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About
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).
Full description
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:
TARGET-VM will be conducted only in Victoria, Australia.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
MODULE 1
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)
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:
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:
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:
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
MODULE 2
Inclusion Criteria:
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
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:
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:
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
Exclusion Criteria:
History of hypersensitivity to any drugs or metabolites of MEK inhibitors or any of the excipients of mirdametinib
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 a MEK inhibitor
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;
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
Impairment of GI function or GI disease that may significantly alter the absorption of the study drug based on investigator discretion
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)
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;
Breast cancer within the past 5 years;
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)
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
Known history of glaucoma
Known history of clinically significant, uncontrolled heart disease and/or recent (within 6 months [24 weeks] of signing informed consent/assent) cardiac events including:
Patient has recorded a left ventricular ejection fraction (LVEF) < 55% at Screening
Patient has experienced a cerebrovascular accident, transient ischaemic attach, or symptomatic pulmonary embolism within 6 months (24 weeks) of signing informed consent/assent.
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)
Patient is unable to understand and comply with treatment instructions and requirements
Primary purpose
Allocation
Interventional model
Masking
50 participants in 2 patient groups
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Central trial contact
Tony Penington, MBBS, FRACS; Michelle de Silva, PhD
Data sourced from clinicaltrials.gov
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