Evaluation of the efficacy and safety of alpelisib (BYL719) in pediatric and adult patients with Megalencephaly-CApillary malformation Polymicrogyria syndrome (MCAP)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire Dijon Bourgogne

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Genetic Phenomena [G05]

Trial duration

3 Nov 2022 → ongoing

Decision date (initial)

2022-09-22

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2022-500197-34-01

ClinicalTrials.gov

NCT05577754

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy on adaptive behavior of alpelisib after 24 months of treatment.

Secondary objectives 10

1. To evaluate in patients with MCAP the efficacy of alpelisib vs placebo on adaptive behavior based on the comparison of the proportion of participants with response at 6 months in each group.
2. To evaluate in patients with MCAP the impact of alpelisib treatment on cerebral and spinal cord vascularization and volume
3. To evaluate in patients with MCAP the safety of alpelisib treatment
4. For exploratory study: To evaluate in patients with MCAP the early efficacy of alpelisib on adaptive behavior of alpelisib
5. For exploratory study: To evaluate in patients with MCAP the efficacy of alpelisib treatment on quality of life and clinical global impression
6. For exploratory study: To evaluate in patients with MCAP the efficacy of alpelisib on neuropsychological parameters
7. For exploratory study: To evaluate in patients with MCAP the impact of alpelisib treatment on epilepsy
8. For exploratory study: To evaluate in patients with MCAP the efficacy of alpelisib on overgrowth and skin lesions if present, when appropriate
9. For exploratory study: To evaluate in patients with MCAP the impact of alpelisib treatment on hypotonia
10. For exploratory study: To quantify in patients with MCAP the passage level of alpelisib throughout the blood-brain barrier and its relationship with systemic exposure of alpelisib

Conditions and MedDRA coding

Megalencephaly-CApillary malformation Polymicrogyria syndrome

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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.
2. Male or female patients age ≥2 years and ≤40 years at the time of informed consent
3. 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.
4. 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
5. 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
6. Able to swallow study drug according to age: tablets, or as drinkable suspension, or granules (under development)
7. For women of child-bearing potential only: negative pregnancy test at screening visit
8. 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
9. For exploratory study only : signed informed optional consent for lumbar puncture

Exclusion criteria 20

1. Patient previously treated with alpelisib
2. Participant with uncontrolled diabetes mellitus (Type I or II) at time of informed consent.
3. History of hypersensitivity to any drugs or metabolites of PI3K inhibitor or any of the excipients of alpelisib at time of informed consent
4. 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
5. 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.
6. Treatment by any mTOR or PI3K-AKT signaling pathway inhibitor within 1 month before inclusion
7. 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
8. 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
9. Debulking or other major surgery performed within 3 months at time of informed consent
10. 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
11. Patient currently, or in the 3 months before inclusion, enrolled in another interventional trial
12. Person not affiliated to a national health insurance scheme
13. Patient, parents or legal authorized representative incapable of expressing consent
14. Inability to attend all trial visits
15. For the optional lumbar puncture only : known intracranial hypertension, active infection at puncture site, known coagulation disorders, Platelets < 50 × 109/L
16. 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.
17. Known history of Steven Johnson’s syndrome, erythema multiform or toxic epidermal necrolysis at time of informed consent
18. 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
19. 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
20. History of acute pancreatitis within 1 year before informed consent or past medical history of chronic pancreatitis at time of informed consent

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Success will be defined as an improvement of at least 4 points in the Vineland II Adaptive Behavior Scale (VABS-II) at 24 months of treatment compared to baseline. We will compare the observed proportion to the expected one

Secondary endpoints 10

1. Response (yes/no) defined as an improvement of at least 4 points in the VABS-II at 6 months of treatment or placebo, compared to baseline. For this endpoint comparison will be made between the alpelisib and placebo groups.
2. Changes in brain volume, vascularization, structural connectivity, assessed by MRI, from baseline to end of treatment period
3. Number, type and severity of adverse events
4. For exploratory study: Improvement of at least 4 points in the VABS-II at 6, 12, and 18 months of treatment, compared to baseline.
5. For exploratory study: Evolution of quality of life (QoL) questionnaires, scores at visual analogue scale, and evolution of Clinical Global Impression of severity (CGI-S) and Global improvement scores (CGI-I) at 6, 12, 18, 24, 30 months of treatment, compared to baseline
6. For exploratory study: Changes in neuropsychological scales adapted to age at 12 and 24 months of treatment compared to baseline for attention, cognition, visuo-spatial disorders, fine motor skills, speech, reasoning and cognitive inhibition abilities and at 24 months of treatment compared to baseline for Intellectual Quotient (IQ) scale
7. For exploratory study: Changes in seizures frequency (weekly diary), and antiepileptic drugs use at 6, 12, 18 and 24 months of treatment compared to baseline
8. For exploratory study: Changes in overgrowth or skin lesions, classified as follow: increase, no changes or reduction according to clinical measures and evaluation of standardized photographs taken at 6, 12, 18 and 24 months of treatment compared to baseline
9. For exploratory study: Changes in Motor Function Measure (MFM) scores at 6, 12, 18 and 24 months of treatment compared to baseline
10. For exploratory study: Level of alpelisib (ng/mL) in cerebrospinal fluid (CSF) and in blood between 6 and 24 months of treatment, and correlation estimate (rho) between CSF and blood levels of alpelisib

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire Dijon Bourgogne

Sponsor organisation

Centre Hospitalier Universitaire Dijon Bourgogne

Address

1 Boulevard Jeanne D Arc

City

Dijon

Postcode

21000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire Dijon Bourgogne

Contact name

Chef de projets

Public contact point

Organisation

Centre Hospitalier Universitaire Dijon Bourgogne

Contact name

Chef de projets

Locations

1 EU/EEA country · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications