Alpelisib for the treatment of lymphatic malformations associated with a PIK3CA mutation

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] - Hemic and Lymphatic Diseases [C15]

Trial duration

7 Feb 2024 → ongoing

Decision date (initial)

2024-03-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy, Dose response, Therapy

Stage 2: To demonstrate the efficacy of alpelisib as measured by the proportion of participants randomized to alpelisib with a radiological response at Week 24 (confirmatory phase) of Stage 2 as compared to those randomized to placebo in at least one of the following groups:
• Group 3 (participants ≥ 18 years of age)
• Group 4 (participants 6 - 17 years of age)

Secondary objectives 2

1. Stage 2: Key secondary objective: to demonstrate the efficacy of alpelisib in the improvement of patient-reported severity of symptoms as measured by the proportion of participants randomized to alpelisib with an improvement of patient-reported severity of symptoms (response) at Week 24 (confirmatory phase) of Stage 2 as compared to those randomized to placebo in at least one of the following groups: Group 3 (participants ≥18 years of age) Group 4 (participants 6 - 17 years of age)
2. To assess the efficacy of alpelisib as measured by the proportion of evaluable participants with a response at Week 24 of Stage 2 in pediatric participants 0-5 years of age.

Conditions and MedDRA coding

lymphatic malformations associated with PIK3CA mutation

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002016-PIP05-23

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 participant, parent, legal authorized representative or guardian.
2. Participant must be willing to remain at the clinical site as required by the protocol and to adhere to study restrictions and examination schedules.
3. Participant has a physician confirmed and documented diagnosis of a symptomatic LyM at the time of informed consent (Note: the physician must confirm that the LyM cannot be included under the PROS diagnostic criteria).
4. Participant is not considered as a candidate for or is not willing to receive non-drug therapies including but not limited to sclerotherapy, embolization, and surgery until the completion of Week 24 at the time of informed consent.
5. Participant has evidence of a somatic mutation(s) in the PIK3CA gene prior to randomization.
6. Participant has at least one measurable LyM lesion confirmed by BIRC assessment prior to randomization.
7. Participants must be able to ingest study drug in tablet or as an oral suspension (Groups 1 to 4) or granules or as an oral suspension (Group 5) as assessed within 7 days before study treatment start. Drug administration via feeding tubes is allowed.

Exclusion criteria 5

1. Participant has a physician-confirmed and documented diagnosis of PROS at the time of informed consent.
2. Participant has a physician-confirmed and documented diagnosis of a Central Conducting Lymphatic Anomaly, General Lymphatic Anomaly, Gorham-Stout disease, Kaposiform lymphangiomatosis at the time of informed consent.
3. Participant has a known history of Stevens-Johnson syndrome, erythema multiforme, or toxic epidermal necrolysis at the time of informed consent.
4. Participant has an established diagnosis of type I diabetes mellitus or uncontrolled type II diabetes mellitus at the time of informed consent.
5. Participant had previous treatment with alpelisib and/or any other PI3K inhibitors with treatment duration longer than 2 weeks at the time of informed consent.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Response (yes/no) at Week 24 (confirmatory phase) of Stage 2, defined by achieving at least 20% reduction in the sum of target lesion volumes (1 to 3 lesions), assessed by MRI by a blinded independent review committee (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.

Secondary endpoints 2

1. Response (yes/no) at Week 24 (confirmatory phase) of Stage 2 defined by achieving at least a 1-point improvement compared to baseline on the patient global impression of severity (PGI-S) scale.
2. Response at Week 24 of Stage 2, 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.

Investigational products

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

Test 5

Placebo 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel Town

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 · 37 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 291 files

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

Application history

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