Assessment of the Efficacy and Safety of Alpelisib (BYL719) in Pediatric and Adult Patients with Megalencephaly-CApillary Malformation Polymicrogyria Syndrome (MCAP)

Inclusion Criteria:

1. Signed informed consent and assent (when applicable) from the patient, parent, orguardian must be obtained prior to any study related screening procedures areperformed.

2. Male or female patients age ≥2 years and ≤40 years at the time of informed consent

3. Patients with diagnosis of MCAP* with neurodevelopmental disorder presentation (fromspecific learning disorder to severe intellectual disability)

4. Documented evidence of a postzygotic or constitutional mutation(s) in the PIK3CAgene performed in local laboratories using a Deoxyribonucleic acid (DNA) basedvalidated test at the time of informed consent.

5. Adequate bone marrow and organ function (assessed during the screening visit):

6. Absolute neutrophil count ≥ 1.5 × 109/L

7. Platelets ≥ 100 × 109/L

8. Hemoglobin ≥ 9.0 g/dL (transfusions are allowed)

9. Calcium (corrected for serum albumin) and magnesium within normal limits or ≤Grade 1 according to NCI-CTCAE version 5.0 if judged clinically notsignificant by the investigator

10. Potassium within normal limits.

11. INR ≤1.5

12. Creatinine Clearance ≥ 30 mL/min using Modification of Diet in Renal Disease

13. (MDRD) (≥18 years old) or creatinine-based Bedside Schwartz (˂18 years old)Glomerular filtration rate (GFR) equation

14. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ×ULN.

15. Total bilirubin< ULN except for patients with Gilbert's syndrome who mayonly be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN

16. Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and Glycosylatedhemoglobin (HbA1c) ≤ 6.5% (both criteria have to be met)

17. Fasting Serum lipase ≤ ULN

18. Able to swallow study drug according to age: tablets, or as drinkable suspension, orgranules (under development)

19. For women of child-bearing potential only: negative pregnancy test at screeningvisit

20. Male patients with sexual partners who are pregnant, possibly pregnant or who couldbecome pregnant should use condoms during sexual intercourse for the duration of thestudy and for one week following discontinuation of alpelisib.

21. For exploratory study only : signed informed optional consent for lumbar puncture

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible for inclusion in this study:

1. Patient previously treated with alpelisib

2. Known impairment of GI function due to concomitant disease that may significantlyalter the absorption of the study drug (e.g., ulcerative diseases, uncontrollednausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) attime of informed consent.

3. Participant with uncontrolled diabetes mellitus (Type I or II) at time of informedconsent.

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

5. Participant with other concurrent severe and/or uncontrolled medical conditions thatwould, in the treating Physician's judgment, contraindicate administration ofalpelisib (e.g., active and/or uncontrolled severe infection, chronic activehepatitis, hepatic impairment Child Pugh score C, immuno-compromised, etc.) at timeof informed consent.

6. Female participants of childbearing potential and male participants who do not agreeat time of informed consent to abstinence or, if sexually active, unwilling to use acondom and/or a highly effective method of contraception for the duration of thestudy and for one week following discontinuation of alpelisib. Highly effectivecontraception methods is one of the following:

7. Total abstinence: when this is in line with the preferred and usual lifestyleof the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception

8. Female sterilization: have had surgical bilateral oophorectomy (with or withouthysterectomy), total hysterectomy or bilateral tubal ligation at least sixweeks before taking alpelisib. In case of oophorectomy alone, only when thereproductive status of the female has been confirmed by follow-up hormone levelassessment

9. Male sterilization at least 6 months prior to screening. The vasectomized malepartner should be the sole partner for that study participant

10. Use of oral, injected or implanted hormonal methods of contraception orplacement of an intrauterine device or intrauterine system or other forms ofhormonal contraception that have comparable efficacy (failure rate <1%), forexample hormone vaginal ring or transdermal hormone contraception If localregulations deviate from the contraception methods listed above to preventpregnancy, local regulations apply and will be described in the ICF.

11. Treatment by any mTOR or PI3K-AKT signaling pathway inhibitor within 1 month beforeinclusion

12. History of prior and or ongoing malignancy (within 5 years before informed consentexcept radically treated Carcinoma in situ of radically treated basal-cell carcinomaof skin or thyroid gland well differentiated microcarcinoma or Stage 1 Wilms' tumorof a histology other than anaplastic), or ongoing investigations or treatment formalignancy at time of informed consent.

13. Treatment with strong inducers of CYP3A4 and inhibitors of Breast Cancer ResistanceProtein (BCRP) that cannot be stopped at least the week prior to the screening

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

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

16. For participants ≥ 6 years of age: Participants with documented pneumonitis orinterstitial lung disease at the time of informed consent and with impaired lungfunction (e.g., FEV1 (Forced expiratory volume) or DLCO (Diffusing Capacity of theLung for Carbon Monoxide) ≤ 70% of predicted) that is not related to PROS.

17. For participants between 2 to 5 years of age: Participants with documented orsuspicious pneumonitis or interstitial lung disease based on MRI images at time ofinformed consent.

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

19. Clinically significant heart disease at time of informed consent, including:

20. History of documented congestive heart failure (New York Heart Associationfunctional classification III-IV)

21. Clinically significant uncontrolled cardiac arrhythmias

22. Long QT syndrome, family history of idiopathic sudden death or congenital longQTsyndrome

23. Corrected QT (QTcF) at screening: >470 ms for ≥18 years old / >450 ms for <18 years old

24. Creatinine clearance < 70ml/min/1.73 m²

25. Patient currently, or in the 3 months before inclusion, enrolled in anotherinterventional trial.

26. Person not affiliated to a national health insurance scheme

27. Patient, parents or legal authorized reprensentative incapable of expressing consent

28. Inability to attend all trial visits

29. For the optional consent only : contra indication to lumbar puncture:

30. Known intracranial hypertension

31. infection at puncture site

32. known coagulation disorders

33. Platelets < 50 × 109/L