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.

Introduction: The megalencephaly capillary malformation polymicrogyria (MCAP syndrome) results from mosaic gain-of-function variants. The main clinical features are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies. Alpelisib (Vijoice) is a recently FDA-approved PI3Kα-specific inhibitor for patients with PIK3CA-related overgrowth spectrum (PROS). During its development, in patients with the MCAP subgroup of PROS, there was no specific, standardised evaluation of the effect on neuro-cognitive functioning. Moreover, it remains unknown if the molecule crosses the blood-brain barrier. Our objective is to evaluate the efficacy of a 24 month treatment with alpelisib on adaptive behaviour in patients with MCAP syndrome.

Methods And Analysis: SESAM is an industry-sponsored two-period multicentre French academic phase II trial, with a 6-month double-blind, placebo-controlled period followed by an open-label period. The primary endpoint is a ≥4-point improvement in the Vineland II Adaptive Behaviour Scale (VABS), 24 months after treatment initiation. Secondary objectives are safety, VABS improvement at 6 months, impact on the quality of life, epilepsy and hypotonia. 20 patients aged 2 to 40 years with an MCAP diagnosis and neurodevelopmental disorders of various degrees, will be followed monthly in local centres, centrally assessed (clinical, biological, neuropsychological and functional evaluation) at baseline and every 6 months. Patients will be evaluated by volumetric MRI at baseline and at 24 months. An optional lumbar puncture will be performed to investigate blood-brain barrier crossing. Inclusions were completed by April 2024, with the end of follow-up in November 2026.Given the efficacy of alpelisib in patients with PROS, if the drug crosses the blood-brain barrier, we can expect a clinical benefit for patients with neurocognitive disorders.

Ethics And Dissemination: Ethical approval was given by CPP Sud-Ouest et Outre-Mer I (reference: 2022-500197-34-01). Findings from this study will be disseminated via publication, reports and conference presentations.

Trial Registration Number: NCT05577754.