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

ConditionsSlow-Flow Vascular MalformationFast-Flow Vascular MalformationVascular MalformationsVenous MalformationLymphatic Malformation, Low FlowLymphatic MalformationLymphangiomaArteriovenous MalformationsVenous Malformation, Low FlowCystic HygromaVascular AnomalyVascular AnomaliesPI3K Gene MutationMAP2K1 Gene MutationPIK3CA-related Overgrowth SpectrumArteriovenous Malformation (AVM)KRAS G12CKRAS G12D
Trial statusRecruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age2+
SponsorMurdoch Childrens Research Institute

About this trial

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).

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Adult or paediatric patient, 2 years of age or over

Patient has a clinical diagnosis of a slow-flow vascular malformation

Patient has received standard therapy for the vascular malformation or in which, in the opinion of the investigator, standard therapy is not appropriate

A documented genetic alteration in the PI3K signalling pathway identified by genetic sequencing prior to enrolment in this study

Disqualifiers

History of hypersensitivity to any drugs or metabolites of PI3K inhibitors or any of the excipients of alpelisib

Severe infection requiring intravenous antibiotics within 4 weeks prior to enrolment

Patient has had a major surgical procedure within 4 weeks prior to enrolment

Prior use of an alpha-specific PI3K inhibitor

Trial design

Design model

Parallel

Treatments tested in this trial

  • Alpelisib

    Drug

    Oral alpha-specific PI3-kinase inhibitor

  • Mirdametinib

    Drug

    An investigational oral MEK inhibitor

Treatment groups

50 Participants
are divided into 2 treatment groups
Group A: Module 1: Slow-flow vascular malformationsExperimental treatment 1 intervention
Group B: Module 2: Fast-flow vascular malformationsExperimental treatment 1 intervention

Trial outcomes

Primary outcomes

1

The number of participants who achieve or exceed a predetermined threshold of improvement in their most significant symptom at 48 weeks based on the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM).

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).

Time frame
At 48 weeks

Secondary outcomes

1

The number of participants who achieve or exceed a predetermined threshold of improvement in their most significant symptom at the 168-day timepoint based on the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM).

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

Time frame
48 weeks, 168-day follow-up
2

The number of participants with an objective response (defined as ≥ 20% reduction from index date in the sum of measurable target lesion volume) by volumetric analysis on MRI.

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.

Time frame
Baseline, 48 weeks
3

Change in symptoms score as recorded on the OVAMA (Outcome measures for VAscular MAlformations) questionnaire.

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.

Time frame
Time frame: Baseline, 48 weeks
4

Change in symptoms score as recorded on the OVAMA (Outcome measures for VAscular MAlformations) which is a set of questions developed specifically to measure symptom burden from vascular malformations.

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

Time frame
Time frame: 48 weeks, Day 168 follow-up

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Murdoch Childrens Research Institute

Lead sponsor

Peter MacCallum Cancer Centre, Australia

Collaborator

Royal Children's Hospital

Collaborator

Source ClinicalTrials.gov
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