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

PHASE2NOT_YET_RECRUITING

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).

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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.

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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 - Note: standard therapy may include treatment with sirolimus. A minimum of 14 days since the last dose of sirolimus is required prior to starting treatment with alpelisib

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: * Haematology: Haemoglobin ≥ 9.0 g/dL; Absolute neutrophil count ≥ 1.5 x 109/L; Platelets ≥ 90 x 109/L, except where bleeding leading to low haemoglobin level is an indication for treatment, in which case haemoglobin < 9.0 g/dL is acceptable. * Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AT) ≤ 3 x ULN; Total bilirubin < 2x ULN except for participants with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN * Renal function: Serum creatinine < 1.5 x ULN * Biochemistry: Calcium (corrected for serum albumin) and magnesium within normal limits or ≤ Grade 1 according to NCI-CTCAE v5.0 if judged clinically not significant by the investigator; Potassium within normal limits, or corrected with supplements * Fasting blood glucose ≤ 7.0 mmol/L and Glycosylated Haemoglobin (HbA1c) ≤ 6.4% (both criteria must be met)

Patient agrees to abstinence or highly effective contraceptive measures for males and women of childbearing potential (WOCBP) * Males who are sexually active must use a condom during intercourse while taking alpelisib and for at least 4 weeks after stopping alpelisib and should not father a child in this period. A condom is required to be used also by vasectomised men in order to prevent delivery of the drug via seminal fluid. In addition, male participants must not donate sperm during the study and for at least 4 weeks after stopping alpelisib * Females who are of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use a highly effective method of contraception during study treatment and for at least 1 week after the last dose of any study treatment. Highly effective contraceptive methods include: * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject) Periodic abstinence (eg., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; * Female sterilisation (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the women has been confirmed by follow up hormone level assessment; * Male partner sterilisation (at least 6 months prior to screening) of the sole partner of a female participant on the study; * Use of oral (estrogen and progesterone), injected or implanted combined hormonal method of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormonal vaginal ring or transdermal hormone contraception. In the case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment. * Women are considered postmenopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhoea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least 6 weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered to be not of child bearing potential.

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% (an assessment of LVEF is not mandatory in screening) * History of clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade Atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II and third degree AV block without pacemaker in place); * Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening; * Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or corrected QT interval > 470 msec at screening (using Fridericia correction); * Bradycardia (heart rate < 50 beats per minute at rest), by electrocardiogram (ECG) or pulse

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

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Eligibility

Age eligible for study : 2 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-10-01

Primary completion: 2026-08-01

Study completion finish: 2026-12-01

Study type

TREATMENT

Phase

PHASE2

Trial 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

Image related to Slow-Flow Vascular Malformation

Condition: Slow-Flow Vascular Malformation, Fast-Flow Vascular Malformation and more
DRUG: Alpelisib and other drugs
Parkville, Victoria, Australia and more
Sponsor: Murdoch Childrens Research Institute

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Find a site

Closest Location:

The Royal Children's Hospital

Research sites nearby

Select from list below to view details:

The Royal Children's Hospital
Parkville, Victoria, Australia
Peter MacCallum Cancer Centre
Parkville, Victoria, Australia

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 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.	DRUG: Alpelisib Oral alpha-specific PI3-kinase inhibitor
EXPERIMENTAL: Module 2: Fast-flow vascular malformations 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.	DRUG: Mirdametinib An investigational oral MEK inhibitor

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome 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

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome 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

Frequently Asked Questions

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References

Clinical Trials Gov: A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations