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

Sponsor

Centre Hospitalier Universitaire Dijon (Other)

Overall Status

Recruiting

CT.gov ID

NCT05577754

Collaborator

(none)

Enrollment

Location

Arms

45.1

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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. It will involve 16 participants with MCAP syndrome.

Assessment will be performed at baseline and after 24 months of treatment and will include MRI, biological and clinical results, attention, language, and Intellectual Quotient (IQ) assessment. Appropriate neuropsychological tests will be used according to the age of patients and their level of cognitive impairment.

Condition or Disease	Intervention/Treatment	Phase
Megalencephaly-capillary Malformation Polymicrogyria Syndrome (MCAP)	Drug: Alpelisib (BYL719) Drug: Matching placebo Procedure: Optional lumbar puncture	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

16 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Phase II Double-blind Multi-center, Placebo-controlled Trial, to Assess the Efficacy and Safety of Alpelisib (BYL719) in Pediatric and Adult Patients With Megalencephaly-CApillary Malformation Polymicrogyria Syndrome (MCAP)

Actual Study Start Date :

Nov 28, 2022

Anticipated Primary Completion Date :

Sep 1, 2026

Anticipated Study Completion Date :

Sep 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Group A	Drug: Alpelisib (BYL719) 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 Drug: Matching placebo During double-blind period of group A: matching placebo will be taken once a day each day over 6 months Procedure: Optional lumbar puncture After 6 months or 24 months of treatment with Alpelisib
Experimental: Group B	Drug: Alpelisib (BYL719) 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 Procedure: Optional lumbar puncture After 6 months or 24 months of treatment with Alpelisib

Arm

Intervention/Treatment

Placebo Comparator: Group A

Drug: Alpelisib (BYL719)

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

Drug: Matching placebo

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

Procedure: Optional lumbar puncture

After 6 months or 24 months of treatment with Alpelisib

Experimental: Group B

Drug: Alpelisib (BYL719)

Procedure: Optional lumbar puncture

After 6 months or 24 months of treatment with Alpelisib

Outcome Measures

Primary Outcome Measures

Improvement of at least 4 points in the Vineland II Adaptive Behavior Scale (VABS-II) [At 24 months of treatment compared to baseline]

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 40 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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 somatic 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
Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and Glycosylated hemoglobin (HbA1c) ≤ 6.5% (both criteria have to be met)
Fasting Serum amylase ≤ 2 × ULN
Fasting Serum lipase ≤ ULN
Able to swallow study drug according to age: tablets, or as drinkable suspension, or granules (under development)
For women of child-bearing potential only: negative pregnancy test at screening visit
Male patients with sexual partners who are pregnant, possibly pregnant or who could become pregnant should use condoms during sexual intercourse for the duration of the study and for one week following discontinuation of alpelisib.
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:

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.
Treatment by any mTOR or PI3K-AKT signaling pathway inhibitor within 1 month before inclusion
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.
For participants between 2 to 5 years of age: Participants with documented or suspicious pneumonitis or interstitial lung disease based on MRI images at time of informed consent.
History of acute pancreatitis within 1 year before informed consent or past medical history of chronic pancreatitis at time of informed consent.
Clinically significant heart disease at time of informed consent, including:
History of documented congestive heart failure (New York Heart Association functional classification III-IV)
Clinically significant uncontrolled cardiac arrhythmias
Long QT syndrome, family history of idiopathic sudden death or congenital long QTsyndrome
Corrected QT (QTcF) at screening: >470 ms for ≥18 years old / >450 ms for <18 years old
Creatinine clearance < 70ml/min/1.73 m²
Patient currently, or in the 3 months before inclusion, enrolled in another interventional trial.
Person not affiliated to a national health insurance scheme
Person under court protection
Inability to attend all trial visits
For the optional consent only : contra indication to lumbar puncture:
Known intracranial hypertension
infection at puncture site
known coagulation disorders
Platelets < 50 × 109/L