Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.

Study Overview
=================
Brief Summary
-----------------
The main purpose of this study in participants with PIK3CA-mutated lymphatic malformations (LyM) is to assess the change in radiological response and symptom severity upon treatment with alpelisib as compared to placebo.

Detailed Description
-----------------
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 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 to alpelisib or placebo. Additionally, in parallel, Stage 2 will include a 24-week open-label core phase in pediatric participants 2-5 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 reviews.

Official Title
-----------------
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.

Conditions
-----------------
Lymphatic Malformations

Intervention / Treatment
-----------------
* Drug: Alpelisib
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: 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 LyM at the time of informed consent Participant is not considered as a candidate for or is not willing to receive local therapy options including but not limited to sclerotherapy, embolization, and surgery until the completion of Week 24 at the time of informed consent. Participant has evidence of a somatic mutation(s) in the PIK3CA gene Participant has at least one measurable LyM lesion confirmed by BIRC assessment prior to randomization. Key Exclusion Criteria: 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

Ages Eligible for Study
-----------------
Minimum Age: 2 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adult participants, alpelisib dose 1 (Stage 1)<br>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) | Drug: Alpelisib<br>* In Stage 1: adult participants (≥18 years of age) will receive dose 1 or dose 2 of alpelisib; pediatric participants (6-17 years of age) will recieve dose 2 or dose 3 of alpelisib. In Stage 2: Adult participants will receive alpelisib at the dose selected for confirmatory phase in adult participants; pediatric participants (6-17 years of age) will will receive alpelisib at the dose selected for confirmatory phase in pediatric participants; and pediatric participants of 2-5 years of age will receive dose 3 of alpelisib<br>* Other names: BYL719;|
| Experimental: Adult participants, alpelisib dose 2 (Stage 1)<br>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). | Drug: Alpelisib<br>* In Stage 1: adult participants (≥18 years of age) will receive dose 1 or dose 2 of alpelisib; pediatric participants (6-17 years of age) will recieve dose 2 or dose 3 of alpelisib. In Stage 2: Adult participants will receive alpelisib at the dose selected for confirmatory phase in adult participants; pediatric participants (6-17 years of age) will will receive alpelisib at the dose selected for confirmatory phase in pediatric participants; and pediatric participants of 2-5 years of age will receive dose 3 of alpelisib<br>* Other names: BYL719;|
| Experimental: Pediatric participants (6-17 years of age), alpelisib dose 2 (Stage 1)<br>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) | Drug: Alpelisib<br>* In Stage 1: adult participants (≥18 years of age) will receive dose 1 or dose 2 of alpelisib; pediatric participants (6-17 years of age) will recieve dose 2 or dose 3 of alpelisib. In Stage 2: Adult participants will receive alpelisib at the dose selected for confirmatory phase in adult participants; pediatric participants (6-17 years of age) will will receive alpelisib at the dose selected for confirmatory phase in pediatric participants; and pediatric participants of 2-5 years of age will receive dose 3 of alpelisib<br>* Other names: BYL719;|
| Experimental: Pediatric participants (6-17 years of age), alpelisib dose 3 (Stage 1)<br>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). | Drug: Alpelisib<br>* In Stage 1: adult participants (≥18 years of age) will receive dose 1 or dose 2 of alpelisib; pediatric participants (6-17 years of age) will recieve dose 2 or dose 3 of alpelisib. In Stage 2: Adult participants will receive alpelisib at the dose selected for confirmatory phase in adult participants; pediatric participants (6-17 years of age) will will receive alpelisib at the dose selected for confirmatory phase in pediatric participants; and pediatric participants of 2-5 years of age will receive dose 3 of alpelisib<br>* Other names: BYL719;|
| Experimental: Adult participants, alpelisib (Stage 2)<br>Adult participants (≥18 years of age) who will receive alpelisib at the dose selected for confirmatory phase in adult participants (Stage 2) | Drug: Alpelisib<br>* In Stage 1: adult participants (≥18 years of age) will receive dose 1 or dose 2 of alpelisib; pediatric participants (6-17 years of age) will recieve dose 2 or dose 3 of alpelisib. In Stage 2: Adult participants will receive alpelisib at the dose selected for confirmatory phase in adult participants; pediatric participants (6-17 years of age) will will receive alpelisib at the dose selected for confirmatory phase in pediatric participants; and pediatric participants of 2-5 years of age will receive dose 3 of alpelisib<br>* Other names: BYL719;|
| Placebo Comparator: Adult participants, placebo (Stage 2)<br>Adult participants (≥18 years of age) who will receive matching placebo | Drug: Placebo<br>* In Stage 2, participants will receive matching placebo for 24 weeks of the study<br>|
| Experimental: Pediatric participants (6-17 years of age), alpelisib (Stage 2)<br>Pediatric participants (6-17 years of age) who will receive alpelisib at the dose selected for confirmatory phase in pediatric participants (Stage 2) | Drug: Alpelisib<br>* In Stage 1: adult participants (≥18 years of age) will receive dose 1 or dose 2 of alpelisib; pediatric participants (6-17 years of age) will recieve dose 2 or dose 3 of alpelisib. In Stage 2: Adult participants will receive alpelisib at the dose selected for confirmatory phase in adult participants; pediatric participants (6-17 years of age) will will receive alpelisib at the dose selected for confirmatory phase in pediatric participants; and pediatric participants of 2-5 years of age will receive dose 3 of alpelisib<br>* Other names: BYL719;|
| Placebo Comparator: Pediatric participants (6-17 years of age), placebo (Stage 2)<br>Pediatric participants (6-17 years of age) who will receive matching placebo | Drug: Placebo<br>* In Stage 2, participants will receive matching placebo for 24 weeks of the study<br>|
| Experimental: Pediatric participants (2-5 years of age), alpelisib (Stage 2)<br>Pediatric participants of 2-5 years who will dose 3 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier | Drug: Alpelisib<br>* In Stage 1: adult participants (≥18 years of age) will receive dose 1 or dose 2 of alpelisib; pediatric participants (6-17 years of age) will recieve dose 2 or dose 3 of alpelisib. In Stage 2: Adult participants will receive alpelisib at the dose selected for confirmatory phase in adult participants; pediatric participants (6-17 years of age) will will receive alpelisib at the dose selected for confirmatory phase in pediatric participants; and pediatric participants of 2-5 years of age will receive dose 3 of alpelisib<br>* Other names: BYL719;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 2:Radiological response rate at Week 24 of Stage 2 (adult and pediatric (6 - 17 years of age) participants) | 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 | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | PGI-S is a single item measure to assess the overall severity of a patient's condition. This single item instrument uses a 5-point rating scale, which ranges from 1 (no symptoms) to 5 (very severe). Lower scores indicate better health status. The percentage of participants with at least a 1-point improvement compared to baseline at Week 24 of Stage 2 in adult and pediatric (6-17 years of age) groups will be assessed | Baseline, Week 24 | 
| Stage 2: Percentage of participants with a radiological response at Week 24 of Stage 2 (pediatric participants 2-5 years of age) | 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 pediatric participants 2-5 years of age will be assessed | 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) | PGI-C is a single item measure to assess the change in overall symptoms severity since the start of study. This single item instrument uses a 7-point rating scale, which ranges from 1 (very much improved) to 7 (very much worse). Lower scores indicate better health status. The change from baseline in PGI-C score will be assessed in adult and pediatric (6-17 years of age) participants | Up to approximately 6 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) | The PROMIS-29 plus 2 Profile v2.1 (completed by adult participant) includes 29 items across domains of depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, ability to participant in social roles and activities, cognitive function abilities and pain intensity.. The PROMIS Pediatric-25 Profile v2.0 (completed by children over 8 years of age) and PROMIS Parent-Proxy-25 Profile v2.0 (completed by parents for children under 8 years of age) include 25 items across the domains of depressive symptoms, anxiety, physical function-mobility, pain interference, fatigue, and peer relationships and pain intensity All items (except the pain intensity item) use a 5-point Likert scale, which ranges from 1 (not at all) to 5 (very much). The pain internsity item is scored on a 0-10 numeric rating scale, where 0 represents no pain and 10 represents worst imaginable pain. The change from baseline in PROMIS domains will be assessed | Up to approximately 6 years | 
| Stage 2: Change from baseline in investigator global impression of change (IGIC) scale (adult and pediatric (6-17 years of age) participants) | The IGIC involves a single question that asks the investigator to rate the change in the patient's condition since the start of treatment or intervention, using a 7-point scale ranging from 1 (Very much improved) to 7 (Very much worse). The change from baseline in IGIC score will be assessed in adult and pediatric (6-17 years of age) participants | Up to approximately 6 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) | The EQ-5D-5L (completed by adult participants) includes 5 items addressing dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 response options, ranging from 1=no problems to 5=extreme problems The EQ-5D-Y (completed by children over 8 years of age) and EQ-5D-Y Proxy version (completed by parent for participants under 8 years of age or unable to record for themselves) includes 5 items addressing dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 3 response options, ranging from 1= no problems to 3= a lot of problems | Up to approximately 6 years | 
| Duration of response (DOR) in adult and pediatric participants who receive alpelisib (Stage 1 and 2) | DOR is defined as the time from first documented response until progression of LyM lesions by BIRC or death. This analysis only applies to participants who are on treatment with alpelisib (Stage 1 and 2) and who achieve response. | Up to approximately 6 years | 
| Radiological response rate of alpelisib in adult and pediatric (6-17 years of age) participants (Stage 1) | 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 (adult and pediatric 6-17 years of age) with radiological response at Week 24 of Stage 1 will be assessed. | Baseline, Week 24 | 
| Radiological response rate of alpelisib in adult and pediatric participants (Stage 1 and 2) | 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, 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 who receive alpelisib (Stage 1 and 2) with radiological response will be assessed. | Up to approximately 6 years | 
| Alpelisib plasma concentrations (Stage 1 and 2) | Alpelisib plasma concentrations in adult and pediatric participants (Stage 1 and 2). | On Day 1 of Week 8, 16, 24, 48 and 120 | 
| Percentage of participants with of LyM-related symptoms, complications, and comorbidities on treatment with alpelisib in adult and pediatric participants at 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 (Stage 1 and 2) | Week 24 | 
| Percentage of participants with of LyM-related symptoms, complications, and comorbidities on treatment with alpelisib in adult and pediatric participants (Stage 1 and 2) | Percentage of participants with of LyM-related symptoms, complications, and comorbidities on treatment with alpelisib in adult and pediatric participants (Stage 1 and 2) | Up to approximately 6 years | 
| Change from baseline in LyM lesions in adult and pediatric participants at Week 24 (Stage 1 and 2) | Change from baseline in the sum of target lesion volumes, the sum of MRI-measurable non-target lesion (if applicable) volumes, and the sum of all MRI-measurable lesion (target and non-target) volumes as assessed by BIRC at Week 24 in adult and pediatric participants (Stage 1 and 2) | Baseline, Week 24 | 
| Change from baseline in LyM lesions in adult and pediatric participants (Stage 1 and 2) | Change from baseline in the sum of target lesion volumes, the sum of MRI-measurable non-target lesion (if applicable) volumes, and the sum of all MRI-measurable lesion (target and non-target) volumes as assessed by BIRC in adult and pediatric participants (Stage 1 and 2) | Up to approximately 6 years | 
| Percentage of participants with changes in non-target lesions in adult and pediatric participants at Week 24 (Stage 1 and 2) | Percentage of participants with changes in non-target lesions as assessed by BIRC at Week 24 in adult and pediatric participants (Stage 1 and 2) | Baseline, Week 24 | 
| Percentage of participants with changes in non-target lesions in adult and pediatric participants (Stage 1 and 2) | Percentage of participants with changes in non-target lesions as assessed by BIRC in adult and pediatric participants (Stage 1 and 2) | Up to approximately 6 years | 
| Percentage of participants with new lesions in adult and pediatric participants at Week 24 (Stage 1 and 2) | The percentage of participants with new lesions as assessed by BIRC at Week 24 in adult and pediatric participants (Stage 1 and 2) | Baseline, Week 24 | 
| Percentage of participants with new lesions in adult and pediatric participants (Stage 1 and 2) | The percentage of participants with new lesions as assessed by BIRC in adult and pediatric participants (Stage 1 and 2) | Up to approximately 6 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cystic lymphangioma, Cystic hygroma, Lymphangioma circumscriptum, Cavernous lymphangioma, Lymphangioma, Macrocystic lymphatic malformation, Microcystic lymphatic malformation, Alpelisib