A research study to find out if the study treatment alpelisib (BYL719) is safe and can help others who have confirmed diagnosis of 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

19 Apr 2021 → ongoing

Decision date (initial)

2024-08-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-508530-34-00

EudraCT number

2020-000561-16

ClinicalTrials.gov

NCT04589650

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Dose response, Efficacy, Pharmacokinetic

The primary objective of this study is to demonstrate the efficacy of alpelisib as measured by the proportion of participants randomized to alpelisib with a confirmed objective response by BIRC in at least one of the following groups:
• Group 1 (≥ 18 yr-old)
• Group 2 (6 - 17 yr-old)
The primary scientific question of interest is, for children/adolescents aged 6 to17 years (in Group 2) and adults (Group 1: ≥ 18 years) with PROS, to assess the benefit of alpelisib with regards to the proportion of confirmed responders by BIRC, considering participants that discontinue treatment prior to confirmation of response and participants that receive surgery as rescue therapy for any PROS lesions prior to confirmation of response as non-responders.

Secondary objectives 15

1. To demonstrate the efficacy of alpelisib vs placebo based on the comparison of the proportion of participants with response at Week 16 in Group 1 or Group 2
2. To assess the efficacy of alpelisib as measured by the proportion of participants with a response at Week 24 (by BIRC) in Groups 1 and 2
3. To assess safety and tolerability of alpelisib as compared to placebo in Groups 1 and 2 up to Week 16
4. To assess the overall safety and tolerability of alpelisib in participants with PROS over time
5. To assess changes in patient-reported pain intensity and overall severity of symptoms at Week 16 on treatment with alpelisib as compared to placebo in pediatric and adult populations
6. To assess changes in target and non-target lesions over time and appearance of new lesions on treatment from baseline over time
7. To assess the PK of alpelisib in adult and pediatric patients with PROS
8. To assess changes in patient-reported pain, health-related quality of life and overall impression of symptoms in pediatric and adult populations over time
9. To assess the duration of response in participants who receive alpelisib
10. To assess the time to treatment failure in participants who are on treatment with alpelisib
11. To assess the rate of overall clinical response as assessed by Investigator at the scheduled protocol visits for disease evaluation (e.g., Week 16, 24, 40, 48, 72, 96 and thereafter every 48 weeks and at Week 264 until the end of extension 2)
12. To assess the proportion of participants with a response at the scheduled protocol visits for disease evaluation during the extension periods.
13. To assess changes in symptoms and complications/comorbidities up to Week 16 on treatment with alpelisib as compared to placebo.
14. To assess changes in symptoms and complications/comorbidities associated with PROS over time
15. To assess the frequency of healthcare visits/hospitalizations due to PROS, rescue surgeries for PROS (incl. avoidance/delay in planned disease-related surgery) over time

Conditions and MedDRA coding

PIK3CA-Related Overgrowth Spectrum (PROS)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Spanish Agency For Medicines And Health Products, National Agency For The Safety Of Medicine And Health Products, Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-002016-PIP03-19

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Signed informed consent and assent (when applicable) from the patient, parent, legal authorized representative or guardian must be obtained prior to any study related screening procedures are performed.
2. Patients with diagnosis of PROS with symptomatic and /or progressive overgrowth and at least one measurable PROS-related lesion confirmed by BIRC assessment.
3. Documented evidence of a somatic mutation(s) in the PIK3CA gene performed in local laboratories.
4. A tissue sample (fresh or archival) is to be sent to a Novartis-designated central Laboratory. If archival tissue is not available, collection of a fresh tissue biopsy is required for participants in Groups 1, 2 and 5, if it is not clinically contraindicated. For participants in Groups 3 and 4, a fresh tissue biopsy is not mandatory. For China only: Tissue sample collection and biomarker assessments are not applicable. For Germany only: If archival tissue is available, it must be sent to a Novartis-designated central laboratory. If no archival tissue is available, obtaining a fresh tissue biopsy is recommended, if it is not clinically contraindicated, but is not mandatory.
5. Karnofsky (in patients > 16 years old at study entry)/Lansky (≤16 yrs of age at study entry) performance status index ≥50.
6. Adequate bone marrow and organ function including Fasting plasma glucose (FPG) ≤ 140 mg/dL (7.7 mmol/L) and Glycosylated hemoglobin (HbA1c) ≤ 6.5% (both criteria have to be met) (as assessed by central laboratory for eligibility).
7. Presence of at least one PROS-related measurable lesion defined as a lesion with longest diameter ≥2 cm, when the volume can be accurately and reproducibly measured by MRI (Magnetic resonance imaging), and associated with complaints, clinical symptoms or functional limitations affecting the patient's everyday life. Measurability must be confirmed by BIRC before randomization.

Exclusion criteria 10

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.
2. Previous treatment with alpelisib and/or any other 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. Radiation exposure for PROS treatment purpose within the previous 12 months on those PROS areas which are expected to qualify for target lesions (except lesion(s) progressing after completion of radiotherapy) at time of informed consent.
4. Debulking or other major surgery performed within 3 months at time of informed consent.
5. Clinically meaningful PROS-related thrombotic event (Grade 2 and more as per CTCAE v.4.03) within 30 days before informed consent, and/or sclerotherapy/embolization for vascular complications performed within 6 weeks before informed consent. Note: Participants receiving anticoagulants for PROS-related coagulopathy, primary or secondary prophylaxis of thrombosis may be included in the study.
6. Participants 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 is not related to PROS. Participants in Groups 3 and 4 with documented or suspicious pneumonitis or interstitial lung disease based on MRI images at time of informed consent.
7. History of acute pancreatitis within 1 year before informed consent or past medical history of chronic pancreatitis at time of informed consent.
8. Participants with an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at time of informed consent
9. Known history of seizure, or epilepsy, regardless of relatedness to PROS spectrum at time of informed consent, when epilepsy is not controlled and/or the patient may not be switched to non-enzyme inducing antiepileptic drug(s) at time of informed consent.
10. Participants with clinically significant worsening of PROS-related laboratory anomalies, 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, particularly if systemic treatment with any other inhibitor of the PI3K/AKT/mTOR pathway was stopped prior to the start of study treatment. This includes but is not limited to hypercoagulability state in participants not receiving prophylactic treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Response (yes/no) defined by achieving at least 20% reduction from baseline in the sum of target lesion volumes (1 to 3 lesions, assessed by MRI by a blinded independent review committee (BIRC)), provided that none of the individual target lesions has ≥ 20% increase from baseline and in absence of progression of non-target lesions and without new lesions.

Secondary endpoints 1

1. The key secondary objective is to demonstrate the efficacy of alpelisib based on the comparison of the proportion of participants achieving response at Week 16 with alpelisib versus placebo in Groups 1 or 2.

Investigational products

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

Test 5

Placebo 1

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 13

Locations

6 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 4 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

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

Documents 126 files

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

Application history

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