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NCT Number: NCT05948943

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

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.

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Key information

Conditions

Lymphatic Malformations Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Hemic and Lymphatic Diseases Lymphangioma Lymphangioma, Cystic Lymphatic Abnormalities Lymphatic Diseases Neoplasm, Lymphatic Tissue Neoplasms Neoplasms by Histologic Type

Age range

0 year–100 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Novartis Investigative Site, CABA, Buenos Aires, Argentina

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key inclusion criteria:

  • 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 2.
  • 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.

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

Treatment and study plan

Alpelisib

Drug

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

Other names: BYL719

Placebo

Drug

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

Primary outcomes

  1. Stage 2:Radiological response rate at Week 24 of Stage 2 (adult and pediatric (6 - 17 years of age) participants)

    Time frame: 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

Secondary outcomes

  1. 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)

    Time frame: Baseline, Week 24

    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

  2. Stage 2: Percentage of participants with a radiological response at Week 24 of Stage 2 (pediatric participants 0-5 years of age)

    Time frame: 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 pediatric participants 0-5 years of age will be assessed

  3. Stage 2: Change from baseline in patient global impression of change (PGI-C) scale (adult and pediatric (6-17 years of age) participants)

    Time frame: Up to approximately 8 years

    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

  4. Stage 2: Change from baseline in patient-reported outcomes measurement information system (PROMIS) profile domains(adult and pediatric (6-17 years of age) participants)

    Time frame: Up to approximately 8 years

    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

  5. Stage 2: Change from baseline in investigator global impression of change (IGIC) scale (adult and pediatric (6-17 years of age) participants)

    Time frame: Up to approximately 8 years

    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

  6. Stage 2: Change from baseline in health utilities of the EuroQol 5-dimension (EQ-5D) (adult and pediatric (6-17 years of age) participants)

    Time frame: Up to approximately 8 years

    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

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

    Time frame: Up to approximately 8 years

    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.

  8. Stage 1: Radiological response rate of alpelisib in adult and pediatric (6-17 years of age) participants

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

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

    Time frame: Up to approximately 8 years

    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.

  10. Stage 1 and 2: Alpelisib plasma concentrations

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

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

  11. 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

    Time frame: 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)

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

    Time frame: Up to approximately 8 years

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

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

    Time frame: Baseline, 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)

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

    Time frame: Up to approximately 8 years

    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)

  15. Stage 1 and 2: Percentage of participants with changes in non-target lesions in adult and pediatric participants at Week 24

    Time frame: Baseline, 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)

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

    Time frame: Up to approximately 8 years

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

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

    Time frame: Baseline, 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)

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

    Time frame: Up to approximately 8 years

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

Study contacts

Contact information is provided by the study sponsor or research team.

Novartis Pharmaceuticals

CONTACT

[email protected]

1-888-669-6682

Novartis Pharmaceuticals

CONTACT

[email protected]

+41613241111

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study 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.

Acronym: EPIK-L1

Important dates

Study start
2023
Primary completion
2028
Study completion
2033
First posted
Jul 17, 2023
Registry last updated
Jul 14, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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