A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations
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).
Study details:
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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- 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
- Adequate performance status (Eastern Cooperative Oncology Group Performance Status Scale (ECOG) 0-2 in patients ≥ 16 years of age; Lansky > 50 in patients < 16 years of age)
- Patient has a life expectancy ≥ 12 weeks
- Patient is able to swallow and retain oral medication
- Adequate haematologic and end-organ function
- Patient agrees to abstinence or highly effective contraceptive measures for males and women of childbearing potential (WOCBP)
- Patient has signed informed consent and is willing and able to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations
Exclusion criteria
- 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
- History of pneumonitis or interstitial lung disease
- Patient is pregnant or lactating at the time of study registration. A pregnancy test is mandated for women of child-bearing potential in the screening period
- Established diagnosis of type I diabetes mellitus, type II diabetes mellitus requiring anti-hyperglycaemic medication or any participant with HbA1c > 6.4%
- Patient who is currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes
- Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of treatment: Strong inducers of CYP3A4, Strong inhibitors of CYP3A4, Inhibitors of BCRP
- History of acute pancreatitis within 1 year of screening or past history of chronic pancreatitis
- Patient with Child Pugh score B or C
- Unresolved osteonecrosis of the jaw
- Impairment of GI function or GI disease that may significantly alter the absorption of the study drug based on investigator discretion
- Known history of Human Immunodeficiency Virus (HIV) infection (testing for HIV is not mandatory in screening)
- Known history of severe cutaneous reactions like Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Erythema Multiforme (EM), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
- Known history of clinically significant, uncontrolled heart disease and/or recent cardiac events including: History of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 6 months prior to the start of study treatment; History of documented congestive heart failure (New York Heart Association functional classification III-IV); History of impaired Left Ventricular Ejection Fraction (LVEF) < 50%; History of clinically significant cardiac arrhythmias; Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg; Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or corrected QT interval > 470 msec at screening; Bradycardia (heart rate < 50 beats per minute at rest)
- Patient has other concurrent severe and/or uncontrolled medical conditions that would, in the Treating Physician's judgement, contraindicate administration of alpelisib (eg. active or uncontrolled severe infection, chronic active hepatitis, immune-compromised, acute or chronic pancreatitis, uncontrolled high blood pressure)
- Patient is unable to understand and comply with treatment instructions and requirements
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE2
Study ID
NCT05983159
Intervention or treatment
DRUG: Alpelisib
DRUG: Mirdametinib
Conditions
- Slow-Flow Vascular Malformation
- Fast-Flow Vascular Malformation
- Vascular Malformations
- Venous Malformation
- Lymphatic Malformation, Low Flow
- Lymphatic Malformation
- Lymphangioma
- Arteriovenous Malformations
- Venous Malformation, Low Flow
- Cystic Hygroma
- Vascular Anomaly
- Vascular Anomalies
- PI3K Gene Mutation
- MAP2K1 Gene Mutation
- PIK3CA-related Overgrowth Spectrum
- Arteriovenous Malformation (AVM)
- KRAS G12C
- KRAS G12D
You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.
Research sites nearby
Closest Location:
Peter MacCallum Cancer Centre
Select from list below to view details:
Peter MacCallum Cancer Centre
Parkville, Victoria, Australia
The Royal Children's Hospital
Parkville, Victoria, Australia
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Who is running the clinical trial?
Murdoch Childrens Research Institute
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: Module 1: Slow-flow vascular malformations
| Drug: Alpelisib |
EXPERIMENTAL: Module 2: Fast-flow vascular malformations
| Drug: Mirdametinib |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| 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). | At 48 weeks |
Secondary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 48 weeks, 168-day follow-up |
| 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. | Baseline, 48 weeks |
| 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: Baseline, 48 weeks |
| 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: 48 weeks, Day 168 follow-up |
| The number of patients who experience adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5. | Not Specified | From Baseline to Day 168 follow-up |
References
Clinical Trials Gov: A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular MalformationsOther trials to consider
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