Clinical trial NCT05948943: Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.
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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Lymphatic Malformations
Keywords: Lymphatic malformations (LyM)
Cystic lymphangioma
Cystic hygroma
Lymphangioma circumscriptum
Cavernous lymphangioma
Lymphangioma
Macrocystic lymphatic malformation
Microcystic lymphatic malformationn
Alpelisib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2023-07-17
Enrollment: 232
Sex: ALL
Minimum age (years): 0
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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.

Eligibility criteria: 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

Primary outcomes:
measure: Stage 2:Radiological response rate at Week 24 of Stage 2 (adult and pediatric (6 - 17 years of age) participants)
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: 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)
timeFrame: Baseline, Week 24
measure: Stage 2: Percentage of participants with a radiological response at Week 24 of Stage 2 (pediatric participants 0-5 years of age)
timeFrame: Baseline, Week 24
measure: Stage 2: Change from baseline in patient global impression of change (PGI-C) scale (adult and pediatric (6-17 years of age) participants)
timeFrame: Up to approximately 8 years
measure: Stage 2: Change from baseline in patient-reported outcomes measurement information system (PROMIS) profile domains(adult and pediatric (6-17 years of age) participants)
timeFrame: Up to approximately 8 years
measure: Stage 2: Change from baseline in investigator global impression of change (IGIC) scale (adult and pediatric (6-17 years of age) participants)
timeFrame: Up to approximately 8 years
measure: Stage 2: Change from baseline in health utilities of the EuroQol 5-dimension (EQ-5D) (adult and pediatric (6-17 years of age) participants)
timeFrame: Up to approximately 8 years
measure: Duration of response (DOR) in adult and pediatric participants who receive alpelisib (Stage 1 and 2)
timeFrame: Up to approximately 8 years
measure: Radiological response rate of alpelisib in adult and pediatric (6-17 years of age) participants (Stage 1)
timeFrame: Baseline, Week 24
measure: Radiological response rate of alpelisib in adult and pediatric participants (Stage 1 and 2)
timeFrame: Up to approximately 8 years
measure: Alpelisib plasma concentrations (Stage 1 and 2)
timeFrame: On Day 1 of Week 8, 16, 24, 48 and 120
measure: 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)
timeFrame: Week 24
measure: Percentage of participants with of LyM-related symptoms, complications, and comorbidities on treatment with alpelisib in adult and pediatric participants (Stage 1 and 2)
timeFrame: Up to approximately 8 years
measure: Change from baseline in LyM lesions in adult and pediatric participants at Week 24 (Stage 1 and 2)
timeFrame: Baseline, Week 24
measure: Change from baseline in LyM lesions in adult and pediatric participants (Stage 1 and 2)
timeFrame: Up to approximately 8 years
measure: Percentage of participants with changes in non-target lesions in adult and pediatric participants at Week 24 (Stage 1 and 2)
timeFrame: Baseline, Week 24
measure: Percentage of participants with changes in non-target lesions in adult and pediatric participants (Stage 1 and 2)
timeFrame: Up to approximately 8 years
measure: Percentage of participants with new lesions in adult and pediatric participants at Week 24 (Stage 1 and 2)
timeFrame: Baseline, Week 24
measure: Percentage of participants with new lesions in adult and pediatric participants (Stage 1 and 2)
timeFrame: Up to approximately 8 years
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Lucile Packard Childrens Hosp
state: California
city: Saint Louis
country: United States
facility: WA Uni School Of Med
state: Missouri
city: Cincinnati
country: United States
facility: Cinn Children Hosp Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: CHOP Abramson Pediatric Resch Ctr
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College Of Medicine
state: Texas
city: Seattle
country: United States
facility: Childrens Hospital and Regional Medical Center
state: Washington
city: Brisbane
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Bordeaux Cedex
country: France
facility: Novartis Investigative Site
city: Bron Cedex
country: France
facility: Novartis Investigative Site
city: Caen
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Paris cedex 10
country: France
facility: Novartis Investigative Site
city: Tours 9
country: France
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden Wuerttemberg
city: Leipzig
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Esplugues De Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: