EPIK-P4: A Phase II single-arm study to assess the efficacy, safety and pharmacokinetics of alpelisib (BYL719) in pediatric and adult patients with PIK3CA-related overgrowth spectrum (PROS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

11 Dec 2025 → ongoing

Decision date (initial)

2025-10-20

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2024-519960-42-00

WHO UTN

U1111-1323-0544

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

To demonstrate the efficacy of alpelisib in at least one of the following groups:
• Group 1 (≥18 yr-old).
• Group 2 (2 to <18 yr-old).

Secondary objectives 10

1. To assess changes from baseline in target and nontarget lesions over time as well as the appearance of new lesions over time.
2. To assess the efficacy of alpelisib at the scheduled protocol timepoints for disease evaluation.
3. To assess the duration of response.
4. To assess the PK of alpelisib in adult and pediatric participants with PROS.
5. To assess changes in participant-reported pain, health-related quality of life and overall impression of symptoms over time.
6. To assess the time to treatment failure in participants who are on treatment with alpelisib.
7. To assess the rate of overall clinical response as assessed by Investigator at the scheduled protocol visits for disease evaluation.
8. To assess changes in symptoms and complications/comorbidities associated with PROS over time.
9. To assess the frequency of healthcare visits/hospitalizations due to PROS as well as rescue surgeries for PROS over time.
10. To assess the overall safety and tolerability of alpelisib over time.

Conditions and MedDRA coding

PIK3CA-Related Overgrowth Spectrum (PROS)

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Male or female participants aged ≥2 years at the time of informed consent/assent.
2. Participants with diagnosis of PROS (according to Clinical Diagnostic Criteria for PROS proposed by Keppler-Noreuil et al 2014) with symptomatic AND progressive overgrowth, who have syndromic disease or isolated features (with the exception of isolated macrodactyly, macrocephaly or epidermal nevus) at the time of informed consent/assent.
3. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories using a DNA-based test AND available archival tissue (if archival tissue sample is not available, a fresh biopsy should be performed, if it is not clinically contraindicated) at the time of informed consent/assent.
4. Karnofsky (in participants >16 years of age at study entry) or Lansky (≤16 years of age at study entry) performance status index ≥50.
5. PGI-S score of mild, moderate, severe, or very severe at screening
6. Adequate bone marrow and organ function.
7. Presence of at least 1 PROS-related measurable lesion (longest diameter ≥2 cm) confirmed by BIRC assessment and associated with complaints, clinical symptoms or functional limitations affecting the participant's everyday life.

Exclusion criteria 7

1. Participant with only isolated macrodactyly, epidermal nevus/nevi and macroencephaly (the only clinical feature or a combination of any of three of them), in absence of other PROS-related lesions at the time of informed consent/assent
2. Previous treatment with alpelisib and/or any other phosphatidylinositol 3-kinase (PI3K) inhibitor(s) (except treatment attempt, defined as the attempt to treat PROS with any of PI3K inhibitors, with treatment duration less than 2 weeks and stopped at least 4 weeks prior to the first dose of study medication with alpelisib).
3. Debulking or other major surgery performed within 3 months at the time of informed consent/assent.
4. Radiation exposure for PROS treatment purpose within 12 months prior to informed consent/assent.
5. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE v4.03) within 30 days before informed consent/assent, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent/assent.
6. Clinically meaningful bleeding from PROS-related lesion (Grade 2 and more as per CTCAE v4.03) within 30 days before study treatment initiation.
7. Participants with clinically significant worsening of PROS-related laboratory abnormalities, physical signs and symptoms (such as, but not limited to increase of D-dimers, worsening of underlying pain, newly occurring swelling or redness) indicating an uncontrolled condition during the screening phase.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of participants achieving confirmed objective response at any time, defined as achieving radiological response confirmed by a subsequent assessment performed at least after 4 weeks.

Secondary endpoints 10

1. Changes from baseline in PROS lesion volumes(as assessed by BIRC) in the: • Sum of target lesion volume. • Sum of MRI-measurable non-target lesion volume. • Sum of all MRI-measurable (target and nontarget)lesion volume. Change from baseline in other non-target lesions(by BIRC). Appearance of new lesions (by BIRC).
2. Proportion of participants with a radiological response at scheduled protocol timepoints
3. Duration of response defined as the time from the first documented confirmed objective response until progression of any PROS lesion (by BIRC) or death due to any cause or rescue surgery for any PROS lesion, whichever comes first
4. Alpelisib plasma concentration at selected time points.
5. Change in scores from Brief Pain Inventory (BPI) items, or Wong-Baker Faces Scale (age appropriate), and Patient Global Impression of Symptom Severity (PGI-S).
6. Time to treatment failure (TTF) is defined as the time from alpelisib treatment start date until disease progression confirmed by BIRC, death, rescue surgery for any PROS lesion or discontinuation of the study treatment due to any reason other than technical problems or study termination by the sponsor.
7. Overall clinical response as assessed by Investigator
8. Change from baseline in PROS-related symptoms and in complications/comorbidities among participants with symptoms and complications/comorbidities present at baseline.
9. Number/percentage of participants with healthcare visits/hospitalized due to PROS; number of hospitalizations. Number/percentage of participants with surgeries required to manage PROS; number of surgeries.
10. Incidence, type and severity of treatment-emergent adverse events per CTCAE v4.03 criteria and other safety data including changes in laboratory values, vital signs, assessments of cardiac function, growth, bone/dental development and sexual maturation (for applicable age).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 14

Locations

7 EU/EEA countries · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 134 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications