participation in a prior investigational study within 4 weeks prior to studytreatment start or within 5 half-lives of the investigational product, whichever waslonger.

• Patients with clinically significant worsening of PROS-related laboratory anomalies,physical signs and symptoms indicating an uncontrolled condition during thescreening phase, particularly if systemic treatment with any other inhibitor of thePI3K/AKT/mTOR pathway was stopped prior to the start of study treatment. Thisincluded but was not limited to hypercoagulability state in patients not receivingprophylactic treatment.

Other inclusion/exclusion criteria may apply