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

Lymphatic Malformations Clinical Trial

— EPIK-L1  

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05948943
• Other study ID #: CBYL719P12201
• Secondary ID: 2023-504146-60-0
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: November 24, 2023
• Est. completion date: January 3, 2030

Study information

• Verified date: February 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: 1-888-669-6682
• Email: novartis.email[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 230
• Est. completion date: January 3, 2030
• Est. primary completion date: January 3, 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Congenital Abnormalities
• Lymphangioma
• Lymphatic Abnormalities
• Lymphatic Malformations

Intervention

Drug:
• Alpelisib
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
• Placebo
In Stage 2, participants will receive matching placebo for 24 weeks of the study

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Brisbane	Queensland
France	Novartis Investigative Site	Bron Cedex
France	Novartis Investigative Site	Caen
France	Novartis Investigative Site	Marseille Cedex 05
France	Novartis Investigative Site	Montpellier Cedex
France	Novartis Investigative Site	Tours 9
Germany	Novartis Investigative Site	Freiburg
Spain	Novartis Investigative Site	Madrid
United States	Lucile Packard Childrens Hosp .	Palo Alto	California
United States	Washington Uni School of Med Pediatric Hem-Onc	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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