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Slow-flow vascular malformations with identified causative variants in the phosphoinositide 3-kinase (PI3K) signalling pathway will receive alpelisib (provided by Novartis Pharmaceuticals), an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up.

Fast-flow vascular malformations with identified causative variants in the RAS-MEK-ERK signalling pathway will receive mirdametinib (provided by SpringWorks Therapeutics, Inc.), an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy, followed by 24 weeks of follow-up.

Alpelisib

Mirdametinib

Michelle de Silva, PhD

Tony Penington, MBBS, FRACS

Stephen Luen, MBChB, FRACP

Anthony Penington, MBBS, FRACS, MD(res), Grad Dip

Michelle de Silva, BSc(Hons), PhD, MGenCouns

Tony Penington, MBBS, FRACS.

Stephen Luen, MBChB, FRACP.

Lydia Pathmanathan, MBBS, FRACP.

Recent studies have demonstrated that growth of vascular malformations can be driven by genetic variants in one of 2 signalling pathways. Targeted drugs specific to these pathways have been developed and shown to be effective in treating cancer. This study will describe the effectiveness of (i) 48 weeks of alpelisib therapy for participants with slow-flow vascular malformations and a gene mutation in one of these signalling pathways (module 1) and (ii) 48 weeks of mirdametinib therapy for participants with fast-flow vascular malformations and a gene mutations in the other signalling pathway (module 2).

TARGET-VM is a modular open-label, signal seeking, phase II trial of targeted therapies for patients with vascular malformations. Patients with vascular malformations which are refractory to standard therapies, or in whom standard therapy is not appropriate, are potentially eligible for the clinical trial. Vascular malformations will be classified as slow-flow or fast-flow lesions using established clinical criteria. Genetic testing to identify causative variants in genes affecting the phosphoinositide 3-kinase (PI3K) signalling pathway for slow-flow vascular malformations or the Mitogen-Activated Protein Kinase (MAPK) signalling pathway for fast-flow vascular malformations must be performed using research protocols or commercial testing assays that are external to this clinical trial.

The study consists of individual modules, each evaluating the clinical efficacy of 48 weeks of targeted therapy. The treatment modules are:

1. Module 1 - Treatment for slow-flow vascular malformations Eligible patients with slow-flow vascular malformations with an identified causative variant in the PI3K signalling pathway will receive alpelisib, an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period).
2. Module 2 - Treatment for fast-flow vascular malformations Eligible patients with fast-flow vascular malformations with an identified causative variant in the MAPK signalling pathway will receive mirdametinib, an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period).

TARGET-VM will be conducted only in Victoria, Australia.

i) Participants with slow-flow vascular malformations with an eligible gene mutation will receive 48 weeks of treatment with open-label alpelisib.

ii) Participants with fast-flow vascular malformations with an eligible gene mutation will receive 48 weeks of treatment with open-label mirdametinib

A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations

A Modular Open Label, Signal Seeking, Phase II Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations (TARGET-VM)

From 6 months post analysis and article publication, the following will be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept The Murdoch Children's Research Institute's (MCRI) conditions for access:

* Individual participant data that underlie the results reported in this article after de-identification
* Trial protocol, Statistical Analysis Plan, PICF The Sponsor-Investigator will be the long-term custodian after the archive period has finished.

Vascular malformations present with a range of different symptoms. Therefore, there is no single outcome measure that can capture the effectiveness of a systemic treatment across different patients. Thus for this study, an individualised primary outcome for each patient informed by their symptoms will be used, termed the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM). The study "Outcome Committee" will define an individualised primary outcome for each patient informed by their symptoms and vascular malformation features prior to starting trial treatments. The VM-PSOM endpoint will therefore define a binary outcome for each patients (achieved or failed to reach the threshold improvement in the chosen measure).

VM-PSOM response at the 168 day follow-up visit assessment compared with the 48 week (end-of-treatment) VM-PSOM.

Objective response rate by volumetric MRI assessment comparing 48 week (end-of-treatment) MRI with baseline MRI. MRI scan will only be performed in patients where their vascular malformation is feasibly evaluable by MRI scan. Objective response is defined as ≥ 20% reduction from index date in the sum of measurable target lesion volume by volumetric analysis on MRI.

The mean scores in the OVAMA (Outcome measures for VAscular MAlformations) questionnaire will be calculated and analysed at specified time points. This is a set of questions developed specifically to measure symptom burden from vascular malformations. These questions are open-ended to allow the subject to describe how they feel. The questions are more tightly structured to allow comparison of answers to other people with vascular malformations. The questions have been designed in a way to determine if symptoms are getting better over time.

The mean scores in the OVAMA (Outcome measures for VAscular MAlformations) questionnaire will be calculated and analysed at specified time points.

Peter MacCallum Cancer Centre, Australia

Royal Children's Hospital

Murdoch Childrens Research Institute

As a single agent, alpelisib will be administered at a starting dose of 350 mg orally once daily on a continuous dosing schedule and can be adjusted for toxicity per the recommendations in this protocol. No pretreatment will be given prior to the medication.

Ian Rabinowitz, MD

This is a compassionate use protocol of BYL719 (alpelisib) treatment for a single patient with locally advanced lymphangioma positive PI3K alpha H1047R mutation.

As a single agent, alpelisib will be administered at a starting dose of 350 mg orally once daily on a continuous dosing schedule and can be adjusted for toxicity per the recommendations in this protocol. No pretreatment will be given prior to the medication.

We plan on treating this individual patient for a tentative period of 12 weeks at which time treating physician will reevaluate the patient's clinical and radiological response and further duration of treatment will be contingent on that assessment.

Compassionate Use of BYL 719 Alpelisib

INST UNM 1601: Compassionate Use of BYL 719 Alpelisib

New Mexico Cancer Care Alliance

Microcystic Lymphatic Malformation

Adult participants (≥18 years of age) who will receive dose 1 of alpelisib an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1)

Adult participants (≥18 years of age) who will receive dose 2 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1).

Pediatric participants 6-17 years of age who will receive dose 2 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1)

Pediatric participants 6-17 years of age who will receive dose 3 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier (Stage 1).

Adult participants (≥18 years of age) who will receive alpelisib at the dose selected for confirmatory phase in adult participants (Stage 2)

Adult participants (≥18 years of age) who will receive matching placebo

Pediatric participants (6-17 years of age) who will receive alpelisib at the dose selected for confirmatory phase in pediatric participants (Stage 2)

Pediatric participants (6-17 years of age) who will receive matching placebo

Pediatric participants of 2-5 years who will dose 3 of alpelisib in an open-label fashion for at least 24 weeks unless they discontinue earlier

In Stage 1: adult participants (≥18 years of age) will receive dose 1 or dose 2 of alpelisib; pediatric participants (6-17 years of age) will recieve dose 2 or dose 3 of alpelisib.

In Stage 2: Adult participants will receive alpelisib at the dose selected for confirmatory phase in adult participants; pediatric participants (6-17 years of age) will will receive alpelisib at the dose selected for confirmatory phase in pediatric participants; and pediatric participants of 2-5 years of age will receive dose 3 of alpelisib

In Stage 2, participants will receive matching placebo for 24 weeks of the study

Placebo

Novartis Pharmaceuticals

Joyce Teng

Katie Schultz

Bryan Sisk

The main purpose of this study in participants with PIK3CA-mutated lymphatic malformations (LyM) is to assess the change in radiological response and symptom severity upon treatment with alpelisib as compared to placebo.

This is a phase II/III multi-center study with two stages:

* Stage 1 is designed to select the dose(s) for the confirmatory phase (DSCP) for alpelisib in Stage 2 and will comprise a 24-week open-label core phase in adult (≥18 years of age) and pediatric participants (6-17 years of age) with PIK3CA-mutated LyM, followed by an extension. After eligibility has been confirmed at screening, participants will be randomized to the different alpelisib doses according to their age. Depending on the results at the end of Stage 1 core phase, the Stage 2 will be opened to adult and/or pediatric participants or the study may be stopped.
* Stage 2 is designed to confirm the efficacy and assess safety of alpelisib at the DSCP in participants with PIK3CA-mutated LyM and will comprise a 24-week randomized, double blind, placebo-controlled confirmatory phase in adult (≥18 years of age) and pediatric participants 6-17 years of age followed by an open-label extension. After eligibility has been confirmed at screening participants will be randomized to alpelisib or placebo.

Additionally, in parallel, Stage 2 will include a 24-week open-label core phase in pediatric participants 2-5 years of age followed by an extension, if pediatric participants will be enrolling in Stage 2.

Based on the results of the 24-week open-label core phase of Stage 1, the dose(s) for Stage 2 will be selected by Novartis in consultation with the Steering Committee (SC). During the 24-week randomized, double blind, placebo-controlled core phase of Stage 2, an Independent Data Monitoring Committee (DMC) will conduct periodic safety reviews.

Stage 1 is open label. For adult and pediatric participants 6-17 years of age, Stage 2 comprises a 24-week double-blind period followed by an open-label period. For pediatric participants 2-5 years of age, Stage 2 is open label.

Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.

A Two-stage Double-blind, Randomized, Placebo-controlled Study to Assess the Efficacy, Safety and Pharmacokinetics of Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.

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

Radiological response 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. The percentage of participants with a radiological response at Week 24 of Stage 2 in adult and pediatric (6-17 years of age) groups will be assessed

PGI-S is a single item measure to assess the overall severity of a patient's condition. This single item instrument uses a 5-point rating scale, which ranges from 1 (no symptoms) to 5 (very severe). Lower scores indicate better health status. The percentage of participants with at least a 1-point improvement compared to baseline at Week 24 of Stage 2 in adult and pediatric (6-17 years of age) groups will be assessed

Radiological response 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. The percentage of participants with a radiological response at Week 24 of Stage 2 in pediatric participants 2-5 years of age will be assessed

PGI-C is a single item measure to assess the change in overall symptoms severity since the start of study. This single item instrument uses a 7-point rating scale, which ranges from 1 (very much improved) to 7 (very much worse). Lower scores indicate better health status. The change from baseline in PGI-C score will be assessed in adult and pediatric (6-17 years of age) participants

The PROMIS-29 plus 2 Profile v2.1 (completed by adult participant) includes 29 items across domains of depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, ability to participant in social roles and activities, cognitive function abilities and pain intensity..

The PROMIS Pediatric-25 Profile v2.0 (completed by children over 8 years of age) and PROMIS Parent-Proxy-25 Profile v2.0 (completed by parents for children under 8 years of age) include 25 items across the domains of depressive symptoms, anxiety, physical function-mobility, pain interference, fatigue, and peer relationships and pain intensity All items (except the pain intensity item) use a 5-point Likert scale, which ranges from 1 (not at all) to 5 (very much). The pain internsity item is scored on a 0-10 numeric rating scale, where 0 represents "no pain" and 10 represents "worst imaginable pain".

The change from baseline in PROMIS domains will be assessed

The IGIC involves a single question that asks the investigator to rate the change in the patient's condition since the start of treatment or intervention, using a 7-point scale ranging from 1 (Very much improved) to 7 (Very much worse). The change from baseline in IGIC score will be assessed in adult and pediatric (6-17 years of age) participants

The EQ-5D-5L (completed by adult participants) includes 5 items addressing dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 response options, ranging from 1=no problems to 5=extreme problems The EQ-5D-Y (completed by children over 8 years of age) and EQ-5D-Y Proxy version (completed by parent for participants under 8 years of age or unable to record for themselves) includes 5 items addressing dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 3 response options, ranging from 1= no problems to 3= a lot of problems

DOR is defined as the time from first documented response until progression of LyM lesions by BIRC or death. This analysis only applies to participants who are on treatment with alpelisib (Stage 1 and 2) and who achieve response.

Radiological response 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.

The percentage of participants (adult and pediatric 6-17 years of age) with radiological response at Week 24 of Stage 1 will be assessed.

Radiological response defined by achieving at least 20% reduction in the sum of target lesion volumes (1 to 3 lesions), assessed by MRI by a BIRC, 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.

The percentage of participants who receive alpelisib (Stage 1 and 2) with radiological response will be assessed.

Alpelisib plasma concentrations in adult and pediatric participants (Stage 1 and 2).

Percentage of participants with of LyM-related symptoms, complications, and comorbidities on treatment with alpelisib in adult and pediatric participants at Week 24 (Stage 1 and 2)

Percentage of participants with of LyM-related symptoms, complications, and comorbidities on treatment with alpelisib in adult and pediatric participants (Stage 1 and 2)

Change from baseline in the sum of target lesion volumes, the sum of MRI-measurable non-target lesion (if applicable) volumes, and the sum of all MRI-measurable lesion (target and non-target) volumes as assessed by BIRC at Week 24 in adult and pediatric participants (Stage 1 and 2)

Change from baseline in the sum of target lesion volumes, the sum of MRI-measurable non-target lesion (if applicable) volumes, and the sum of all MRI-measurable lesion (target and non-target) volumes as assessed by BIRC in adult and pediatric participants (Stage 1 and 2)

Percentage of participants with changes in non-target lesions as assessed by BIRC at Week 24 in adult and pediatric participants (Stage 1 and 2)

Percentage of participants with changes in non-target lesions as assessed by BIRC in adult and pediatric participants (Stage 1 and 2)

The percentage of participants with new lesions as assessed by BIRC at Week 24 in adult and pediatric participants (Stage 1 and 2)

The percentage of participants with new lesions as assessed by BIRC in adult and pediatric participants (Stage 1 and 2)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations	NCT05983159	Slow-Flow Vascu... Fast-Flow Vascu... Vascular Malfor... Venous Malforma... Lymphatic Malfo... Lymphatic Malfo... Lymphangioma Arteriovenous M... Venous Malforma... Cystic Hygroma Vascular Anomal... Vascular Anomal... PI3K Gene Mutat... MAP2K1 Gene Mut... PIK3CA-related ... Arteriovenous M... KRAS G12C KRAS G12D	Alpelisib Mirdametinib	2 Years -	Murdoch Childrens Research Institute
Compassionate Use of BYL 719 Alpelisib	NCT03941782	Lymphangioma	Alpelisib	18 Years -	New Mexico Cancer Care Alliance
A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations	NCT05983159	Slow-Flow Vascu... Fast-Flow Vascu... Vascular Malfor... Venous Malforma... Lymphatic Malfo... Lymphatic Malfo... Lymphangioma Arteriovenous M... Venous Malforma... Cystic Hygroma Vascular Anomal... Vascular Anomal... PI3K Gene Mutat... MAP2K1 Gene Mut... PIK3CA-related ... Arteriovenous M... KRAS G12C KRAS G12D	Alpelisib Mirdametinib	2 Years -	Murdoch Childrens Research Institute
Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.	NCT05948943	Lymphatic Malfo...	Alpelisib Placebo	2 Years -	Novartis
Alpelisib in Pediatric and Adult Patients With Lymphatic Malformations Associated With a PIK3CA Mutation.	NCT05948943	Lymphatic Malfo...	Alpelisib Placebo	2 Years -	Novartis

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