Study Assessing the Efficacy, Safety and PK of Alpelisib (BYL719) in Pediatric and Adult Patients With PIK3CA-related Overgrowth Spectrum

NCT04589650 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 2 other identifiers: CBYL719F122012023-508530-34-00
• Study Type: interventional
• Target: 206
• Locations: 12 countries
• Sites: 36

Brief Summary

This is a prospective Phase II multi-center study with an initial 16-week, randomized, double-blind, placebo-controlled period, followed by two extension periods to assess the efficacy, safety and pharmacokinetics (PK) of alpelisib in pediatric and adult patients with PIK3CA-related overgrowth spectrum (PROS)

Conditions

PIK3CA-related Overgrowth Spectrum (PROS)

Keywords

PIK3CA-related overgrowth spectrum (PROS); Alpelisib; BYL719; Adult; Pediatric; Phase II

Outcome Measures

Primary Outcomes (1)

• Proportion of Participants Randomized to Alpelisib With a Confirmed Objective Response by BIRC in Group 1 and Group 2

  A responder is defined by achieving a \>=20% reduction from baseline in the sum of target lesion volumes (via BIRC), provided that none of the individual target lesions have a \>=20% increase from baseline and in absence of progression of non target lesions and without new lesions. Confirmation of response requires a subsequent imaging assessment performed at least 4 weeks after the onset of response. Participants who permanently discontinued alpelisib prior to confirmation of response, and participants who received surgery as rescue therapy prior to confirmation of response are considered as non-responders.

  Up to 48 weeks

Secondary Outcomes (22)

• Key Secondary Objective: Proportion of Participants With Response at Week 16 by BIRC in Group 1 and Group 2

  Week 16

• Proportion of Participants With a Response at Week 24 (by BIRC) in Groups 1 and 2

  Week 24

• Frequency and Severity of Adverse Events in Groups 1 and 2 up to Week 16

  Up to Week 16

• Frequency and Severity of Adverse Events in All Groups of Participants Over Time

  Up to approximately 5 years

• Change From Baseline to Week 16 in Brief Pain Inventory (BPI) Worst Pain Intensity in Group 1 and 2

  Baseline, Week 4, Week 8, Week 12, Week 16

Study Arms (7)

Adult cohort (group 1)- Alpelisib

EXPERIMENTAL

During double-blind randomized study period (from baseline up to Week 16), adult participants will be randomized to receive alpelisib (125 mg, oral, once daily). After Week 16, participants will continue their active treatment at the same dose level.

Drug: Alpelisib

Adult cohort (group 1)- Placebo

PLACEBO COMPARATOR

During double-blind randomized study period (from baseline up to Week 16), adult participants will be randomized to receive placebo. After Week 16, participants will be switched to active treatment with alpelisib at the placebo dose level received at the end of the placebo period.

Drug: Alpelisib; Drug: Placebo

Pediatric cohort (group 2: 6 to 17 years old) -Alpelisib

EXPERIMENTAL

During double-blind randomized study period (from baseline up to Week 16, pediatric participants (6 to 17 years old) will be randomized to receive alpelisib (50 mg, oral, once daily). After Week 16, participants will continue their active treatment at the same dose level.

Drug: Alpelisib

Pediatric cohort (group 2: 6 to 17 years old)-Placebo

PLACEBO COMPARATOR

During double-blind randomized study period (from baseline up to Week 16), pediatric participants (6 to 17 years old) will be randomized to receive Placebo. After Week 16, participants will be switched to active treatment with alpelisib at the placebo dose level received at the end of the placebo period.

Drug: Alpelisib; Drug: Placebo

Pediatric cohort (group 3: 0 to 5 years old)- Alpelisib granules

EXPERIMENTAL

Pediatric participants (0 to 5 years old) will receive alpelisib granules formulation with an age-dependent starting dose (\<1 month: 20 mg every other day; 1 to \<6 months: 20 mg daily; 6 to \<2 years: 40 mg daily; 2 to \<6 years: 50 mg daily).

Drug: Alpelisib

Pediatric cohort (group 4: 2 to 5 years old)- Alpelisib FCT

EXPERIMENTAL

Pediatric participants (2 to 5 years old) will receive 50 mg of alpelisib film-coated tablets (FCT) once daily in an open-label setting.

Drug: Alpelisib

Pediatric cohort (group 5: 6-17 years old)-Alpelisib FCT

EXPERIMENTAL

Pediatric participants (6 to 17 year old) will receive 125 mg alpelisib film-coated (FCT) once daily, in an open-label setting.

Drug: Alpelisib

Interventions

Alpelisib DRUG

Adult participants (group 1) will receive 125 mg of alpelisib oral tablets once daily. Pediatric participants (Group 2: 6 to 17 years old) will receive 50 mg of alpelisib oral tablets once daily. Pediatric participants (Group 4: 2 to 5 years old) will receive 50 mg of alpelisib oral tablets once daily, Pediatric participants (Group 3: 0 to 5 years old) will receive alpelisib granules formulation with an age-dependent starting dose and maximum dose levels ranging from 20 mg every other day to 50 mg once daily. Pediatric participants (Group 5: 6 to 17 years old) will receive 125 mg of alpelisib oral tablets once daily.

Also known as: BYL719

Adult cohort (group 1)- Alpelisib; Adult cohort (group 1)- Placebo; Pediatric cohort (group 2: 6 to 17 years old) -Alpelisib; Pediatric cohort (group 2: 6 to 17 years old)-Placebo; Pediatric cohort (group 3: 0 to 5 years old)- Alpelisib granules; Pediatric cohort (group 4: 2 to 5 years old)- Alpelisib FCT; Pediatric cohort (group 5: 6-17 years old)-Alpelisib FCT

Placebo DRUG

Participants will receive matching placebo once daily up to week 16.

Adult cohort (group 1)- Placebo; Pediatric cohort (group 2: 6 to 17 years old)-Placebo

Eligibility Criteria

• Age: 0 Days - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent and assent (when applicable) from the patient, parent, legal authorized representative, or guardian prior to any study-related screening procedures were performed.
• Male or female patients age above 0 day at the time of informed consent: Group 1: ≥ 18 years old, Group 2: 6-17 years old, Group 3: ≥ 0-5 years old, Group 4: ≥ 2-5 years old, Group 5: 6-17 years old.
• Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth and at least one measurable PROS-related lesion confirmed by BIRC assessment who had syndromic disease or isolated features at the time of informed consent. Patients, who previously had been receiving systemic treatment for PROS, could enter the study.
• Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories using a DNA-based test validated according to the local regulations at the time of informed consent.
• A tissue sample (fresh or archival) was to be sent to a Novartis-designated central laboratory.
• Karnofsky (in patients \> 16 years old at study entry)/Lansky (≤ 16 years of age at study entry) performance status index ≥ 50.
• Adequate bone marrow and organ function as assessed by central laboratory for eligibility.
• Presence of at least one PROS-related measurable lesion defined as a lesion with longest diameter ≥ 2 cm, when the volume could be accurately and reproducibly measured by MRI, and associated with complaints, clinical symptoms or functional limitations affecting the patient's everyday life. Measurability was confirmed by BIRC before randomization.
• Able to swallow study drug (as assessed within 7 days before study treatment start):
• Groups 1, 2, 4, and 5: FCT, or as drinkable suspension when applicable.
• Group 3: granules. Drug administration via feeding tube is allowed.

You may not qualify if:

• Patient with only isolated macrodactyly, epidermal nevus/nevi and macroencephaly (the only clinical feature or a combination of any three of them), in absence of other PROS-related lesions at the time of informed consent.
• Previous treatment with alpelisib and/or any other PI3K inhibitor(s).
• Radiation exposure for PROS treatment purpose within the previous 12 months on those PROS areas, which were expected to qualify for target lesions (except lesion(s) progressing after completion of radiotherapy) at time of informed consent.
• Debulking or other major surgery performed within 3 months at time of informed consent.
• Clinically meaningful bleeding related to PROS: Grade 2 within 14 days or grade 3 and more within 28 days before study treatment start as per CTCAE v4.03.
• Clinically meaningful PROS-related thrombotic event (grade 2 and more as per CTCAE v4.03) within 30 days before informed consent, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent.
• History of prior and or ongoing malignancy or ongoing investigations or treatment for malignancy at time of informed consent.
• Clinically significant heart disease at time of informed consent.
• Patients in Groups 1, 2, and 5 with documented pneumonitis or interstitial lung disease at time of informed consent and with impaired lung function (e.g., FEV1 or DLCO ≤ 70% of predicted) that was not related to PROS. Patients in Groups 3 and 4 with documented or suspicious pneumonitis or interstitial lung disease based on MRI images at time of informed consent.
• History of acute pancreatitis within 1 year before informed consent or past medical history of chronic pancreatitis at time of informed consent.
• Patients with an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at time of informed consent.
• Known impairment of gastrointestinal (GI) function due to concomitant GI disease that may significantly alter the absorption of the study drug at time of informed consent.
• History of hypersensitivity to any drugs or metabolites of PI3K inhibitor or any of the excipients of alpelisib at time of informed consent.
• Known history of Steven Johnson's syndrome, erythema multiforme or toxic epidermal necrolysis at time of informed consent.
• Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum at time of informed consent, when epilepsy was not controlled and/or the patient may not be switched to non-enzyme inducing antiepileptic drug(s) at time of informed consent.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (36)

UCSF Birthmarks and Vascular Center

San Francisco, California, 94158, United States

Location

Childrens Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Washington Univ School Of Medicine

St Louis, Missouri, 63110, United States

Location

Fink Childrens Ambulatory Care Ctr

New York, New York, 10016, United States

Location

UNC Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Cinn Children Hosp Medical Center

Cincinnati, Ohio, 45206, United States

Location

Cincinnati Children s Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

CHOP Abramson Pediatric Resch Ctr

Philadelphia, Pennsylvania, 19104, United States

Location

Unv of TX Southwestern Medical Center

Dallas, Texas, 75235, United States

Location

Baylor College Of Medicine

Houston, Texas, 77030, United States

Location

Childrens Hospital and Regional Medical Center

Seattle, Washington, 98105, United States

Location

Novartis Investigative Site

Montreal, Quebec, H2W 1T8, Canada

Location

Novartis Investigative Site

Montreal, Quebec, H3T 1C5, Canada

Location

Novartis Investigative Site

Beijing, 100730, China

Location

Novartis Investigative Site

Shanghai, 200011, China

Location

Novartis Investigative Site

Bordeaux, 33076, France

Location

Novartis Investigative Site

Dijon, 21000, France

Location

Novartis Investigative Site

Paris, 75015, France

Location

Novartis Investigative Site

Tours, 37044, France

Location

Novartis Investigative Site

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Novartis Investigative Site

Düsseldorf, North Rhine-Westphalia, 40225, Germany

Location

Novartis Investigative Site

Leipzig, Saxony, 04103, Germany

Location

Novartis Investigative Site

Hamburg, 22149, Germany

Location

Novartis Investigative Site

Heidelberg, 69120, Germany

Location

Novartis Investigative Site

Hong Kong, 999077, Hong Kong

Location

Novartis Investigative Site

Roma, RM, 00165, Italy

Location

Novartis Investigative Site

Torino, TO, 10126, Italy

Location

Novartis Investigative Site

Nijmegen, Gelderland, 6500HB, Netherlands

Location

Novartis Investigative Site

Oslo, 0372, Norway

Location

Novartis Investigative Site

Esplugues, Barcelona, 08950, Spain

Location

Novartis Investigative Site

Madrid, 28046, Spain

Location

Novartis Investigative Site

Bern, 3010, Switzerland

Location

Novartis Investigative Site

Zurich, 8032, Switzerland

Location

Novartis Investigative Site

West Midlands, Birmingham, B4 6NH, United Kingdom

Location

Novartis Investigative Site

London, SW17 0QT, United Kingdom

Location

Novartis Investigative Site

Manchester, M13 9WL, United Kingdom

Location

Related Publications (2)

• Fujino A, Kuniyeda K, Nozaki T, Ozeki M, Ohyama T, Sato I, Kamibeppu K, Tanaka A, Uemura N, Kanmuri K, Nakamura K, Kobayashi F, Suenobu S, Nomura T, Hayashi A, Nagao M, Kato A, Aramaki-Hattori N, Imagawa K, Ishikawa K, Ochi J, Horiuchi S, Nagabukuro H. The Prospective Natural History Study of Patients with Intractable Venous Malformation and Klippel-Trenaunay Syndrome to Guide Designing a Proof-of-Concept Clinical Trial for Novel Therapeutic Intervention. Lymphat Res Biol. 2024 Feb;22(1):27-36. doi: 10.1089/lrb.2023.0023. Epub 2023 Dec 19.

  PMID: 38112724 DERIVED

• Madsen RR, Semple RK. PIK3CA-related overgrowth: silver bullets from the cancer arsenal? Trends Mol Med. 2022 Apr;28(4):255-257. doi: 10.1016/j.molmed.2022.02.009. Epub 2022 Mar 8.

  PMID: 35272946 DERIVED

MeSH Terms

Interventions

Alpelisib

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants, investigator staff, and persons performing the assessments will remain blinded to the identity of the treatment from the time of randomization until primary analysis i.e. the last participants (Groups 1 and 2) completes Week 48 from randomization or discontinues earlier.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: October 14, 2020
• First Posted: October 19, 2020
• Study Start: April 19, 2021
• Primary Completion: March 20, 2024
• Study Completion (Estimated): January 9, 2031
• Last Updated: April 30, 2026
• Results First Posted: February 10, 2025

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

DE (5); HK (1); FR (4); US (11); IT (2); NL (1); CA (2); CN (2); ES (2); CH (2); GB (3); NO (1)