• 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

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

• Patient has a clinical diagnosis of a fast-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 mirdametinib

• A documented genetic alteration in the RAS-MEK-ERK 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

• 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

• 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.

• 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.

⁃ 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