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)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 16
- 主要终点
- Proportion of participants with response at end of treatment assessed by the Vineland II Adaptive Behavior Scale (VABS-II)
研究概览
简要总结
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)
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 2 Years 至 40 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •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 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.
- •7. For exploratory study only : signed informed optional consent for lumbar puncture
排除标准
- •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
- •Patient, parents or legal authorized reprensentative incapable of expressing consent
- •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
研究组 & 干预措施
Group A
干预措施: Alpelisib (BYL719) (Drug)
Group A
干预措施: Matching placebo (Drug)
Group A
干预措施: Optional lumbar puncture + blood sample (Procedure)
Group B
干预措施: Alpelisib (BYL719) (Drug)
Group B
干预措施: Optional lumbar puncture + blood sample (Procedure)
结局指标
主要结局
Proportion of participants with response at end of treatment assessed by the Vineland II Adaptive Behavior Scale (VABS-II)
时间窗: 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.
次要结局
- 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)