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.
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.
Arms & interventions
- DrugAlpelisib
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
- DrugPlacebo
In Stage 2, participants will receive matching placebo for 24 weeks of the study
Outcome measures
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
Time frame: 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)
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)
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)
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)
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)
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)
Time frame: Up to approximately 8 years
Stage 1 and 2: Duration of response (DOR) in adult and pediatric participants who receive alpelisib
Time frame: Up to approximately 8 years
Stage 1: Radiological response rate of alpelisib in adult and pediatric (6-17 years of age) participants
Time frame: Baseline, Week 24
Stage 1 and 2: Radiological response rate of alpelisib in adult and pediatric participants
Time frame: Up to approximately 8 years
Stage 1 and 2: Alpelisib plasma concentrations
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
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
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
Time frame: Baseline, Week 24
Stage 1 and 2: Change from baseline in LyM lesions in adult and pediatric participants
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
Time frame: Baseline, Week 24
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
Stage 1 and 2: Percentage of participants with new lesions in adult and pediatric participants at Week 24
Time frame: Baseline, Week 24
Stage 1 and 2: Percentage of participants with new lesions in adult and pediatric participants
Time frame: Up to approximately 8 years
Eligibility criteria
Study locations (16)
UCSF Benioff Children s Hospital
Oakland, California, 94609
Lucile Packard Childrens Hosp
Palo Alto, California, 94304
Childrens National Medical Center
Washington D.C., District of Columbia, 20010-2970
Nemours Childrens Clinic
Jacksonville, Florida, 32207
Childrens Hosp Boston Dept of Heme
Boston, Massachusetts, 02115
WA Uni School Of Med
St Louis, Missouri, 63110
Cinn Children Hosp Medical Center
Cincinnati, Ohio, 45229-3039
Univ Hospital Of Cleveland
Cleveland, Ohio, 44106
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Nationwide Children s Hospital
Columbus, Ohio, 43205
Oregon Health Science University
Portland, Oregon, 97239
CHOP Abramson Pediatric Resch Ctr
Philadelphia, Pennsylvania, 19104
Childrens Hosp Pittsburgh UPMC
Pittsburgh, Pennsylvania, 15224
Baylor College Of Medicine
Houston, Texas, 77030
U of TX Health Science Ct
Houston, Texas, 77030
Childrens Hospital and Regional Medical Center
Seattle, Washington, 98105