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)
Overview
- Phase
- Phase 2
- Intervention
- Alpelisib (BYL719)
- Conditions
- Megalencephaly-capillary Malformation Polymicrogyria Syndrome (MCAP)
- Sponsor
- Centre Hospitalier Universitaire Dijon
- Enrollment
- 20
- Locations
- 16
- Primary Endpoint
- Proportion of participants with response at end of treatment assessed by the Vineland II Adaptive Behavior Scale (VABS-II)
- Status
- Recruiting
- Last Updated
- 2 months ago
Overview
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)
Detailed Description
This study consists of a screening period up to 90 days, a first double-blind, placebo-controlled period of 6 months, followed by an open label period of alpelisib treatment, to reach a 24-month duration of treatment for all patients. The study will enroll 18-40 years old adults and 2-18 years old paediatric patients. Eligible patients will be randomized in a 1:1 ratio for the first period (alpelisib or placebo). A first assessment will be performed at 6 months. Patients completing this first period will enter the open label period, and either start alpelisib if they were on placebo, continue at the same dose if responders, or increase dose if not responders (dose increase only possible for children of 5 years old and over), and if no unacceptable toxicity occurs. Patients will be followed monthly in local centres, and 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. Participant may be discontinued from treatment with alpelisib earlier due to unacceptable toxicity, confirmed disease progression, death, and/or any other reason at the discretion of the investigator or the participant.
Investigators
Eligibility Criteria
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 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.
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
Arms & Interventions
Group A
Intervention: Alpelisib (BYL719)
Group A
Intervention: Matching placebo
Group A
Intervention: Optional lumbar puncture + blood sample
Group B
Intervention: Alpelisib (BYL719)
Group B
Intervention: Optional lumbar puncture + blood sample
Outcomes
Primary Outcomes
Proportion of participants with response at end of treatment assessed by the Vineland II Adaptive Behavior Scale (VABS-II)
Time Frame: At 24 months of treatment compared to baseline
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.
Secondary Outcomes
- 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.)
- Evolution of scores at visual analogue scale(At 6, 12, 18, 24 months of treatment, compared to baseline.)
- Evolution of Clinical Global Impression of severity (CGI-S)(At 6, 12, 18, 24 months of treatment, compared to baseline.)
- Evolution of Global improvement scores (CGI-I)(At 6, 12, 18, 24 months of treatment, compared to baseline.)
- Changes in neuropsychological scales adapted to age for attention, cognition, visuo-spatial disorders, fine motor skills, speech, reasoning and cognitive inhibition abilities(At 12 and 24 months of treatment compared to baseline)
- Changes in seizures frequency(At 6, 12, 18 and 24 months of treatment compared to baseline)
- Changes in overgrowth or skin lesions(At 6, 12, 18 and 24 months of treatment compared to baseline)
- Changes in Motor Function Measure (MFM) scores(At 6, 12, 18 and 24 months of treatment compared to baseline)
- Pharmacokinetic parameters of alpelisib (ng/mL) in cerebrospinal fluid (CSF) and blood(Between 6 and 24 months of treatment)