xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05983159</url>
    </required_header>
    <id_info>
      <org_study_id>85218</org_study_id>
      <nct_id>NCT05983159</nct_id>
    </id_info>
    <brief_title>A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations</brief_title>
    <acronym>TARGET-VM</acronym>
    <official_title>A Modular Open Label, Signal Seeking, Phase II Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations (TARGET-VM)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Murdoch Childrens Research Institute</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Peter MacCallum Cancer Centre, Australia</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Royal Children's Hospital</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Murdoch Childrens Research Institute</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>Yes</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        Recent studies have demonstrated that growth of vascular malformations can be driven by&#xD;
        genetic variants in one of 2 signalling pathways. Targeted drugs specific to these pathways&#xD;
        have been developed and shown to be effective in treating cancer. This study will describe&#xD;
        the effectiveness of (i) 12 months of alpelisib therapy for participants with slow-flow&#xD;
        vascular malformations and a gene mutation in one of these signalling pathways (module 1) and&#xD;
        (ii) 12 months of mirdametinib therapy for participants with fast-flow vascular malformations&#xD;
        and a gene mutations in the other signalling pathway (module 2).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        TARGET-VM is a modular open-label, signal seeking, phase II trial of targeted therapies for&#xD;
        patients with vascular malformations. Patients with vascular malformations which are&#xD;
        refractory to standard therapies, or in whom standard therapy is not appropriate, are&#xD;
        potentially eligible for the clinical trial. Vascular malformations will be classified as&#xD;
        slow-flow or fast-flow lesions using established clinical criteria. Genetic testing to&#xD;
        identify causative variants in genes affecting the phosphoinositide 3-kinase (PI3K)&#xD;
        signalling pathway for slow-flow vascular malformations or the Mitogen-Activated Protein&#xD;
        Kinase (MAPK) signalling pathway for fast-flow vascular malformations must be performed using&#xD;
        research protocols or commercial testing assays that are external to this clinical trial.&#xD;
  &#xD;
        The study consists of individual modules, each evaluating the clinical efficacy of 12 months&#xD;
        of targeted therapy. The treatment modules are:&#xD;
  &#xD;
          1. Module 1 - Treatment for slow-flow vascular malformations Eligible patients with&#xD;
             slow-flow vascular malformations with an identified causative variant in the PI3K&#xD;
             signalling pathway will receive alpelisib, an oral alpha-specific PI3-kinase inhibitor&#xD;
             for a total duration of 12 months as monotherapy (treatment period), followed by 6&#xD;
             months of follow-up (follow-up period).&#xD;
  &#xD;
          2. Module 2 - Treatment for fast-flow vascular malformations Eligible patients with&#xD;
             fast-flow vascular malformations with an identified causative variant in the MAPK&#xD;
             signalling pathway will receive mirdametinib, an investigational oral MEK inhibitor for&#xD;
             a total duration of 12 months as monotherapy (treatment period), followed by 6 months of&#xD;
             follow-up (follow-up period).&#xD;
  &#xD;
        TARGET-VM will be conducted only in Victoria, Australia.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 2023</start_date>
    <completion_date type="Anticipated">September 2028</completion_date>
    <primary_completion_date type="Anticipated">September 2026</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>i) Participants with slow-flow vascular malformations with an eligible gene mutation will receive 12 months of treatment with open-label alpelisib.&#xD;
  )ii Participants with fast-flow vascular malformations with an eligible gene mutation will receive 12 months of treatment with open-label mirdametinib</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>The number of participants who achieve or exceed a predetermined threshold of improvement in their most significant symptom at 12 months based on the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM).</measure>
      <time_frame>At 12 months</time_frame>
      <description>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 &quot;Outcome Committee&quot; 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).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>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).</measure>
      <time_frame>12 months, 168-day follow-up</time_frame>
      <description>VM-PSOM response at the 168 day follow-up visit assessment compared with the 12 month (end-of-treatment) VM-PSOM.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>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.</measure>
      <time_frame>Baseline, 12 months</time_frame>
      <description>Objective response rate by volumetric MRI assessment comparing 12 month (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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in symptoms score as recorded on the OVAMA (Outcome measures for VAscular MAlformations) questionnaire.</measure>
      <time_frame>Time frame: Baseline, 12 months</time_frame>
      <description>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.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>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.</measure>
      <time_frame>Time frame: 12 months, Day 168 follow-up</time_frame>
      <description>The mean scores in the OVAMA (Outcome measures for VAscular MAlformations) questionnaire will be calculated and analysed at specified time points.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>The number of patients who experience adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.</measure>
      <time_frame>From Baseline to Day 168 follow-up</time_frame>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">30</enrollment>
    <condition>Slow-Flow Vascular Malformation</condition>
    <condition>Fast-Flow Vascular Malformation</condition>
    <condition>Vascular Malformations</condition>
    <condition>Venous Malformation</condition>
    <condition>Lymphatic Malformation, Low Flow</condition>
    <condition>Lymphatic Malformation</condition>
    <condition>Lymphangioma</condition>
    <condition>Arteriovenous Malformations</condition>
    <condition>Venous Malformation, Low Flow</condition>
    <condition>Cystic Hygroma</condition>
    <condition>Vascular Anomaly</condition>
    <condition>Vascular Anomalies</condition>
    <condition>PI3K Gene Mutation</condition>
    <condition>MAP2K1 Gene Mutation</condition>
    <condition>PIK3CA-related Overgrowth Spectrum</condition>
    <condition>Arteriovenous Malformation (AVM)</condition>
    <condition>KRAS G12C</condition>
    <condition>KRAS G12D</condition>
    <arm_group>
      <arm_group_label>Module 1: Slow-flow vascular malformations</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>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 12 months as monotherapy, followed by 6 months of follow-up.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Module 2: Fast-flow vascular malformations</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>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 12 months as monotherapy, followed by 6 months of follow-up.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Alpelisib</intervention_name>
      <description>Oral alpha-specific PI3-kinase inhibitor</description>
      <arm_group_label>Module 1: Slow-flow vascular malformations</arm_group_label>
      <other_name>BYL719</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Mirdametinib</intervention_name>
      <description>An investigational oral MEK inhibitor</description>
      <arm_group_label>Module 2: Fast-flow vascular malformations</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Adult or paediatric patient, 2 years of age or over where Body Surface Area (BSA) is&#xD;
               greater than or equal to 0.4m2.&#xD;
  &#xD;
            2. Patient has a clinical diagnosis of a fast-flow vascular malformation&#xD;
  &#xD;
            3. Patient has received standard therapy for the vascular malformation or in which, in&#xD;
               the opinion of the investigator, standard therapy is not appropriate&#xD;
  &#xD;
               - Note: standard therapy may include treatment with sirolimus. A minimum of 14 days&#xD;
               since the last dose of sirolimus is required prior to starting treatment with&#xD;
               mirdametinib&#xD;
  &#xD;
            4. A documented genetic alteration in the RAS-MEK-ERK signalling pathway identified by&#xD;
               genetic sequencing prior to enrolment in this study&#xD;
  &#xD;
            5. Adequate performance status (Eastern Cooperative Oncology Group Performance Status&#xD;
               Scale (ECOG) 0-2 in patients ≥ 16 years of age; Lansky &gt; 50 in patients &lt; 16 years of&#xD;
               age)&#xD;
  &#xD;
            6. Patient has a life expectancy ≥ 12 weeks&#xD;
  &#xD;
            7. Participant has the ability to swallow capsules whole if the capsule dosage form is&#xD;
               being utilized. This criterion does not apply if participant is utilizing the&#xD;
               dispersible tablet form of study treatment&#xD;
  &#xD;
            8. Adequate haematologic and end-organ function:&#xD;
  &#xD;
                 -  Haematology: Haemoglobin ≥ 9.0 g/dL; Absolute neutrophil count ≥ 1.5 x 109/L;&#xD;
                    Platelets ≥ 90 x 109/L, except where bleeding leading to low haemoglobin level is&#xD;
                    an indication for treatment, in which case haemoglobin &lt; 9.0 g/dL is acceptable.&#xD;
  &#xD;
                 -  Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase&#xD;
                    (AT) ≤ 2 x upper limit of normal (ULN); Total bilirubin &lt; 1.5x ULN (isolated&#xD;
                    bilirubin &gt; 1.5x ULN is acceptable if bilirubin is fractioned and direct&#xD;
                    bilirubin &lt; 35%), except where impaired hepatic function is a consequence of the&#xD;
                    fast-flow malformation and hence is an indication for treatment, in which case&#xD;
                    impaired hepatic function is acceptable.&#xD;
  &#xD;
                 -  Renal function: Serum creatinine &lt; 1.5 x ULN&#xD;
  &#xD;
                 -  Biochemistry: Calcium (corrected for serum albumin) and magnesium within normal&#xD;
                    limits or ≤ Grade 1 according to NCI-CTCAE v5.0 if judged clinically not&#xD;
                    significant by the investigator; Potassium within normal limits or corrected with&#xD;
                    supplements; Phosphate ≤ 1x ULN.&#xD;
  &#xD;
            9. Patient agrees to abstinence or highly effective contraceptive measures if of&#xD;
               childbearing potential (WOCBP)&#xD;
  &#xD;
                 -  Males who are sexually active must use a condom during intercourse while taking&#xD;
                    mirdametinib and for at least 90 days after stopping mirdametinib and should not&#xD;
                    father a child in this period. A condom is required to be used also by&#xD;
                    vasectomised men in order to prevent delivery of the drug via seminal fluid. In&#xD;
                    addition, male participants must not donate sperm during the study and for at&#xD;
                    least 90 days after stopping mirdametinib&#xD;
  &#xD;
                 -  Females who are of child-bearing potential, defined as all individuals&#xD;
                    physiologically capable of becoming pregnant, must use a highly effective method&#xD;
                    of contraception during study treatment and for at least 180 days after the last&#xD;
                    dose of any study treatment. Highly effective contraceptive methods include:&#xD;
  &#xD;
                      -  Total abstinence (when this is in line with the preferred and usual&#xD;
                         lifestyle of the subject) Periodic abstinence (eg., calendar, ovulation,&#xD;
                         symptothermal, post-ovulation methods) and withdrawal are not acceptable&#xD;
                         methods of contraception;&#xD;
  &#xD;
                      -  Female sterilisation (have had surgical bilateral oophorectomy with or&#xD;
                         without hysterectomy), total hysterectomy or bilateral tubal ligation at&#xD;
                         least 6 weeks before taking study treatment. In case of oophorectomy alone,&#xD;
                         only when the reproductive status of the women has been confirmed by follow&#xD;
                         up hormone level assessment;&#xD;
  &#xD;
                      -  Male partner sterilisation (at least 6 months prior to screening) of the&#xD;
                         sole partner of a female participant on the study;&#xD;
  &#xD;
                      -  Use of oral (estrogen and progesterone), injected or implanted combined&#xD;
                         hormonal method of contraception or placement of an intrauterine device&#xD;
                         (IUD) or intrauterine system (IUS), or forms of hormonal contraception that&#xD;
                         have comparable efficacy (failure rate &lt; 1%), for example hormonal vaginal&#xD;
                         ring or transdermal hormone contraception. In the case of use of oral&#xD;
                         contraception, women should have been stable on the same pill for a minimum&#xD;
                         of 3 months before taking study treatment.&#xD;
  &#xD;
                 -  Women are considered postmenopausal and not of childbearing potential if they&#xD;
                    have had 12 months of natural (spontaneous) amenorrhoea with an appropriate&#xD;
                    clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have&#xD;
                    had surgical bilateral oophorectomy (with or without hysterectomy), total&#xD;
                    hysterectomy, or bilateral tubal ligation at least 6 weeks before taking study&#xD;
                    treatment. In the case of oophorectomy alone, only when the reproductive status&#xD;
                    of the woman has been confirmed by follow up hormone level assessment is she&#xD;
                    considered to be not of childbearing potential.&#xD;
  &#xD;
           10. Patient has signed informed consent and is willing and able to comply with the&#xD;
               protocol for the duration of the study, including undergoing treatment and scheduled&#xD;
               visits and examinations&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. History of hypersensitivity to any drugs or metabolites of MEK inhibitors or any of&#xD;
               the excipients of mirdametinib&#xD;
  &#xD;
            2. Severe infection requiring intravenous antibiotics within 4 weeks prior to enrolment&#xD;
  &#xD;
            3. Patient has had a major surgical procedure within 4 weeks prior to enrolment&#xD;
  &#xD;
            4. Prior use of a MEK inhibitor&#xD;
  &#xD;
            5. Patient has abnormal QT interval corrected by Fridericia's formula (&gt; 450 msec for&#xD;
               male participants, &gt; 470 msec for female participants, or &gt; 480 msec for participants&#xD;
               with bundle branch block) (triplicate ECG readings taken approximately 2 to 3 minutes&#xD;
               apart and averaged) at Screening;&#xD;
  &#xD;
            6. Patient is pregnant or lactating at the time of study registration. A pregnancy test&#xD;
               is mandated for persons of child-bearing potential in the screening period&#xD;
  &#xD;
            7. Impairment of GI function or GI disease that may significantly alter the absorption of&#xD;
               the study drug based on investigator discretion&#xD;
  &#xD;
            8. Any clinically significant active or known history of liver disease, or known hepatic&#xD;
               or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic&#xD;
               gallstones)&#xD;
  &#xD;
            9. Lymphoma, leukaemia, or any malignancy within the past 5 years except for basal cell&#xD;
               or squamous epithelial carcinomas of the skin that have been resected with no evidence&#xD;
               of metastatic disease for 3 years;&#xD;
  &#xD;
           10. Breast cancer within the past 5 years;&#xD;
  &#xD;
           11. Known history of Human Immunodeficiency Virus (HIV) infection (testing for HIV is not&#xD;
               mandatory in screening)&#xD;
  &#xD;
           12. Known history of severe cutaneous reactions like Stevens-Johnson Syndrome (SJS), Toxic&#xD;
               Epidermal Necrolysis (TEN), Erythema Multiforme (EM), or Drug Reaction with&#xD;
               Eosinophilia and Systemic Symptoms (DRESS)&#xD;
  &#xD;
           13. Patient has a history of, or evidence of, retinal pathology on ophthalmologic&#xD;
               examination that is considered a risk factor for central serous retinopathy, retinal&#xD;
               vein occlusion (RVO), or neovascular macular degeneration. Patients will be excluded&#xD;
               from study participation if they have any of the following risk factors for RVO at&#xD;
               Screening:&#xD;
  &#xD;
                 -  Intraocular pressure &gt; 21 mmHg;&#xD;
  &#xD;
                 -  Serum cholesterol &gt; 7.8 mmol/L;&#xD;
  &#xD;
                 -  Serum triglycerides &gt; 3.4 mmol/L;&#xD;
  &#xD;
                 -  Hyperglycaemia (fasting blood glucose &gt; 7.0 mol/L );&#xD;
  &#xD;
                 -  Age specific hypertension&#xD;
  &#xD;
                      -  Patients ≥ 13 years of age with a blood pressure ≥ 140/90 mmHg&#xD;
  &#xD;
                      -  Patients ≤ 12 years of age with a blood pressure ≥ 95th percentile for age +&#xD;
                         12 mmHg&#xD;
  &#xD;
           14. Known history of glaucoma&#xD;
  &#xD;
           15. Known history of clinically significant, uncontrolled heart disease and/or recent&#xD;
               (within 6 months [24 weeks] of signing informed consent/assent) cardiac events&#xD;
               including:&#xD;
  &#xD;
                 -  History of angina pectoris, coronary artery bypass graft (CABG), symptomatic&#xD;
                    pericarditis, or myocardial infarction within 6 months prior to the start of&#xD;
                    study treatment;&#xD;
  &#xD;
                 -  History of documented congestive heart failure (New York Heart Association&#xD;
                    functional classification III-IV);&#xD;
  &#xD;
                 -  History of clinically significant cardiac arrhythmias, (e.g., ventricular&#xD;
                    tachycardia), complete left bundle branch block, high grade Atrioventricular (AV)&#xD;
                    block (e.g. bifascicular block, Mobitz type II and third degree AV block without&#xD;
                    pacemaker in place);&#xD;
  &#xD;
                 -  Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 140 mmHg&#xD;
                    and/or Diastolic Blood Pressure (DBP) ≥ 90 mmHg, with or without&#xD;
                    anti-hypertensive medication. Initiation or adjustment of antihypertensive&#xD;
                    medication(s) is allowed prior to screening;&#xD;
  &#xD;
                 -  Long QT syndrome, family history of idiopathic sudden death or congenital long QT&#xD;
                    syndrome, or corrected QT interval &gt; 470 msec at screening (using Fridericia&#xD;
                    correction);&#xD;
  &#xD;
                 -  Bradycardia (heart rate &lt; 50 beats per minute at rest), by electrocardiogram&#xD;
                    (ECG) or pulse&#xD;
  &#xD;
           16. Patient has recorded a left ventricular ejection fraction (LVEF) &lt; 55% at Screening&#xD;
  &#xD;
           17. Patient has experienced a cerebrovascular accident, transient ischaemic attach, or&#xD;
               symptomatic pulmonary embolism within 6 months (24 weeks) of signing informed&#xD;
               consent/assent.&#xD;
  &#xD;
           18. Patient has other concurrent severe and/or uncontrolled medical conditions that would,&#xD;
               in the Treating Physician's judgement, contraindicate administration of mirdametinib&#xD;
               (eg. active or uncontrolled severe infection, chronic active hepatitis,&#xD;
               immune-compromised, acute or chronic pancreatitis, uncontrolled high blood pressure)&#xD;
  &#xD;
           19. Patient is unable to understand and comply with treatment instructions and&#xD;
               requirements&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>2 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Tony Penington, MBBS, FRACS.</last_name>
      <role>Principal Investigator</role>
      <affiliation>Study Principal Investigator</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Stephen Luen, MBChB, FRACP.</last_name>
      <role>Principal Investigator</role>
      <affiliation>Principal Investigator</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Lydia Pathmanathan, MBBS, FRACP.</last_name>
      <role>Principal Investigator</role>
      <affiliation>Principal Investigator</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Michelle De Silva</last_name>
      <phone>+61383416200</phone>
      <email>michelle.desilva@vcgs.org.au</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Tony Penington</last_name>
      <phone>+61383416200</phone>
      <email>tony.penington@rch.org.au</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Peter MacCallum Cancer Centre</name>
        <address>
          <city>Parkville</city>
          <state>Victoria</state>
          <zip>3052</zip>
          <country>Australia</country>
        </address>
      </facility>
      <contact>
        <last_name>Stephen Luen, MBChB, FRACP</last_name>
        <phone>+61385595000</phone>
        <email>stephen.luen@petermac.org</email>
      </contact>
      <investigator>
        <last_name>Stephen Luen, MBChB, FRACP</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>The Royal Children's Hospital</name>
        <address>
          <city>Parkville</city>
          <state>Victoria</state>
          <zip>3052</zip>
          <country>Australia</country>
        </address>
      </facility>
      <contact>
        <last_name>Anthony Penington, MBBS, FRACS, MD(res), Grad Dip</last_name>
        <phone>+61403342847</phone>
        <email>Tony.Penington@rch.org.au</email>
      </contact>
      <contact_backup>
        <last_name>Michelle de Silva, BDc(Hons), PhD, MGenCouns</last_name>
        <phone>+61400008054</phone>
        <email>Michelle.desilva@vcgs.org.au</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>Australia</country>
    </location_countries>
    <reference>
      <citation>Garzon MC, Huang JT, Enjolras O, Frieden IJ. Vascular malformations: Part I. J Am Acad Dermatol. 2007 Mar;56(3):353-70; quiz 371-4. doi: 10.1016/j.jaad.2006.05.069.</citation>
      <PMID>17317485</PMID>
    </reference>
    <reference>
      <citation>Penington, A.P., R.; Sleebs, N.; Halliday, J. , Epidemiology of Vascular Malformations Poster, in International Society for the Study of Vascluar Anomalies World Congress. 2022: Vancouver, British Columbia, Canada.</citation>
    </reference>
    <reference>
      <citation>Wagner KM, Lokmic Z, Penington AJ. Prolonged antibiotic treatment for infected low flow vascular malformations. J Pediatr Surg. 2018 Apr;53(4):798-801. doi: 10.1016/j.jpedsurg.2017.05.022. Epub 2017 May 27.</citation>
      <PMID>28599969</PMID>
    </reference>
    <reference>
      <citation>Cheng J, Liu B, Farjat AE, Routh J. The Public Health Burden of Lymphatic Malformations in Children: National Estimates in the United States, 2000-2009. Lymphat Res Biol. 2017 Sep;15(3):241-245. doi: 10.1089/lrb.2017.0009. Epub 2017 Jul 31.</citation>
      <PMID>28759318</PMID>
    </reference>
    <reference>
      <citation>Liu AS, Mulliken JB, Zurakowski D, Fishman SJ, Greene AK. Extracranial arteriovenous malformations: natural progression and recurrence after treatment. Plast Reconstr Surg. 2010 Apr;125(4):1185-1194. doi: 10.1097/PRS.0b013e3181d18070.</citation>
      <PMID>20335868</PMID>
    </reference>
    <reference>
      <citation>Chen RJ, Vrazas JI, Penington AJ. Surgical Management of Intramuscular Venous Malformations. J Pediatr Orthop. 2021 Jan;41(1):e67-e73. doi: 10.1097/BPO.0000000000001667.</citation>
      <PMID>32815867</PMID>
    </reference>
    <reference>
      <citation>Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008 Jun 12;358(24):2649-51. doi: 10.1056/NEJMc0708819. No abstract available.</citation>
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    <verification_date>September 2023</verification_date>
    <study_first_submitted>July 27, 2023</study_first_submitted>
    <study_first_submitted_qc>August 7, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 9, 2023</study_first_posted>
    <last_update_submitted>September 11, 2023</last_update_submitted>
    <last_update_submitted_qc>September 11, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Targeted therapy</keyword>
    <keyword>vascular malformations</keyword>
    <keyword>skin diseases, vascular</keyword>
    <keyword>Phosphatidylinositol 3-Kinases</keyword>
    <keyword>MEK inhibitor 1</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Hemangioma</mesh_term>
      <mesh_term>Lymphangioma</mesh_term>
      <mesh_term>Arteriovenous Malformations</mesh_term>
      <mesh_term>Vascular Malformations</mesh_term>
      <mesh_term>Lymphatic Abnormalities</mesh_term>
      <mesh_term>Congenital Abnormalities</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05983159
  org study id: 85218
  nct id: NCT05983159
  lead sponsor: 
  collaborator: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  is us export: Yes
  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) 12 months of alpelisib therapy for participants with slow-flow
        vascular malformations and a gene mutation in one of these signalling pathways (module 1) and
        (ii) 12 months 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 12 months
        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 12 months as monotherapy (treatment period), followed by 6
             months 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 12 months as monotherapy (treatment period), followed by 6 months of
             follow-up (follow-up period).
  
        TARGET-VM will be conducted only in Victoria, Australia.
  allocation: Non-Randomized
  intervention model: Parallel Assignment
  intervention model description: i) Participants with slow-flow vascular malformations with an eligible gene mutation will receive 12 months of treatment with open-label alpelisib.
  )ii Participants with fast-flow vascular malformations with an eligible gene mutation will receive 12 months of treatment with open-label mirdametinib
  primary purpose: Treatment
  masking: None (Open Label)
  measure: The number of participants who achieve or exceed a predetermined threshold of improvement in their most significant symptom at 12 months based on the Vascular Malformation Patient Specific Outcome Measure (VM-PSOM).
  time frame: At 12 months
  description: 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).
  measure: 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).
  time frame: 12 months, 168-day follow-up
  description: VM-PSOM response at the 168 day follow-up visit assessment compared with the 12 month (end-of-treatment) VM-PSOM.
  measure: 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.
  time frame: Baseline, 12 months
  description: Objective response rate by volumetric MRI assessment comparing 12 month (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.
  measure: Change in symptoms score as recorded on the OVAMA (Outcome measures for VAscular MAlformations) questionnaire.
  time frame: Time frame: Baseline, 12 months
  description: 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.
  measure: 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.
  time frame: Time frame: 12 months, Day 168 follow-up
  description: The mean scores in the OVAMA (Outcome measures for VAscular MAlformations) questionnaire will be calculated and analysed at specified time points.
  measure: The number of patients who experience adverse events as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.
  time frame: From Baseline to Day 168 follow-up
  arm group label: Module 1: Slow-flow vascular malformations
  arm group type: Experimental
  description: 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 12 months as monotherapy, followed by 6 months of follow-up.
  arm group label: Module 2: Fast-flow vascular malformations
  arm group type: Experimental
  description: 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 12 months as monotherapy, followed by 6 months of follow-up.
  intervention type: Drug
  intervention name: Alpelisib
  description: Oral alpha-specific PI3-kinase inhibitor
  arm group label: Module 1: Slow-flow vascular malformations
  other name: BYL719
  intervention type: Drug
  intervention name: Mirdametinib
  description: An investigational oral MEK inhibitor
  arm group label: Module 2: Fast-flow vascular malformations
  criteria: 
  gender: All
  minimum age: 2 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Tony Penington, MBBS, FRACS.
  role: Principal Investigator
  affiliation: Study Principal Investigator
  last name: Stephen Luen, MBChB, FRACP.
  role: Principal Investigator
  affiliation: Principal Investigator
  last name: Lydia Pathmanathan, MBBS, FRACP.
  role: Principal Investigator
  affiliation: Principal Investigator
  last name: Michelle De Silva
  phone: +61383416200
  email: michelle.desilva@vcgs.org.au
  last name: Tony Penington
  phone: +61383416200
  email: tony.penington@rch.org.au
  facility: 
  contact: 
  investigator: 
  facility: 
  contact: 
  contact backup: 
  country: Australia
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  PMID: 17317485
  citation: Penington, A.P., R.; Sleebs, N.; Halliday, J. , Epidemiology of Vascular Malformations Poster, in International Society for the Study of Vascluar Anomalies World Congress. 2022: Vancouver, British Columbia, Canada.
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  citation: Chen RJ, Vrazas JI, Penington AJ. Surgical Management of Intramuscular Venous Malformations. J Pediatr Orthop. 2021 Jan;41(1):e67-e73. doi: 10.1097/BPO.0000000000001667.
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  responsible party type: Sponsor
  mesh term: Hemangioma
  mesh term: Lymphangioma
  mesh term: Arteriovenous Malformations
  mesh term: Vascular Malformations
  mesh term: Lymphatic Abnormalities
  mesh term: Congenital Abnormalities