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

NCT05577754 | Recruiting Phase 2 DMC

• 1 other identifier: OLIVIER FAIVRE Novartis 2021
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 13

Brief Summary

This study is a two periods multi-center Phase II trial, with a 6 months double-blind, placebo-controlled period followed by open label period, to assess the efficacy and safety of alpelisib (BYL719) in pediatric and adult patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP)

Conditions

Megalencephaly-capillary Malformation Polymicrogyria Syndrome (MCAP)

Keywords

Neurodevelopmental disorders; alpelisib; therapeutic trial; PIK3CA; MCAP

Outcome Measures

Primary Outcomes (1)

• Proportion of participants with response at end of treatment assessed by the Vineland II Adaptive Behavior Scale (VABS-II)

  Response defined by an improvement of at least 4 points in the Vineland II Adaptive Behavior Scale (VABS-II). The VABS-II consists of a form which will be filled during an interview with an adult who is familiar with the everyday activities of the patient (usually the parents). It is organized within a three-domain structure: communication, daily living skills, and socialization. In addition, VABS-II has a motor skills domain for the youngest children (younger than 6) and an optional maladaptive behavior index \[Sparrow et al.,2016\]. The domains (communication, daily living skills, and socialization) - standard scores have a mean of 100 and a standard deviation of 15. Adaptive levels can also be determined. A global standard score can also be computed (the Adaptive Behavior Composite standard score) and also has a mean of 100 and a standard deviation of 15.

  At 24 months of treatment compared to baseline

Secondary Outcomes (13)

• Proportion of patients randomized with a response (yes/no) in group A and group B

  6 months of treatment in double blind period

• Changes from baseline in brain volume, vascularization, structural connectivity

  baseline to end of treatment period

• Frequency and severity of adverse events

  Up to 34 months

• Proportion of participants with response at end of treatment

  At 6, 12 and 18 months of treatment, compared to baseline

• Change in quality of life assessed by Pediatric Quality of Life Inventory 4.0 or San Martin questionnaires

  At 6, 12, 18, 24 months of treatment, compared to baseline.

Study Arms (2)

Group A

PLACEBO COMPARATOR

Drug: Alpelisib (BYL719); Drug: Matching placebo; Procedure: Optional lumbar puncture + blood sample

Group B

EXPERIMENTAL

Drug: Alpelisib (BYL719); Procedure: Optional lumbar puncture + blood sample

Interventions

Alpelisib (BYL719) DRUG

Administration during open label and double-blind period of group B: alpelisib will be taken once a day each day over 24 mois During open label period of group A: alpelisib will be taken once a day each day over 24 months

Group A; Group B

Matching placebo DRUG

During double-blind period of group A: matching placebo will be taken once a day each day over 6 months

Group A

Optional lumbar puncture + blood sample PROCEDURE

Between 6 and 24 months of treatment with Alpelisib

Group A; Group B

Eligibility Criteria

• Age: 2 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Signed informed consent and assent (when applicable) from the patient, parent, or guardian must be obtained prior to any study related screening procedures are performed.
• Male or female patients age ≥2 years and ≤40 years at the time of informed consent
• Patients with diagnosis of MCAP\* with neurodevelopmental disorder presentation (from specific learning disorder to severe intellectual disability)
• Documented evidence of a postzygotic or constitutional mutation(s) in the PIK3CA gene performed in local laboratories using a Deoxyribonucleic acid (DNA) based validated test at the time of informed consent.
• Adequate bone marrow and organ function (assessed during the screening visit):
• Absolute neutrophil count ≥ 1.5 × 109/L
• Platelets ≥ 100 × 109/L
• Hemoglobin ≥ 9.0 g/dL (transfusions are allowed)
• Calcium (corrected for serum albumin) and magnesium within normal limits or ≤Grade 1 according to NCI-CTCAE version 5.0 if judged clinically not significant by the investigator
• Potassium within normal limits.
• INR ≤1.5
• Creatinine Clearance ≥ 30 mL/min using Modification of Diet in Renal Disease
• (MDRD) (≥18 years old) or creatinine-based Bedside Schwartz (˂18 years old) Glomerular filtration rate (GFR) equation
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.
• Total bilirubin\< ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN

You may not qualify if:

• Patient previously treated with alpelisib
• Known impairment of GI function due to concomitant disease that may significantly alter the absorption of the study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) at time of informed consent.
• Participant with uncontrolled diabetes mellitus (Type I or II) at time of informed consent.
• History of hypersensitivity to any drugs or metabolites of PI3K inhibitor or any of the excipients of alpelisib at time of informed consent.
• Participant with other concurrent severe and/or uncontrolled medical conditions that would, in the treating Physician's judgment, contraindicate administration of alpelisib (e.g., active and/or uncontrolled severe infection, chronic active hepatitis, hepatic impairment Child Pugh score C, immuno-compromised, etc.) at time of informed consent.
• Female participants of childbearing potential and male participants who do not agree at time of informed consent to abstinence or, if sexually active, unwilling to use a condom and/or a highly effective method of contraception for the duration of the study and for one week following discontinuation of alpelisib. Highly effective contraception methods is one of the following:
• Total abstinence: when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before taking alpelisib. In case of oophorectomy alone, only when the reproductive status of the female has been confirmed by follow-up hormone level assessment
• Male sterilization at least 6 months prior to screening. The vasectomized male partner should be the sole partner for that study participant
• Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.
• History of prior and or ongoing malignancy (within 5 years before informed consent except radically treated Carcinoma in situ of radically treated basal-cell carcinoma of skin or thyroid gland well differentiated microcarcinoma or Stage 1 Wilms' tumor of a histology other than anaplastic), or ongoing investigations or treatment for malignancy at time of informed consent.
• Treatment with strong inducers of CYP3A4 and inhibitors of Breast Cancer Resistance Protein (BCRP) that cannot be stopped at least the week prior to the screening
• Debulking or other major surgery performed within 3 months at time of informed consent
• Known history of Steven Johnson's syndrome, erythema multiform or toxic epidermal necrolysis at time of informed consent.
• For participants ≥ 6 years of age: Participants with documented pneumonitis or interstitial lung disease at the time of informed consent and with impaired lung function (e.g., FEV1 (Forced expiratory volume) or DLCO (Diffusing Capacity of the Lung for Carbon Monoxide) ≤ 70% of predicted) that is not related to PROS.

Sponsors & Collaborators

• Centre Hospitalier Universitaire Dijon: lead
• Novartis Pharmaceuticals: collaborator

Study Sites (13)

CHU Amiens

Amiens, 80054 Amiens, France

RECRUITING

CHU d'Angers

Angers, 49933, France

RECRUITING

CHRU Brest

Brest, 29200, France

NOT YET RECRUITING

HCL - Groupement Hospitalier Est Hôpital Femme-Mère-Enfant

Bron, 69677, France

RECRUITING

Chu Estaing

Clermont-Ferrand, 63003, France

RECRUITING

Chu Dijon Bourgogne

Dijon, 21000, France

RECRUITING

CHU Dijon Bourgogne - CIC-P

Dijon, 21079, France

ACTIVE NOT RECRUITING

CHU de Lille

Lille, 59037, France

RECRUITING

CHRU Nîmes

Nîmes, 30029, France

RECRUITING

AP-HP Hôpital Necker-Enfants Malades - CIC

Paris, 75015, France

ACTIVE NOT RECRUITING

AP-HP Hôpital Necker-Enfants Malades

Paris, 75015, France

RECRUITING

CHU Rennes

Rennes, 35023, France

RECRUITING

CHRU Tours

Tours, 37044, France

RECRUITING

Related Publications (3)

• Sparrow SSC, D.V.; Saulnier, C.A. Vineland-3: Vineland Adaptive Behavior Scales. 3rd ed. Pearson Assessments; Minneapolis, MN, USA. 2016.

  BACKGROUND

• Curie A, Brun A, Cheylus A, Reboul A, Nazir T, Bussy G, Delange K, Paulignan Y, Mercier S, David A, Marignier S, Merle L, de Freminville B, Prieur F, Till M, Mortemousque I, Toutain A, Bieth E, Touraine R, Sanlaville D, Chelly J, Kong J, Ott D, Kassai B, Hadjikhani N, Gollub RL, des Portes V. A Novel Analog Reasoning Paradigm: New Insights in Intellectually Disabled Patients. PLoS One. 2016 Feb 26;11(2):e0149717. doi: 10.1371/journal.pone.0149717. eCollection 2016.

  PMID: 26918704 BACKGROUND

• Luu M, Vabres P, Espitalier A, Maurer A, Garde A, Racine C, Carpentier M, Rega A, Loffroy R, Hadouiri N, Boddaert N, Curie A, Guibaud L, Chebbi M, Charligny J, Kuentz P, Canaud G, Bahi-Buisson N, Fleck C, Cransac A, Bardou M, Faivre L; SESAM study group. A phase II double-blind multicentre, placebo-controlled trial to assess the efficacy and safety of alpelisib (BYL719) in paediatric and adult patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP): the SESAM study protocol. BMJ Open. 2024 Dec 20;14(12):e084614. doi: 10.1136/bmjopen-2024-084614.

  PMID: 39806603 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Megalencephaly cutis marmorata telangiectatica congenita; Neurodevelopmental Disorders; Hereditary Sensory and Autonomic Neuropathies

Interventions

Alpelisib; Blood Specimen Collection

Condition Hierarchy (Ancestors)

Mental Disorders; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Central Study Contacts

Laurence OLIVIER-FAIVRE

CONTACT

0380295313; laurence.faivre@chu-dijon.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 10, 2022
• First Posted: October 13, 2022
• Study Start: November 28, 2022
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: February 24, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

FR (13)