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)

Trial ID: 2022-500197-34-01
Protocol: SESAM
Sponsor: Centre Hospitalier Universitaire De Dijon

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Diseases & Conditions

PIK3CA related overgrowth spectrum

Objectives

The primary objective of this study is to evaluate the **efficacy** of alpelisib on adaptive behavior in patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP) after 24 months of treatment. This is clinically relevant as it aims to determine the long-term impact of alpelisib on the adaptive functioning of individuals affected by this condition, potentially leading to improved management strategies.

Secondary objectives include:

Evaluating the efficacy of alpelisib versus placebo on adaptive behavior based on the proportion of participants with a response at 6 months.
Assessing the impact of alpelisib treatment on cerebral and spinal cord vascularization and volume.
Evaluating the safety of alpelisib treatment.
Exploratory studies to assess early efficacy on adaptive behavior, quality of life, clinical global impression, neuropsychological parameters, and the impact on epilepsy, overgrowth, skin lesions, and hypotonia.
Quantifying the passage level of alpelisib through the blood-brain barrier and its relationship with systemic exposure.

Participants

The clinical trial involves a study population comprising both **male** and **female** participants aged between 2 and 40 years. The trial focuses on individuals diagnosed with **Megalencephaly-Capillary malformation Polymicrogyria syndrome** (MCAP) who present with neurodevelopmental disorders ranging from specific learning disorders to severe intellectual disabilities. Participants are required to have documented evidence of a postzygotic or constitutional mutation in the PIK3CA gene. The trial population was selected based on specific inclusion criteria, including adequate bone marrow and organ function, and the ability to swallow the study drug in various forms. The study does not provide information on the total number of participants, as this data was not disclosed by the sponsor. The trial includes a vulnerable population, and lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is a **Phase II**, double-blind, multi-center, placebo-controlled study designed to evaluate the efficacy and safety of **alpelisib** in pediatric and adult patients diagnosed with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP). The primary objective is to assess the efficacy of alpelisib on adaptive behavior after 24 months of treatment. The trial involves a randomized allocation of participants to either the alpelisib group or the placebo group, ensuring that neither the participants nor the investigators are aware of the group assignments, thus maintaining the double-blind nature of the study.

The trial is expected to last until March 2027, with participant involvement spanning up to 24 months. The study begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as age, diagnosis of MCAP, and adequate organ function. Following successful screening, participants will be randomized and commence treatment. Study visits are scheduled at regular intervals to monitor progress, assess safety, and evaluate efficacy. These visits include assessments at 6, 12, 18, and 24 months, with the primary endpoint being an improvement of at least 4 points in the Vineland II Adaptive Behavior Scale (VABS-II) at 24 months compared to baseline. Secondary endpoints include changes in brain volume, vascularization, and structural connectivity, as well as the number and severity of adverse events.

The end-of-study visit marks the conclusion of the participant's involvement, where final assessments are conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial's design ensures rigorous monitoring and data collection to support the evaluation of alpelisib's therapeutic potential in this rare condition.

Treatment

The clinical trial involves the administration of **Alpelisib**, an experimental medication, to evaluate its efficacy and safety in patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP). **Alpelisib** is provided in the form of a film-coated tablet, with a maximum daily dose of 300 mg. The route of administration is oral, and the treatment period extends up to 24 months. The active substance in the medication is **Alpelisib**, a chemical compound classified under antineoplastic agents. The trial aims to assess the impact of **Alpelisib** on adaptive behavior over the specified treatment duration.

In addition to the experimental treatment, a placebo, referred to as **Alpelisib placebo**, is utilized in this double-blind, placebo-controlled trial. The placebo is designed to match the experimental medication in appearance and administration route, ensuring the integrity of the study's blinding process. The placebo does not contain the active substance **Alpelisib** and serves as a comparator to evaluate the true efficacy of the experimental treatment. The administration of the placebo follows the same schedule as the active treatment, maintaining consistency across the study groups.

Efficacy

The efficacy of alpelisib in the clinical trial will be assessed primarily through the **Vineland II Adaptive Behavior Scale (VABS-II)**. The primary endpoint is defined as an improvement of at least 4 points in the VABS-II after 24 months of treatment compared to baseline. This will involve comparing the observed proportion of patients achieving this improvement to the expected proportion. Secondary endpoints include a similar improvement of at least 4 points in the VABS-II at 6 months of treatment, with comparisons made between the alpelisib and placebo groups.

Additional secondary endpoints will evaluate changes in brain volume, vascularization, and structural connectivity using MRI from baseline to the end of the treatment period. The trial will also monitor the number, type, and severity of adverse events. Exploratory endpoints include improvements in VABS-II at 6, 12, and 18 months, changes in quality of life scores, and evolution of Clinical Global Impression scores at various timepoints. Neuropsychological scales will be adapted to age to assess changes in attention, cognition, and other cognitive abilities at 12 and 24 months. Seizure frequency, antiepileptic drug use, and changes in overgrowth or skin lesions will also be evaluated at multiple intervals. Motor Function Measure scores and levels of alpelisib in cerebrospinal fluid and blood will be assessed, with correlation estimates between these levels being calculated.

Inclusion and Exclusion Criteria

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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) * The most recent set of diagnostic criteria for MCAP includes five core features: progressive megalencephaly (criterion 1), developmental vascular disorders (criterion 2), distal limb anomalies (criterion 3), cortical brain malformations (criterion 4), connective tissue dysplasia (criterion 5) plus supportive features. MCAP syndrome is diagnosed in the presence of criterion 1 plus either criterion 2 or criterion 3 (Mirzaa et al., 2013). However, in cases of constitutional variants, these diagnostic criteria can be flawed since criterion 2 is generally not expected in the absence of mosaicism.
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): a.Absolute neutrophil count ≥ 1.5 × 109/L; b.Platelets ≥ 100 × 109/L; c.Hemoglobin ≥ 9.0 g/dL (transfusions are allowed); d.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; e. Potassium within normal limits.; f. INR ≤1.5; g. Creatinine Clearance ≥ 30 mL/min using Modification of Diet in Renal Disease; h. (MDRD) (≥18 years old) or creatinine-based Bedside Schwartz (˂18 years old) Glomerular filtration rate (GFR) equation; i. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.; j. 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; k. Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and Glycosylated hemoglobin (HbA1c) ≤ 6.5% (both criteria have to be met); l. 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

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Exclusion Criteria

Patient previously treated with alpelisib
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: a. 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; b. 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; c. Male sterilization at least 6 months prior to screening. The vasectomized male partner should be the sole partner for that study participant; d. 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
Clinically significant heart disease at time of informed consent, including: a. History of documented congestive heart failure (New York Heart Association functional classification III-IV); b. Clinically significant uncontrolled cardiac arrhythmias; c. Long QT syndrome, family history of idiopathic sudden death or congenital long QTsyndrome; d. Corrected QT (QTcF) at screening: >470 ms for ≥18 years old / >450 ms for <18 years old; e. 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
Patient, parents or legal authorized representative incapable of expressing consent
Inability to attend all trial visits
For the optional lumbar puncture only : known intracranial hypertension, active infection at puncture site, known coagulation disorders, Platelets < 50 × 109/L
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.
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