A Two-stage Double-blind, Randomized, Placebo-controlled Study to Assess the Efficacy, Safety and Pharmacokinetics of Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 232
- 试验地点
- 75
- 主要终点
- Stage 2:Radiological response rate at Week 24 of Stage 2 (adult and pediatric (6 - 17 years of age) participants)
研究概览
简要总结
The main purpose of this study in participants with PIK3CA-mutated LyM is to assess the change in radiological response and symptom severity upon treatment with alpelisib film-coated tablets (FCT) as compared to placebo.
详细描述
This is a phase II/III multi-center study with two stages:
- Stage 1 is designed to select the dose(s) for the confirmatory phase (DSCP) for alpelisib in Stage 2 and will comprise a 24-week open-label core phase in adult (≥18 years of age) and pediatric participants (6-17 years of age) with PIK3CA-mutated LyM, followed by an extension. After eligibility has been confirmed at screening, participants will be randomized in a 1:1 ratio to the different alpelisib doses according to their age. Depending on the results at the end of Stage 1 core phase, the Stage 2 will be opened to adult and/or pediatric participants or the study may be stopped.
- Stage 2 is designed to confirm the efficacy and assess safety of alpelisib at the DSCP in participants with PIK3CA-mutated LyM and will comprise a 24-week randomized, double blind, placebo-controlled confirmatory phase in adult (≥18 years of age) and pediatric participants 6-17 years of age followed by an open-label extension. After eligibility has been confirmed at screening participants will be randomized in a 2:1 ratio to alpelisib or placebo.
Additionally, in parallel, Stage 2 will include a 24-week open-label core phase in pediatric participants 0-5 years of age followed by an extension, if pediatric participants will be enrolling in Stage 2.
Based on the results of the 24-week open-label core phase of Stage 1, the dose(s) for Stage 2 will be selected by Novartis in consultation with the Steering Committee (SC). During the 24-week randomized, double blind, placebo-controlled core phase of Stage 2, an Independent Data Monitoring Committee (DMC) will conduct periodic safety and efficacy reviews to assess the risk benefit profile of the treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 0 Years 至 100 Years（Child, Adult, Older 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 participant, parent, legal authorized representative or guardian.
- •Participant must be willing to remain at the clinical site as required by the protocol and be willing to adhere to study restrictions and examination schedules.
- •Participant has a physician confirmed and documented diagnosis of a symptomatic LyM at the time of informed consent (Note: the physician must confirm that the LyM cannot be included under the PROS diagnostic criteria).
- •Participant is not considered as a candidate for or is not willing to receive non-drug therapies including but not limited to sclerotherapy, embolization, and surgery until the completion of Week 24 in Stage 1 and
- •Participant has evidence of a somatic mutation(s) in the PIK3CA gene prior to randomization.
- •Participant has at least one measurable LyM lesion confirmed by BIRC assessment prior to randomization.
- •Participants must be able to ingest study drug (either in tablet form or as a drinkable suspension [Groups 1 to 4] or granules or as an oral suspension [Group 5]) as assessed within 7 days before study treatment start. Drug administration via feeding tubes is allowed.
排除标准
- •Participant has a physician-confirmed and documented diagnosis of PROS at the time of informed consent.
- •Participant has a physician-confirmed and documented diagnosis of a Central Conducting Lymphatic Anomaly, General Lymphatic Anomaly, Gorham-Stout disease, Kaposiform lymphangiomatosis at the time of informed consent.
- •Participant has a known history of Stevens-Johnson syndrome, erythema multiforme, or toxic epidermal necrolysis at the time of informed consent.
- •Participant has an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at the time of informed consent.
- •Participant had previous treatment with alpelisib and/or any other PI3K inhibitors with treatment duration longer than 2 weeks at the time of informed consent.
- •Other inclusion/exclusion criteria may apply
研究组 & 干预措施
Adult participants, alpelisib dose 2 (Stage 1)
Adult participants (≥18 years of age) who will receive dose 2 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1).
干预措施: Alpelisib (Drug)
Pediatric participants (6-17 years of age), alpelisib (Stage 2)
Pediatric participants (6-17 years of age) who will receive alpelisib at the dose selected for confirmatory phase in pediatric participants (Stage 2)
干预措施: Alpelisib (Drug)
Pediatric participants (0-5 years of age), alpelisib (Stage 2)
Pediatric participants of 0-5 years who will dose 3 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier
干预措施: Alpelisib (Drug)
Adult participants, placebo (Stage 2)
Adult participants (≥18 years of age) who will receive matching placebo
干预措施: Placebo (Drug)
Pediatric participants (6-17 years of age), placebo (Stage 2)
Pediatric participants (6-17 years of age) who will receive matching placebo
干预措施: Placebo (Drug)
Adult participants, alpelisib (Stage 2)
Adult participants (≥18 years of age) who will receive alpelisib at the dose selected for confirmatory phase in adult participants (Stage 2)
干预措施: Alpelisib (Drug)
Pediatric participants (6-17 years of age), alpelisib dose 2 (Stage 1)
Pediatric participants 6-17 years of age who will receive dose 2 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1)
干预措施: Alpelisib (Drug)
Pediatric participants (6-17 years of age), alpelisib dose 3 (Stage 1)
Pediatric participants 6-17 years of age who will receive dose 3 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1).
干预措施: Alpelisib (Drug)
Adult participants, alpelisib dose 1 (Stage 1)
Adult participants (≥18 years of age) who will receive dose 1 of alpelisib an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1)
干预措施: Alpelisib (Drug)
结局指标
主要结局
Stage 2:Radiological response rate at Week 24 of Stage 2 (adult and pediatric (6 - 17 years of age) participants)
时间窗: Baseline, Week 24
Radiological response defined by achieving at least 20% reduction in the sum of target lesion volumes (1 to 3 lesions), assessed by MRI by a BIRC at Week 24, provided that none of the individual target lesions has at least 20% increase from baseline and in absence of progression of non-target lesions and without new lesions. The percentage of participants with a radiological response at Week 24 of Stage 2 in adult and pediatric (6-17 years of age) groups will be assessed
次要结局
- Stage 2: Percentage of participants with at least a 1-point improvement compared to baseline based on patient global impression of severity (PGI-S) scale at Week 24 of Stage 2 (adult and pediatric (6 - 17 years of age) participants)(Baseline, Week 24)
- Stage 2: Percentage of participants with a radiological response at Week 24 of Stage 2 (pediatric participants 0-5 years of age)(Baseline, Week 24)
- Stage 2: Change from baseline in patient global impression of change (PGI-C) scale (adult and pediatric (6-17 years of age) participants)(Up to approximately 8 years)
- Stage 2: Change from baseline in patient-reported outcomes measurement information system (PROMIS) profile domains(adult and pediatric (6-17 years of age) participants)(Up to approximately 8 years)
- Stage 2: Change from baseline in investigator global impression of change (IGIC) scale (adult and pediatric (6-17 years of age) participants)(Up to approximately 8 years)
- Stage 2: Change from baseline in health utilities of the EuroQol 5-dimension (EQ-5D) (adult and pediatric (6-17 years of age) participants)(Up to approximately 8 years)
- Stage 2: Percentage of participants with at least a 1-point improvement compared to baseline based on patient global impression of severity (PGI-S) scale at Week 24 of Stage 2 (adult and pediatric (6 - 17 years of age) participants)(Baseline, Week 24)
- Stage 2: Percentage of participants with a radiological response at Week 24 of Stage 2 (pediatric participants 0-5 years of age)(Baseline, Week 24)
- Stage 2: Change from baseline in patient global impression of change (PGI-C) scale (adult and pediatric (6-17 years of age) participants)(Up to approximately 8 years)
- Stage 2: Change from baseline in patient-reported outcomes measurement information system (PROMIS) profile domains(adult and pediatric (6-17 years of age) participants)(Up to approximately 8 years)
- Stage 2: Change from baseline in investigator global impression of change (IGIC) scale (adult and pediatric (6-17 years of age) participants)(Up to approximately 8 years)
- Stage 2: Change from baseline in health utilities of the EuroQol 5-dimension (EQ-5D) (adult and pediatric (6-17 years of age) participants)(Up to approximately 8 years)
- Stage 1 and 2: Alpelisib plasma concentrations(On Day 1 of Week 8, 16, 24, 48 and 120)
- Stage 1 and 2: Duration of response (DOR) in adult and pediatric participants who receive alpelisib(Up to approximately 8 years)
- Stage 1: Radiological response rate of alpelisib in adult and pediatric (6-17 years of age) participants(Baseline, Week 24)
- Stage 1 and 2: Percentage of participants with changes in non-target lesions in adult and pediatric participants(Up to approximately 8 years)
- Stage 1 and 2: Radiological response rate of alpelisib in adult and pediatric participants(Up to approximately 8 years)
- Stage 1 and 2: Change from baseline in LyM lesions in adult and pediatric participants at Week 24(Baseline, Week 24)
- Stage 1 and 2: Percentage of participants with of LyM-related symptoms, complications, and comorbidities on treatment with alpelisib in adult and pediatric participants at Week 24(Week 24)
- Stage 1 and 2: Percentage of participants with of LyM-related symptoms, complications, and comorbidities on treatment with alpelisib in adult and pediatric participants(Up to approximately 8 years)
- Stage 1 and 2: Change from baseline in LyM lesions in adult and pediatric participants(Up to approximately 8 years)
- Stage 1 and 2: Percentage of participants with changes in non-target lesions in adult and pediatric participants at Week 24(Baseline, Week 24)
- Stage 1 and 2: Percentage of participants with new lesions in adult and pediatric participants at Week 24(Baseline, Week 24)
- Stage 1 and 2: Percentage of participants with new lesions in adult and pediatric participants(Up to approximately 8 years)