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

NCT ID: NCT04589650

Last Updated: 2025-12-17

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 203 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-04-19
• Study Completion Date: 2031-01-17

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)

Detailed Description

This is a Phase II multi-center study with an upfront 16-week, randomized, double-blind, placebo-controlled period, and extension periods, to assess the efficacy, safety and PK of alpelisib in pediatric and adult participants with PROS.

Study period 1 - Core Period: Double-blind treatment, with an upfront 16-week placebo-controlled period (From Randomization to the end of Week 24) - Groups 1 and 2 At study start, participants in Group 1 and Group 2 will be enrolled and randomized in a 2:1 ratio (104 participants in the active arms and 52 participants in the placebo arms) to alpelisib or matching placebo. The upfront placebo-controlled period will continue for the first 16 weeks. At the conclusion of week 16, those participants who were randomized to receive placebo will be switched to active treatment with alpelisib in a blinded fashion at the dose level received at the end of the placebo period. Those participants who were randomized to receive alpelisib, will continue their treatment at the same dose level.

During the initial 16 weeks of the Core period, study treatment will be given in a blinded fashion, starting from week 17 of the Core period in open label fashion. The randomized treatment assignment to the treatment arms will remain blinded to participants, Investigators and the study team until the time of the primary analysis, when the last participant reaches week 48 from randomization or discontinues earlier.

Study period 1 - Exploratory; Group 4, open label treatment with the alpelisib FCT formulation After the implementation of Global Protocol Amendment 01, approximately 6 participants 2 to 5 years of age will be enrolled in exploratory Group 4. These participants will receive alpelisib FCT in an open label setting.

Study period 2 - Extension 1: treatment with alpelisib (week 25 up to the end of week 48) - Groups 1 and 2 Participants (Group 1 and Group 2) will continue their treatment during this study period.

For Groups 1 and 2, dose escalation is NOT allowed during first 4 weeks of Extension 1 period (weeks 25-28).

Once a participant (Groups 1 and 2) has completed initial 24 weeks of study treatment and reached Week 29, dose escalation will be allowed (Refer to Section 6.5.1):

• Group 1: Alpelisib (125mg, or 200mg, or 250 mg QD)
• Group 2: Alpelisib (50mg, or 125mg, or 200mg, or 250 mg QD)

Study period 2 - Exploratory: Group 4, open label treatment with the alpelisib FCT formulation

For Group 4 dose escalation is allowed once participant has reached the age of 6 years old, has completed the initial 24 weeks of study treatment, and has reached week 25:

• Group 4: Alpelisib (50 mg, or 125 mg, or 200 mg, or 250 mg QD)

Study period 3 - Extension 2: long-term treatment with alpelisib (Week 49 up to 5 years) - Groups 1 and 2 Groups 1 and 2 participants who continue the study until Week 48 and have clinical benefit from the study treatment, will enter a long-term extension period. Dose escalation and treatment beyond progression are allowed in both Group 1 and Group 2.

Study period 3 - Exploratory: Group 4, open label treatment with the alpelisib FCT formulation Group 4 participants who continue the study until Week 48 and have clinical benefit from the study treatment, will enter a long-term extension period. Dose escalation is allowed once a participant has reached the age of 6 years old, has completed the initial 24 weeks of study treatment, and has reached Week 25.

Exploratory study part: Group 3, open label treatment with the alpelisib granules formulation Group 3 will be an exploratory group of participants who are 0 to 5 years old and will receive the 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. Group 3 will be open to enrollment only after implementation of Global Protocol Amendment 05. Dose escalation is allowed once a participant has reached the age of 6 years, has completed the initial 24 weeks of study treatment, and has reached Week 25.

Group 5 open-label treatment with the alpelisib FCT formulation:

Participants of Group 5 will be enrolled after implementation of Global Protocol Amendment 02 and immediately after enrollment of Group 2 has been completed and will receive a starting dose of 125 mg alpelisib FCT formulation once daily in an open-label setting.

Dose escalation is allowed for those who did not derive sufficient clinical benefit at the Investigator's discretion and once participant has reached at least Week 25.

Study period 4 - Extension 3: treatment with alpelisib (from Week 264 until last patient enrolled completes 5 years of treatment) All participants from all groups will be followed until the last patient enrolled completes 5 years of treatment or discontinues early, to collect additional safety of alpelisib and in order to ensure patient access to treatment in the absence of global commercial supply in pediatric and adult participants with PROS. Visits will be performed every 24 weeks and additional safety assessments every 48 weeks.

It is planned to enroll approximately 192 participants in total, 78 adults and 114 children and adolescents. A total of approximately 156 male or female participants (of age ≥ 6 years) with PROS will be randomized in a 2:1 ratio in Groups 1 and 2 (approximately 78 participants per age group). Additional exploratory groups (Group 3, Group 4 and Group 5) will include approximately a total of 36 participants (approximately 15 in Group 3, 6 in Group 4 and 15 in Group 5).

Conditions

PIK3CA-related Overgrowth Spectrum (PROS)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Adult cohort (group 1)- Alpelisib

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.

Group Type: EXPERIMENTAL

Alpelisib

Intervention Type: 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.

Adult cohort (group 1)- Placebo

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.

Group Type: PLACEBO_COMPARATOR

Alpelisib

Intervention Type: 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.

Placebo

Intervention Type: DRUG

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

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

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.

Group Type: EXPERIMENTAL

Alpelisib

Intervention Type: 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.

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

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.

Group Type: PLACEBO_COMPARATOR

Alpelisib

Intervention Type: 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.

Placebo

Intervention Type: DRUG

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

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

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).

Group Type: EXPERIMENTAL

Alpelisib

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

Alpelisib

Intervention Type: 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.

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

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

Group Type: EXPERIMENTAL

Alpelisib

Intervention Type: 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.

Interventions

Alpelisib

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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

BYL719

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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.
• Patient with other concurrent severe and/or uncontrolled medical conditions that could, in the Treating Physician's judgment, contraindicate administration of alpelisib at time of informed consent. Patient with an active documented COVID-19 infection at time of informed consent could be included only when completely recovered and had no symptoms for at least 28 days before first dose of study medication.
• Pregnant or breastfeeding female patients at time of informed consent.
• Female patients of child-bearing potential who did not consent to use a highly effective method of contraception and male patients who did not consent to use a condom and/or a highly effective method of contraception for the duration of the study and for one week following discontinuation of alpelisib.
• Patient was receiving any of the following medications and could not discontinue 7 days prior to the start of the treatment: strong inducers of CYP3A4 or inhibitors of breast cancer resistance protein (BCRP).
• Not able to understand and to comply with study instructions and requirements at time of informed consent.
• Participation in a prior investigational study within 4 weeks prior to study treatment start or within 5 half-lives of the investigational product, whichever was longer.
• Patients with clinically significant worsening of PROS-related laboratory anomalies, physical signs and symptoms indicating an uncontrolled condition during the screening phase, particularly if systemic treatment with any other inhibitor of the PI3K/AKT/mTOR pathway was stopped prior to the start of study treatment. This included but was not limited to hypercoagulability state in patients not receiving prophylactic treatment.

• Minimum Eligible Age: 0 Days
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

UCSF Birthmarks and Vascular Center

San Francisco, California, United States

Childrens Hospital Colorado

Aurora, Colorado, United States

Washington Univ School Of Medicine

St Louis, Missouri, United States

Fink Childrens Ambulatory Care Ctr

New York, New York, United States

UNC Chapel Hill

Chapel Hill, North Carolina, United States

Cincinnati Children s Hospital Medical Center

Cincinnati, Ohio, United States

Cinn Children Hosp Medical Center

Cincinnati, Ohio, United States

CHOP Abramson Pediatric Resch Ctr

Philadelphia, Pennsylvania, United States

Unv of TX Southwestern Medical Center

Dallas, Texas, United States

Baylor College Of Medicine

Houston, Texas, United States

Childrens Hospital and Regional Medical Center

Seattle, Washington, United States

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Beijing, , China

Novartis Investigative Site

Shanghai, , China

Novartis Investigative Site

Bordeaux, , France

Novartis Investigative Site

Dijon, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Tours, , France

Novartis Investigative Site

Freiburg im Breisgau, Baden-Wurttemberg, Germany

Novartis Investigative Site

Düsseldorf, North Rhine-Westphalia, Germany

Novartis Investigative Site

Leipzig, Saxony, Germany

Novartis Investigative Site

Hamburg, , Germany

Novartis Investigative Site

Heidelberg, , Germany

Novartis Investigative Site

Pokfulam, , Hong Kong

Novartis Investigative Site

Roma, RM, Italy

Novartis Investigative Site

Torino, TO, Italy

Novartis Investigative Site

Nijmegen, Gelderland, Netherlands

Novartis Investigative Site

Oslo, , Norway

Novartis Investigative Site

Esplugues, Barcelona, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Bern, , Switzerland

Novartis Investigative Site

Zurich, , Switzerland

Novartis Investigative Site

West Midlands, Birmingham, United Kingdom

Novartis Investigative Site

London, , United Kingdom

Novartis Investigative Site

Manchester, , United Kingdom

Countries

United States; Canada; China; France; Germany; Hong Kong; Italy; Netherlands; Norway; Spain; Switzerland; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 38112724 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35272946 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2023-508530-34-00

Identifier Type: REGISTRY

Identifier Source: secondary_id

CBYL719F12201

Identifier Type: -

Identifier Source: org_study_id