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.

MODULE 1

Inclusion Criteria:

1. Adult or paediatric patient, 2 years of age or over

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

3. 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

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

5. 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)

6. Patient has a life expectancy ≥ 12 weeks

7. Patient is able to swallow and retain oral medication

8. 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)

9. 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.

10. 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:

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

2. Severe infection requiring intravenous antibiotics within 4 weeks prior to enrolment

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

4. Prior use of an alpha-specific PI3K inhibitor

5. History of pneumonitis or interstitial lung disease

6. 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

7. Established diagnosis of type I diabetes mellitus, type II diabetes mellitus requiring anti-hyperglycaemic medication or any participant with HbA1c > 6.4%

8. Patient who is currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes

9. 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

10. History of acute pancreatitis within 1 year of screening or past history of chronic pancreatitis

11. Patient with Child Pugh score B or C

12. Unresolved osteonecrosis of the jaw

13. Impairment of GI function or GI disease that may significantly alter the absorption of the study drug based on investigator discretion

14. Known history of Human Immunodeficiency Virus (HIV) infection (testing for HIV is not mandatory in screening)

15. 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)

16. 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

17. 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)

18. Patient is unable to understand and comply with treatment instructions and requirements

MODULE 2

Inclusion Criteria:

1. Adult or paediatric patient, 2 years of age or over where Body Surface Area (BSA) is greater than or equal to 0.4m2.

2. Patient has a clinical diagnosis of a fast-flow vascular malformation

3. 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 mirdametinib

4. A documented genetic alteration in the RAS-MEK-ERK signalling pathway identified by genetic sequencing prior to enrolment in this study

5. 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)

6. Patient has a life expectancy ≥ 12 weeks

7. Participant has the ability to swallow capsules whole if the capsule dosage form is being utilized. This criterion does not apply if participant is utilizing the dispersible tablet form of study treatment

8. 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) ≤ 2 x upper limit of normal (ULN); Total bilirubin < 1.5x ULN (isolated bilirubin > 1.5x ULN is acceptable if bilirubin is fractioned and direct bilirubin < 35%), except where impaired hepatic function is a consequence of the fast-flow malformation and hence is an indication for treatment, in which case impaired hepatic function is acceptable.
   • 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; Phosphate ≤ 1x ULN.

9. Patient agrees to abstinence or highly effective contraceptive measures if of childbearing potential (WOCBP)

   • Males who are sexually active must use a condom during intercourse while taking mirdametinib and for at least 90 days after stopping mirdametinib 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 90 days after stopping mirdametinib

   • Females who are of child-bearing potential, defined as all individuals physiologically capable of becoming pregnant, must use a highly effective method of contraception during study treatment and for at least 180 days 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 childbearing 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 childbearing potential.

10. 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:

1. History of hypersensitivity to any drugs or metabolites of MEK inhibitors or any of the excipients of mirdametinib

2. Severe infection requiring intravenous antibiotics within 4 weeks prior to enrolment

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

4. Prior use of a MEK inhibitor

5. Patient has abnormal QT interval corrected by Fridericia's formula (> 450 msec for male participants, > 470 msec for female participants, or > 480 msec for participants with bundle branch block) (triplicate ECG readings taken approximately 2 to 3 minutes apart and averaged) at Screening;

6. Patient is pregnant or lactating at the time of study registration. A pregnancy test is mandated for persons of child-bearing potential in the screening period

7. Impairment of GI function or GI disease that may significantly alter the absorption of the study drug based on investigator discretion

8. Any clinically significant active or known history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)

9. Lymphoma, leukaemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years;

10. Breast cancer within the past 5 years;

11. Known history of Human Immunodeficiency Virus (HIV) infection (testing for HIV is not mandatory in screening)

12. 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)

13. Patient has a history of, or evidence of, retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration. Patients will be excluded from study participation if they have any of the following risk factors for RVO at Screening:

    • Intraocular pressure > 21 mmHg;

    • Serum cholesterol > 7.8 mmol/L;

    • Serum triglycerides > 3.4 mmol/L;

    • Hyperglycaemia (fasting blood glucose > 7.0 mol/L );

    • Age specific hypertension

      • Patients ≥ 13 years of age with a blood pressure ≥ 140/90 mmHg
      • Patients ≤ 12 years of age with a blood pressure ≥ 95th percentile for age + 12 mmHg

14. Known history of glaucoma

15. Known history of clinically significant, uncontrolled heart disease and/or recent (within 6 months [24 weeks] of signing informed consent/assent) 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 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) ≥ 140 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 90 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

16. Patient has recorded a left ventricular ejection fraction (LVEF) < 55% at Screening

17. Patient has experienced a cerebrovascular accident, transient ischaemic attach, or symptomatic pulmonary embolism within 6 months (24 weeks) of signing informed consent/assent.

18. Patient has other concurrent severe and/or uncontrolled medical conditions that would, in the Treating Physician's judgement, contraindicate administration of mirdametinib (eg. active or uncontrolled severe infection, chronic active hepatitis, immune-compromised, acute or chronic pancreatitis, uncontrolled high blood pressure)

19. Patient is unable to understand and comply with treatment instructions and requirements

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.

Available from 6 months following analysis and article publication

Future researchers must be from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept MCRI's conditions for access