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

Phase 3RecruitingNCT05948943

Novartis Pharmaceuticals232 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

232

Conditions

Lymphatic Malformations

Interventions

AlpelisibDRUG

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 receive 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 0-5 years of age will receive dose 3 of alpelisib

PlaceboDRUG

In Stage 2, participants will receive matching placebo for 24 weeks of the study

Eligibility

Sex: ALLMin age: 0 YearsMax age: 100 Years

Medical Language ↔ Plain English

Key inclusion criteria: 1. Signed informed consent and assent (when applicable) from the participant, parent, legal authorized representative or guardian. 2. 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. 3. 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). 4. 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 2. 5. Participant has evidence of a somatic mutation(s) in the PIK3CA gene prior to randomization. 6. Participant has at least one measurable LyM lesion confirmed by BIRC assessment prior to randomization. 7. 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. Key exclusion criteria: 1. Participant has a physician-confirmed and documented diagnosis of PROS at the time of informed consent. 2. 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. 3. Participant has a known history of Stevens-Johnson syndrome, erythema multiforme, or toxic epidermal necrolysis at the time of informed consent. 4. Participant has an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at the time of informed consent. 5. 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

Locations (44)

Outcomes

Primary Outcomes

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

Time frame: Baseline, Week 24

Secondary Outcomes

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

Time frame: 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)

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 0-5 years of age will be assessed

Time frame: 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)

Central Contacts

Novartis Pharmaceuticals

CONTACT

1-888-669-6682 novartis.email@novartis.com

Novartis Pharmaceuticals

CONTACT

+41613241111 novartis.email@novartis.com

Data from ClinicalTrials.gov

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UCSF Benioff Children s Hospital

Oakland, California, United States

RECRUITING

Lucile Packard Childrens Hosp

Palo Alto, California, United States

RECRUITING

Childrens National Medical Center

Washington D.C., District of Columbia, United States

RECRUITING

Childrens Hosp Boston Dept of Heme

Boston, Massachusetts, United States

RECRUITING

WA Uni School Of Med

St Louis, Missouri, United States

RECRUITING

Cinn Children Hosp Medical Center

Cincinnati, Ohio, United States

RECRUITING

Univ Hospital Of Cleveland

Cleveland, Ohio, United States

RECRUITING

Cleveland Clinic Foundation

Cleveland, Ohio, United States

RECRUITING

Oregon Health Science University

Portland, Oregon, United States

RECRUITING

CHOP Abramson Pediatric Resch Ctr

Philadelphia, Pennsylvania, United States

RECRUITING

...and 34 more locations

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

Time frame: 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)

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 intensity 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

Time frame: 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)

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

Time frame: 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)

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

Time frame: Up to approximately 8 years

Stage 1 and 2: Duration of response (DOR) in adult and pediatric participants who receive alpelisib

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.

Time frame: Up to approximately 8 years

Stage 1: Radiological response rate of alpelisib in 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 (adult and pediatric 6-17 years of age) with radiological response at Week 24 of Stage 1 will be assessed.

Time frame: Baseline, Week 24

Stage 1 and 2: Radiological response rate of alpelisib in adult and pediatric 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, 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.

Time frame: Up to approximately 8 years

Stage 1 and 2: Alpelisib plasma concentrations

Alpelisib plasma concentrations in adult and pediatric participants (Stage 1 and 2).

Time frame: On Day 1 of Week 8, 16, 24, 48 and 120

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

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)

Time frame: 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

Percentage of participants with of LyM-related symptoms, complications, and comorbidities on treatment with alpelisib in adult and pediatric participants (Stage 1 and 2)

Time frame: Up to approximately 8 years

Stage 1 and 2: Change from baseline in LyM lesions in adult and pediatric participants at Week 24

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)

Time frame: Baseline, Week 24

Stage 1 and 2: Change from baseline in LyM lesions in adult and pediatric participants

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)

Time frame: 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

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)

Time frame: Baseline, Week 24

Stage 1 and 2: Percentage of participants with changes in non-target lesions in adult and pediatric participants

Percentage of participants with changes in non-target lesions as assessed by BIRC in adult and pediatric participants (Stage 1 and 2)

Time frame: Up to approximately 8 years

Stage 1 and 2: Percentage of participants with new lesions in adult and pediatric participants at Week 24

The percentage of participants with new lesions as assessed by BIRC at Week 24 in adult and pediatric participants (Stage 1 and 2)

Time frame: Baseline, Week 24

Stage 1 and 2: Percentage of participants with new lesions in adult and pediatric participants

The percentage of participants with new lesions as assessed by BIRC in adult and pediatric participants (Stage 1 and 2)

Time frame: Up to approximately 8 years