<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/NCT03231306</url>
  </required_header>
  <id_info>
    <org_study_id>IRB-170616001</org_study_id>
    <nct_id>NCT03231306</nct_id>
  </id_info>
  <brief_title>Phase II Study of Binimetinib in Children and Adults With NF1 Plexiform Neurofibromas</brief_title>
  <acronym>NF108-BINI</acronym>
  <official_title>A Phase II Study of Binimetinib in Children and Adults With NF1 Associated Plexiform Neurofibromas (PNOC010)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Alabama at Birmingham</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Array BioPharma</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pacific Pediatric Neuro-Oncology Consortium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Alabama at Birmingham</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a phase II open label study that will evaluate children ≥ 1 year of age and adults&#xD;
      with neurofibromatosis type 1 (NF1) and plexiform neurofibromas treated with the MEK&#xD;
      inhibitor, binimetinib. The primary objective is to determine if there is an adequate level&#xD;
      of disease responsiveness to binimetinib in children and adults with NF1 and inoperable&#xD;
      plexiform neurofibromas. The objective response to binimetinib is defined as ≥ 20% decrease&#xD;
      in tumor volume reduction by 12 courses.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients ≥ 1 year with progressive NF1 and PN(s) by serial imaging or causing significant&#xD;
      morbidity and that can be analyzed by volumetric MRI are eligible for this study. Initially,&#xD;
      the study will open to adult patients,18 years and older, (Stratum A). The pediatric patients&#xD;
      (Statum B) will be receive the pediatric maximum tolerated dose (MTD) of binimetinib that is&#xD;
      currently being established in an ongoing phase 1 study (NCT02285439). For adult subjects,&#xD;
      binimetinib (established adult RP2D) is taken orally twice a day. Dosing will be continuous,&#xD;
      with 28 days defined as a course and will continue for a total of 24 courses or until one of&#xD;
      the Off Treatment or Off Study criteria are met. Subjects will undergo volumetric assays of&#xD;
      their targeted PN using MRI after every 4 courses for the first year and then every 6&#xD;
      courses. MRI review of the volumetric assays will occur centrally under the guidance of Dr.&#xD;
      Dombi at NCI. Subjects may receive additional courses beyond course 8 only if there is at&#xD;
      least a 15% reduction in volume of the target tumor, as measured from baseline. Treatment&#xD;
      beyond course 12 will be only be given to those subjects who achieve a response of ≥ 20%&#xD;
      tumor shrinkage by volumetric analysis and can continue on therapy up to an additional year&#xD;
      for a maximum of 24 total courses. For those who respond to binimetinib after 12 courses, an&#xD;
      MRI scan of the target lesion must be performed at 4 and 12 months after stopping drug in&#xD;
      order to determine whether response is maintained post-therapy. Subjects will be carefully&#xD;
      monitored for development of binimetinib associated toxicities. Subjects will be removed from&#xD;
      the study for significant toxicity, treatment delay of ≥ 21 days, or objective progression of&#xD;
      tumor growth by ≥ 20% by volumetric analysis at any time.&#xD;
&#xD;
      The investigational nature and objectives of this trial, the procedures and treatment&#xD;
      involved, the risks, discomforts, and benefits, and potential alternatives therapies will be&#xD;
      carefully explained to the subject and/or subject's parent(s) or guardian by the site&#xD;
      Principal Investigator or designated associate investigator. A signed informed consent&#xD;
      document will be obtained prior to determining eligibility and entry criteria to this trial.&#xD;
      Subjects entered on this trial will be treated with therapeutic intent and response to&#xD;
      therapy will be closely monitored. This protocol involves greater than minimal risk but&#xD;
      presents the potential for direct benefit to individual subjects.&#xD;
&#xD;
      Schedule of study evaluations are summarized below:&#xD;
&#xD;
      Pre-Study (Eligibility Screening):&#xD;
&#xD;
        -  Physical assessment, vital signs and neurological exam&#xD;
&#xD;
        -  Complete medical history including past and current medical conditions, treatments, and&#xD;
           surgeries.&#xD;
&#xD;
        -  Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks&#xD;
&#xD;
        -  Review of current medications&#xD;
&#xD;
        -  Blood draw (about two tablespoons) for routine safety tests&#xD;
&#xD;
        -  Serum or urine pregnancy test for females of childbearing age&#xD;
&#xD;
        -  Eye exam&#xD;
&#xD;
        -  Electrocardiogram (ECG) and echocardiogram (ECHO) or multigated acquisition (MUGA) scan&#xD;
           of your heart&#xD;
&#xD;
        -  MRI of neurofibroma tumors&#xD;
&#xD;
        -  Functional evaluation: Depending on the location of your plexiform neurofibroma,&#xD;
           specific functional assessments will be performed. The functional assessments may&#xD;
           include a 6-Minute Walk-Test if you have a plexiform neurofibroma affecting your legs or&#xD;
           airway, evaluation of muscle strength and range of motion if you have plexiform&#xD;
           neurofibroma affecting your arms or legs, and/or grooved pegboard test if you have&#xD;
           plexiform neurofibroma affecting your hands. The study team will review all evaluations&#xD;
           that apply to you in detail&#xD;
&#xD;
        -  Completion of health-related questionnaires on quality of life, pain assessment, bowel&#xD;
           and bladder dysfunction, and PN symptom checklist (upon study entry)&#xD;
&#xD;
        -  Photography of visible PN (optional)&#xD;
&#xD;
      End of course 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24:&#xD;
&#xD;
        -  Medical history update and hospitalization since last study visit&#xD;
&#xD;
        -  Physical assessment, vital signs, and neurological exam&#xD;
&#xD;
        -  Karnofsky/Lansky performance status to assess your ability to perform everyday tasks&#xD;
&#xD;
        -  Review of your medication diary and any side effects you may be experiencing&#xD;
&#xD;
        -  Review of current medications&#xD;
&#xD;
        -  Blood draw (about two tablespoons) for routine safety tests&#xD;
&#xD;
        -  Serum or urine pregnancy test for females of childbearing age&#xD;
&#xD;
      End of course 4, 8, 12, 18, and 24:&#xD;
&#xD;
        -  Eye exam&#xD;
&#xD;
        -  MRI of neurofibromas&#xD;
&#xD;
        -  ECHO and ECG&#xD;
&#xD;
        -  Functional evaluation: (see description above)&#xD;
&#xD;
        -  Completion of health-related questionnaires on quality of life, pain assessment, bowel&#xD;
           and bladder dysfunction, and PN symptom checklist&#xD;
&#xD;
        -  Photography of visible PN (optional): If you agree to take part, photographs of visible&#xD;
           PN will be taken. Photos will be taken before treatment and then after cycles 4, 8, 12,&#xD;
           18, and 24.&#xD;
&#xD;
      End of course 1 and 4:&#xD;
&#xD;
      • Blood draw (about one tablespoon) for cytokine studies (optional)&#xD;
&#xD;
      End of Treatment Visit (this is an additional visit if the visit is not within the specified&#xD;
      times mentioned above):&#xD;
&#xD;
        -  Physical assessment, vital signs and neurological exam&#xD;
&#xD;
        -  Medical history update and hospitalization since last study visit&#xD;
&#xD;
        -  Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks&#xD;
&#xD;
        -  Review of your medication diary and any side effects you may be experiencing&#xD;
&#xD;
        -  Review of current medications&#xD;
&#xD;
        -  Blood draw (about two tablespoons) for routine safety tests&#xD;
&#xD;
        -  Serum or urine pregnancy test for females of childbearing age&#xD;
&#xD;
        -  Eye exam&#xD;
&#xD;
        -  Electrocardiogram (ECG) and ECHO or multigated acquisition (MUGA) scan of your heart&#xD;
&#xD;
        -  MRI of neurofibroma tumors (for those who respond to binimetinib after 12 courses, an&#xD;
           MRI at 4 and 12 months after stopping drug)&#xD;
&#xD;
        -  Functional evaluation: (see description above)&#xD;
&#xD;
        -  Completion of health-related questionnaires on quality of life, pain assessment, bowel&#xD;
           and bladder dysfunction, and PN symptom checklist&#xD;
&#xD;
        -  Photography of visible PN (optional)&#xD;
&#xD;
      The sample size is 20 subjects for each adult and children cohorts with a minimum target of&#xD;
      17 evaluable subjects per cohort. Evaluable is defined as: any subjects who received ≥ one&#xD;
      dose of binimetinib and had a ≥ Grade 3 binimetinib associated toxicity, or in absence of a ≥&#xD;
      Grade 3 toxicity, any subjects who completed one full course of therapy; subjects who have&#xD;
      completed at least two courses of therapy and had their first follow-up MRI evaluation except&#xD;
      for discovery of a target tumor other than a PN; and any subjects who has at least two&#xD;
      samples drawn for plasma cytokines/growth factors, one at baseline and at least one other&#xD;
      after starting therapy.&#xD;
&#xD;
      Data Safety Monitoring Board (DSMB) and a Medical Monitor have been established for this&#xD;
      study for the purpose of ensuring data compliance and regular monitoring. An early stopping&#xD;
      rules have been defined within the protocol. The early stopping rule will invoked for both&#xD;
      Strata separately to potentially prevent accrual subjects onto the study in the event that&#xD;
      binimetinib is associated with a higher than acceptable rate of dose-limiting toxicity (DLT)&#xD;
      requiring removal from study (10% or higher) during the first 2 courses. Toxicity will be&#xD;
      continuously monitored. If at any time &gt;2 of the first 10 subjects or 4 or more of the first&#xD;
      15 total subjects are removed for toxicity, then accrual will be stopped until the DSMB&#xD;
      reviews the safety and efficacy data for the study. Based on the review, the DSMB can either&#xD;
      recommend termination of the study or reopen recruitment. The Medical Monitor is a qualified&#xD;
      physician who is not associated with this protocol and is a member of the DSMB. The Medical&#xD;
      Monitor may perform oversight functions duties: may discuss the research protocol with the&#xD;
      investigators, interview human subjects, and consult with others outside of the study about&#xD;
      the research; shall have the authority to stop the research protocol in progress, remove&#xD;
      individual subjects from protocol, and take whatever steps are necessary to protect the&#xD;
      safety and well being of human subjects until the Institutional Review Board (IRB) can assess&#xD;
      the monitor's report; and shall have the responsibility to promptly report the observation&#xD;
      and findings to the IRB or other designated official/organization. The Medical Monitor is&#xD;
      specifically required to review and provide written report of all unanticipated problems&#xD;
      involving risk to subjects or others and serious adverse events.&#xD;
&#xD;
      In addition, as part of the Data Safety Monitoring Plan, the Study Chairs and the NF&#xD;
      Consortium Clinical Research Nurse Manager will review subject eligibility, study progress,&#xD;
      safety issues, protocol deviations and adverse events. Monthly reports will be generated by&#xD;
      the NF Consortium Data Management Center to assess completeness of data. Monthly phone&#xD;
      conferences will take place between NF Consortium Operations Center and the Protocol Team to&#xD;
      address data issues.&#xD;
&#xD;
      The sample size for this trial is based on safety and feasibility factors. The data needed&#xD;
      for safety is based on risk versus benefit, and for feasibility, we expect at least efficacy&#xD;
      of 25% response rate. For safety reasons, subjects who do not achieve at least 15% reduction&#xD;
      in volume of target tumor after 8 courses will be discontinued from the trial, as the&#xD;
      likelihood of achieving a 20% reduction in tumor volume by 12 months is minimal. Safety&#xD;
      analysis set will be described and summarized based on information regarding study treatment&#xD;
      administrations, drug dosing and course compliance, and safety variables (e.g. adverse&#xD;
      events/serious adverse events). All analyses for outcome results will be based on evaluable&#xD;
      subjects. Given the difference in the clinical behavior of PN in the adults and pediatric&#xD;
      subjects, the adult and children stratum will be analyzed independently.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 28, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2026</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2025</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change from Baseline Target Tumor Volume at 12 months</measure>
    <time_frame>Approximately 12 months</time_frame>
    <description>To determine the objective response defined as 20% or greater tumor volume reduction. Patients will undergo volumetric assays of their target PN using MRI.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>To evaluate the toxicity of protracted binimetinib administration in this patient population. Subjects will be monitored continuously for adverse events and serious adverse events throughout the study.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Neurofibromatosis Type 1</condition>
  <condition>Plexiform Neurofibroma</condition>
  <arm_group>
    <arm_group_label>Open label study of Binimetinib (MEK162)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects (≥ 18 years) (Stratum A) will receive a course of binimetinib by mouth twice a day (12 hours apart) of 45 mg/dose. Duration of each course is 4 weeks. After 8 courses, subjects will receive additional courses if MRI results showed at least 15% reduction in volume of the target tumor. Subjects can continue on therapy and will be evaluated at the end of 12 courses. Subjects who have ≥ 20% reduction in volume of the target tumor according to the MRI results can continue therapy up to an additional year (maximum of 24 total courses). Subjects who have not met the tumor reduction at the specified times will be removed from the study therapy. Subjects will be carefully monitored for toxicities associated with binimetinib.&#xD;
Recruitment of subjects 1 - 17 years of age (Stratum B) is currently available. The pediatric maximum tolerated dose (MTD) of binimetinib the pediatric patients (Statum B) was established by a phase 1 study (NCT022).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Binimetinib</intervention_name>
    <description>Adult subjects (18 years and older) will receive binimetinib by mouth twice daily of 45mg/dose. Pediatric subjects (1-17 years of age) are being treated on the pediatric MTD established by a phase I study (NCT02285439).</description>
    <arm_group_label>Open label study of Binimetinib (MEK162)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          -  Clinical diagnosis of NF1 using the NIH Consensus Conference criteria OR a documented&#xD;
             constitutional NF1 mutation&#xD;
&#xD;
          -  Plexiform neurofibroma(s) that are progressive or causing significant morbidity&#xD;
&#xD;
          -  Presence of new plexiform neurofibroma on MRI or CT (documented by comparison with&#xD;
             prior MRI or CT)&#xD;
&#xD;
          -  Measurable plexiform neurofibroma(s) amenable to volumetric MRI analysis. Tumors must&#xD;
             be at least 3 mL in volume (most PNs 3 cm in longest diameter will meet this criteria)&#xD;
&#xD;
          -  Patients must be ≥ 18 years of age at the time of enrollment.&#xD;
&#xD;
          -  Performance Level: Karnofsky or Lansky ≥ 50%. If unable to walk due to paralysis, but&#xD;
             in a wheelchair, patients will be considered ambulatory for the purpose of assessing&#xD;
             the performance level&#xD;
&#xD;
          -  Ability to swallow capsules/tablets&#xD;
&#xD;
          -  Ability to comply with follow up procedures&#xD;
&#xD;
          -  The effects of binimetinib on the developing human fetus are unknown. For this reason,&#xD;
             women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for&#xD;
             the duration of study participation, and 3 months after completion of binimetinib&#xD;
             administration. Should a woman become pregnant or suspect she is pregnant while she or&#xD;
             her partner is participating in this study, she should inform her treating physician&#xD;
             immediately.&#xD;
&#xD;
          -  Negative urine or serum β-HCG test (females of childbearing potential only).&#xD;
&#xD;
        Prior Therapy:&#xD;
&#xD;
          -  Patients are eligible if complete resection of a plexiform neurofibroma with&#xD;
             acceptable morbidity is not feasible, or if a subject with surgical option refuses&#xD;
             surgery,&#xD;
&#xD;
          -  Patients who underwent surgery for a progressive plexiform neurofibroma will be&#xD;
             eligible to enter the study after the surgery, provided the plexiform neurofibroma was&#xD;
             incompletely resected and is evaluable by volumetric analysis.&#xD;
&#xD;
          -  Patients previously treated for a plexiform neurofibroma or other tumor/malignancy,&#xD;
             but must have fully recovered from the acute toxic effects of all prior chemotherapy&#xD;
             or radiotherapy prior to entering this study.&#xD;
&#xD;
          -  Must not have received myelosuppressive chemotherapy within 3 weeks of entry onto this&#xD;
             study.&#xD;
&#xD;
          -  At least 7 days since the completion of therapy with a hematopoietic growth factor&#xD;
             that supports platelet, red or white cell number or function.&#xD;
&#xD;
          -  At least 4 weeks since the completion of therapy with a biologic anti-neoplastic&#xD;
             agent. For agents that have known adverse events occurring beyond 14 days after&#xD;
             administration, this period must be extended beyond the time during which adverse&#xD;
             events are known to occur.&#xD;
&#xD;
          -  Patients must not have received an investigational drug within 4 weeks.&#xD;
&#xD;
          -  Patients with endocrine deficiencies are allowed to receive physiologic or stress&#xD;
             doses of steroids, if necessary.&#xD;
&#xD;
          -  Radiation ≥ 6 months from involved field radiation to index plexiform neurofibroma(s),&#xD;
             ≥ 6 weeks must have elapsed if patient has received radiation to areas outside index&#xD;
             plexiform neurofibroma(s). Patients who have received radiation to the orbit at any&#xD;
             time are excluded.&#xD;
&#xD;
          -  At least 3 weeks since undergoing any major surgery and must be recovered from effects&#xD;
             of surgery.&#xD;
&#xD;
        Organ Function Requirements:&#xD;
&#xD;
          -  Adequate bone marrow function defined as:&#xD;
&#xD;
               -  Peripheral absolute neutrophil count (ANC) ≥ 1500/µL&#xD;
&#xD;
               -  Platelet count ≥ 100,000/µL (transfusion independent, defined as not receiving&#xD;
                  platelet transfusions for at least 7 days prior to enrollment)&#xD;
&#xD;
               -  Hemoglobin ≥ 10.0 gm/dL without transfusions.&#xD;
&#xD;
          -  Adequate renal function defined as:&#xD;
&#xD;
               -  Maximum serum creatinine based on age/gender or a creatinine clearance or&#xD;
                  radioisotope GFR ≥ 70 ml/min/1.73 m²&#xD;
&#xD;
          -  Adequate liver function defined as:&#xD;
&#xD;
               -  Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN)&#xD;
                  for age&#xD;
&#xD;
               -  SGPT (ALT) ≤ 2.5 x upper limit of normal (ULN) for age&#xD;
&#xD;
               -  Serum albumin ≥ 2 g/dL&#xD;
&#xD;
          -  Adequate cardiac function defined as:&#xD;
&#xD;
               -  Left ventricular fractions (LVEF) ≥ 50% as determined by a multigated acquisition&#xD;
                  (MUGA) scan or echocardiogram&#xD;
&#xD;
               -  QTc interval ≤ 480 ms.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Chronic treatment with systemic steroids or another immunosuppressive agent.&#xD;
&#xD;
          -  Evidence of an active optic glioma or other low-grade glioma, requiring treatment with&#xD;
             chemotherapy or radiation therapy. Patients not requiring treatment are eligible for&#xD;
             this protocol.&#xD;
&#xD;
          -  Patients with malignant glioma, malignant peripheral nerve sheath tumor, or other&#xD;
             malignancy requiring treatment in the last 12 months.&#xD;
&#xD;
          -  Patients who have received radiation to the orbit at any time previously.&#xD;
&#xD;
          -  Ophthalmologic conditions:&#xD;
&#xD;
               -  Current or past history of central serous retinopathy&#xD;
&#xD;
               -  Current or past history of retinal vein occlusion&#xD;
&#xD;
               -  Known intraocular pressure (IOP) &gt; 21 mmHg (or ULN adjusted by age) or&#xD;
                  uncontrolled glaucoma (irrespective of IOP). Patients with known glaucoma and&#xD;
                  increased IOP who do not have meaningful vision (light perception only or no&#xD;
                  light perception) and are not experiencing pain related to the glaucoma, may be&#xD;
                  eligible after review. Patients with orbital plexiform neurofibromas should have&#xD;
                  IOP measured prior to enrollment.&#xD;
&#xD;
               -  Patients with any other significant abnormality on ophthalmic examination will be&#xD;
                  reviewed for potential eligibility.&#xD;
&#xD;
               -  Ophthalmological findings secondary to long-standing optic pathway glioma (such&#xD;
                  as visual loss, optic nerve pallor or strabismus) or long-standing&#xD;
                  orbito-temporal PN (such as visual loss, strabismus) will NOT be considered a&#xD;
                  significant abnormality for the purposes of the study&#xD;
&#xD;
          -  Uncontrolled arterial hypertension despite medical treatment defined as CTCAE grade 3&#xD;
             or higher.&#xD;
&#xD;
          -  Impaired cardiovascular function or clinically significant cardiovascular diseases,&#xD;
             including:&#xD;
&#xD;
               -  History of acute coronary syndromes (including myocardial infarction, unstable&#xD;
                  angina, coronary artery bypass grafting, coronary angioplasty, or stenting) &lt; 6&#xD;
                  months prior to screening&#xD;
&#xD;
               -  Symptomatic chronic heart failure, history or current evidence of clinically&#xD;
                  significant cardiac arrhythmia and/or conduction abnormality &lt; 6 months prior to&#xD;
                  screening except atrial fibrillation and paroxysmal supraventricular tachycardia&#xD;
&#xD;
          -  Other concurrent severe and/or uncontrolled medical disease, which could compromise&#xD;
             participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension,&#xD;
             severe infection, severe malnutrition, chronic liver or renal disease, active upper GI&#xD;
             tract ulceration, congestive heart failure, etc.)&#xD;
&#xD;
          -  Subjects who have an uncontrolled infection.&#xD;
&#xD;
          -  Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,&#xD;
             and/or active hepatitis C infection.&#xD;
&#xD;
          -  Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative&#xD;
             disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small&#xD;
             bowel resection).&#xD;
&#xD;
          -  History of Gilbert's syndrome or patients who are known to be homozygous for UGT1A1&#xD;
             (7/7).&#xD;
&#xD;
          -  Patients who have neuromuscular disorders that are associated with elevated CK (e.g.,&#xD;
             inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal&#xD;
             muscular atrophy)&#xD;
&#xD;
          -  Patients who are planning to embark on a new strenuous exercise regimen after first&#xD;
             dose of study treatment. NB: muscular activities, such as strenuous exercise, that can&#xD;
             result in significant increases in plasma CK levels should be avoided while on&#xD;
             binimetinib treatment.&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to binimetinib.&#xD;
&#xD;
          -  Women who are pregnant or breastfeeding.&#xD;
&#xD;
          -  Any other condition that would contraindicate, in the Investigator's judgement, the&#xD;
             patient's participation in the clinical study due to safety concerns or compliance&#xD;
             with clinical study procedures, e.g. infection/inflammation, intestinal obstruction,&#xD;
             unable to swallow medication, social/ psychological issues, etc.&#xD;
&#xD;
          -  History of noncompliance to medical regimens.&#xD;
&#xD;
          -  Patients unwilling to or unable to comply with the protocol, or who in the opinion of&#xD;
             the investigator may not be able to comply with the safety monitoring requirements of&#xD;
             the study.&#xD;
&#xD;
          -  Prior treatment with a MEK inhibitor of any kind.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Year</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bruce Korf, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>University of Alabama at Birmingham</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California at Los Angeles</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF Benioff Children's Hospital Oakland</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94609</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California, San Diego - Rady Children's Hospital</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92123</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94153</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's National Medical Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lurie Children's Hospital of Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60637</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins University</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Institute of Health - National Cancer Institute</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Boston Children's Hospital / Dana Farber Cancer Institute / Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New York University Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10016</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cinncinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nationwide Children's Hospital</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oregon Health and Science University Hospital</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Philadelphia</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19096</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Washington - Seattle Children's Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://clinicaltrials.gov/show/NCT01362803</url>
    <description>A phase 1 study of mitogen activated protein kinase (MEK) 1 inhibitor AZD6244 hydrogen sulfate (selumetinib sulfate) in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN)</description>
  </link>
  <link>
    <url>https://scholar.google.com</url>
    <description>Chow, L., et al. &quot;A first in human dose-ranging study to assess the pharmacokinetics, pharmacodynamics, and toxicities of the MEK inhibitor, ARRY-142886 (AZD6244), in patients with advanced solid malignancies.&quot; CLINICAL CANCER RESEARCH. Vol. 11. No.24</description>
  </link>
  <reference>
    <citation>Wu J, Williams JP, Rizvi TA, Kordich JJ, Witte D, Meijer D, Stemmer-Rachamimov AO, Cancelas JA, Ratner N. Plexiform and dermal neurofibromas and pigmentation are caused by Nf1 loss in desert hedgehog-expressing cells. Cancer Cell. 2008 Feb;13(2):105-16. doi: 10.1016/j.ccr.2007.12.027.</citation>
    <PMID>18242511</PMID>
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    <citation>Kebudi R, Cakir FB, Gorgun O. Interferon-alpha for unresectable progressive and symptomatic plexiform neurofibromas. J Pediatr Hematol Oncol. 2013 Apr;35(3):e115-7. doi: 10.1097/MPH.0b013e318270cd24.</citation>
    <PMID>23042022</PMID>
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    <citation>Citak EC, Oguz A, Karadeniz C, Okur A, Memis L, Boyunaga O. Management of plexiform neurofibroma with interferon alpha. Pediatr Hematol Oncol. 2008 Sep;25(7):673-8. doi: 10.1080/08880010802315983.</citation>
    <PMID>18850480</PMID>
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    <citation>Jakacki RI, Dombi E, Potter DM, Goldman S, Allen JC, Pollack IF, Widemann BC. Phase I trial of pegylated interferon-alpha-2b in young patients with plexiform neurofibromas. Neurology. 2011 Jan 18;76(3):265-72. doi: 10.1212/WNL.0b013e318207b031.</citation>
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    <citation>Widemann BC, Arceci RJ, Jayaprakash N, Fox E, Zannikos P, Goodspeed W, Goodwin A, Wright JJ, Blaney SM, Adamson PC, Balis FM. Phase 1 trial and pharmacokinetic study of the farnesyl transferase inhibitor tipifarnib in children and adolescents with refractory leukemias: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011 Feb;56(2):226-33. doi: 10.1002/pbc.22775. Epub 2010 Sep 21.</citation>
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    <PMID>16421428</PMID>
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    <citation>Babovic-Vuksanovic D, Widemann BC, Dombi E, Gillespie A, Wolters PL, Toledo-Tamula MA, O'Neill BP, Fox E, MacDonald T, Beck H, Packer RJ. Phase I trial of pirfenidone in children with neurofibromatosis 1 and plexiform neurofibromas. Pediatr Neurol. 2007 May;36(5):293-300. doi: 10.1016/j.pediatrneurol.2007.01.009.</citation>
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    <PMID>22961690</PMID>
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    <PMID>12509763</PMID>
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    <PMID>10469432</PMID>
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    <citation>Wu J, Dombi E, Jousma E, Scott Dunn R, Lindquist D, Schnell BM, Kim MO, Kim A, Widemann BC, Cripe TP, Ratner N. Preclincial testing of sorafenib and RAD001 in the Nf(flox/flox) ;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging. Pediatr Blood Cancer. 2012 Feb;58(2):173-80. doi: 10.1002/pbc.23015. Epub 2011 Feb 11.</citation>
    <PMID>21319287</PMID>
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    <citation>Kissil JL, Blakeley JO, Ferner RE, Huson SM, Kalamarides M, Mautner VF, McCormick F, Morrison H, Packer R, Ramesh V, Ratner N, Rauen KA, Stevenson DA, Hunter-Schaedle K, North K. What's new in neurofibromatosis? Proceedings from the 2009 NF Conference: new frontiers. Am J Med Genet A. 2010 Feb;152A(2):269-83. doi: 10.1002/ajmg.a.33189.</citation>
    <PMID>20082461</PMID>
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    <citation>Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW. Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell. 2008 Oct 31;135(3):437-48. doi: 10.1016/j.cell.2008.08.041.</citation>
    <PMID>18984156</PMID>
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    <citation>Jessen WJ, Miller SJ, Jousma E, Wu J, Rizvi TA, Brundage ME, Eaves D, Widemann B, Kim MO, Dombi E, Sabo J, Hardiman Dudley A, Niwa-Kawakita M, Page GP, Giovannini M, Aronow BJ, Cripe TP, Ratner N. MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest. 2013 Jan;123(1):340-7. doi: 10.1172/JCI60578. Epub 2012 Dec 10.</citation>
    <PMID>23221341</PMID>
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    <citation>Chang T, Krisman K, Theobald EH, Xu J, Akutagawa J, Lauchle JO, Kogan S, Braun BS, Shannon K. Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest. 2013 Jan;123(1):335-9. doi: 10.1172/JCI63193. Epub 2012 Dec 10. Erratum In: J Clin Invest. 2016 Jan;126(1):404.</citation>
    <PMID>23221337</PMID>
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    <citation>Nutakki K, Hingtgen CM, Monahan P, Varni JW, Swigonski NL. Development of the adult PedsQL neurofibromatosis type 1 module: initial feasibility, reliability and validity. Health Qual Life Outcomes. 2013 Feb 21;11:21. doi: 10.1186/1477-7525-11-21.</citation>
    <PMID>23432799</PMID>
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    <citation>Rosser T, Packer RJ. Neurofibromas in children with neurofibromatosis 1. J Child Neurol. 2002 Aug;17(8):585-91; discussion 602-4, 646-51. doi: 10.1177/088307380201700808.</citation>
    <PMID>12403557</PMID>
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    <citation>Le LQ, Parada LF. Tumor microenvironment and neurofibromatosis type I: connecting the GAPs. Oncogene. 2007 Jul 12;26(32):4609-16. doi: 10.1038/sj.onc.1210261. Epub 2007 Feb 12.</citation>
    <PMID>17297459</PMID>
  </reference>
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    <citation>Prada CE, Jousma E, Rizvi TA, Wu J, Dunn RS, Mayes DA, Cancelas JA, Dombi E, Kim MO, West BL, Bollag G, Ratner N. Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. Acta Neuropathol. 2013 Jan;125(1):159-68. doi: 10.1007/s00401-012-1056-7. Epub 2012 Oct 26.</citation>
    <PMID>23099891</PMID>
  </reference>
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    <citation>Wolkenstein P, Zeller J, Revuz J, Ecosse E, Leplege A. Quality-of-life impairment in neurofibromatosis type 1: a cross-sectional study of 128 cases. Arch Dermatol. 2001 Nov;137(11):1421-5. doi: 10.1001/archderm.137.11.1421.</citation>
    <PMID>11708944</PMID>
  </reference>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>July 21, 2017</study_first_submitted>
  <study_first_submitted_qc>July 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2017</study_first_posted>
  <last_update_submitted>December 14, 2022</last_update_submitted>
  <last_update_submitted_qc>December 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Alabama at Birmingham</investigator_affiliation>
    <investigator_full_name>Bruce Korf, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Neurofibroma, Plexiform</keyword>
  <keyword>Genes, Neurofibromatosis</keyword>
  <keyword>Peripheral nerve tumors</keyword>
  <keyword>Neurofibromatosis 1</keyword>
  <keyword>Neurofibromas</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurofibromatoses</mesh_term>
    <mesh_term>Neurofibromatosis 1</mesh_term>
    <mesh_term>Neurofibroma</mesh_term>
    <mesh_term>Neurofibroma, Plexiform</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT03231306
org study id: IRB-170616001
nct id: NCT03231306
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a phase II open label study that will evaluate children ≥ 1 year of age and adults
      with neurofibromatosis type 1 (NF1) and plexiform neurofibromas treated with the MEK
      inhibitor, binimetinib. The primary objective is to determine if there is an adequate level
      of disease responsiveness to binimetinib in children and adults with NF1 and inoperable
      plexiform neurofibromas. The objective response to binimetinib is defined as ≥ 20% decrease
      in tumor volume reduction by 12 courses.
Patients ≥ 1 year with progressive NF1 and PN(s) by serial imaging or causing significant
      morbidity and that can be analyzed by volumetric MRI are eligible for this study. Initially,
      the study will open to adult patients,18 years and older, (Stratum A). The pediatric patients
      (Statum B) will be receive the pediatric maximum tolerated dose (MTD) of binimetinib that is
      currently being established in an ongoing phase 1 study (NCT02285439). For adult subjects,
      binimetinib (established adult RP2D) is taken orally twice a day. Dosing will be continuous,
      with 28 days defined as a course and will continue for a total of 24 courses or until one of
      the Off Treatment or Off Study criteria are met. Subjects will undergo volumetric assays of
      their targeted PN using MRI after every 4 courses for the first year and then every 6
      courses. MRI review of the volumetric assays will occur centrally under the guidance of Dr.
      Dombi at NCI. Subjects may receive additional courses beyond course 8 only if there is at
      least a 15% reduction in volume of the target tumor, as measured from baseline. Treatment
      beyond course 12 will be only be given to those subjects who achieve a response of ≥ 20%
      tumor shrinkage by volumetric analysis and can continue on therapy up to an additional year
      for a maximum of 24 total courses. For those who respond to binimetinib after 12 courses, an
      MRI scan of the target lesion must be performed at 4 and 12 months after stopping drug in
      order to determine whether response is maintained post-therapy. Subjects will be carefully
      monitored for development of binimetinib associated toxicities. Subjects will be removed from
      the study for significant toxicity, treatment delay of ≥ 21 days, or objective progression of
      tumor growth by ≥ 20% by volumetric analysis at any time.

      The investigational nature and objectives of this trial, the procedures and treatment
      involved, the risks, discomforts, and benefits, and potential alternatives therapies will be
      carefully explained to the subject and/or subject's parent(s) or guardian by the site
      Principal Investigator or designated associate investigator. A signed informed consent
      document will be obtained prior to determining eligibility and entry criteria to this trial.
      Subjects entered on this trial will be treated with therapeutic intent and response to
      therapy will be closely monitored. This protocol involves greater than minimal risk but
      presents the potential for direct benefit to individual subjects.

      Schedule of study evaluations are summarized below:

      Pre-Study (Eligibility Screening):

        -  Physical assessment, vital signs and neurological exam

        -  Complete medical history including past and current medical conditions, treatments, and
           surgeries.

        -  Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks

        -  Review of current medications

        -  Blood draw (about two tablespoons) for routine safety tests

        -  Serum or urine pregnancy test for females of childbearing age

        -  Eye exam

        -  Electrocardiogram (ECG) and echocardiogram (ECHO) or multigated acquisition (MUGA) scan
           of your heart

        -  MRI of neurofibroma tumors

        -  Functional evaluation: Depending on the location of your plexiform neurofibroma,
           specific functional assessments will be performed. The functional assessments may
           include a 6-Minute Walk-Test if you have a plexiform neurofibroma affecting your legs or
           airway, evaluation of muscle strength and range of motion if you have plexiform
           neurofibroma affecting your arms or legs, and/or grooved pegboard test if you have
           plexiform neurofibroma affecting your hands. The study team will review all evaluations
           that apply to you in detail

        -  Completion of health-related questionnaires on quality of life, pain assessment, bowel
           and bladder dysfunction, and PN symptom checklist (upon study entry)

        -  Photography of visible PN (optional)

      End of course 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 21, and 24:

        -  Medical history update and hospitalization since last study visit

        -  Physical assessment, vital signs, and neurological exam

        -  Karnofsky/Lansky performance status to assess your ability to perform everyday tasks

        -  Review of your medication diary and any side effects you may be experiencing

        -  Review of current medications

        -  Blood draw (about two tablespoons) for routine safety tests

        -  Serum or urine pregnancy test for females of childbearing age

      End of course 4, 8, 12, 18, and 24:

        -  Eye exam

        -  MRI of neurofibromas

        -  ECHO and ECG

        -  Functional evaluation: (see description above)

        -  Completion of health-related questionnaires on quality of life, pain assessment, bowel
           and bladder dysfunction, and PN symptom checklist

        -  Photography of visible PN (optional): If you agree to take part, photographs of visible
           PN will be taken. Photos will be taken before treatment and then after cycles 4, 8, 12,
           18, and 24.

      End of course 1 and 4:

      • Blood draw (about one tablespoon) for cytokine studies (optional)

      End of Treatment Visit (this is an additional visit if the visit is not within the specified
      times mentioned above):

        -  Physical assessment, vital signs and neurological exam

        -  Medical history update and hospitalization since last study visit

        -  Karnofsky/Lansky performance status to assess of your ability to perform everyday tasks

        -  Review of your medication diary and any side effects you may be experiencing

        -  Review of current medications

        -  Blood draw (about two tablespoons) for routine safety tests

        -  Serum or urine pregnancy test for females of childbearing age

        -  Eye exam

        -  Electrocardiogram (ECG) and ECHO or multigated acquisition (MUGA) scan of your heart

        -  MRI of neurofibroma tumors (for those who respond to binimetinib after 12 courses, an
           MRI at 4 and 12 months after stopping drug)

        -  Functional evaluation: (see description above)

        -  Completion of health-related questionnaires on quality of life, pain assessment, bowel
           and bladder dysfunction, and PN symptom checklist

        -  Photography of visible PN (optional)

      The sample size is 20 subjects for each adult and children cohorts with a minimum target of
      17 evaluable subjects per cohort. Evaluable is defined as: any subjects who received ≥ one
      dose of binimetinib and had a ≥ Grade 3 binimetinib associated toxicity, or in absence of a ≥
      Grade 3 toxicity, any subjects who completed one full course of therapy; subjects who have
      completed at least two courses of therapy and had their first follow-up MRI evaluation except
      for discovery of a target tumor other than a PN; and any subjects who has at least two
      samples drawn for plasma cytokines/growth factors, one at baseline and at least one other
      after starting therapy.

      Data Safety Monitoring Board (DSMB) and a Medical Monitor have been established for this
      study for the purpose of ensuring data compliance and regular monitoring. An early stopping
      rules have been defined within the protocol. The early stopping rule will invoked for both
      Strata separately to potentially prevent accrual subjects onto the study in the event that
      binimetinib is associated with a higher than acceptable rate of dose-limiting toxicity (DLT)
      requiring removal from study (10% or higher) during the first 2 courses. Toxicity will be
      continuously monitored. If at any time >2 of the first 10 subjects or 4 or more of the first
      15 total subjects are removed for toxicity, then accrual will be stopped until the DSMB
      reviews the safety and efficacy data for the study. Based on the review, the DSMB can either
      recommend termination of the study or reopen recruitment. The Medical Monitor is a qualified
      physician who is not associated with this protocol and is a member of the DSMB. The Medical
      Monitor may perform oversight functions duties: may discuss the research protocol with the
      investigators, interview human subjects, and consult with others outside of the study about
      the research; shall have the authority to stop the research protocol in progress, remove
      individual subjects from protocol, and take whatever steps are necessary to protect the
      safety and well being of human subjects until the Institutional Review Board (IRB) can assess
      the monitor's report; and shall have the responsibility to promptly report the observation
      and findings to the IRB or other designated official/organization. The Medical Monitor is
      specifically required to review and provide written report of all unanticipated problems
      involving risk to subjects or others and serious adverse events.

      In addition, as part of the Data Safety Monitoring Plan, the Study Chairs and the NF
      Consortium Clinical Research Nurse Manager will review subject eligibility, study progress,
      safety issues, protocol deviations and adverse events. Monthly reports will be generated by
      the NF Consortium Data Management Center to assess completeness of data. Monthly phone
      conferences will take place between NF Consortium Operations Center and the Protocol Team to
      address data issues.

      The sample size for this trial is based on safety and feasibility factors. The data needed
      for safety is based on risk versus benefit, and for feasibility, we expect at least efficacy
      of 25% response rate. For safety reasons, subjects who do not achieve at least 15% reduction
      in volume of target tumor after 8 courses will be discontinued from the trial, as the
      likelihood of achieving a 20% reduction in tumor volume by 12 months is minimal. Safety
      analysis set will be described and summarized based on information regarding study treatment
      administrations, drug dosing and course compliance, and safety variables (e.g. adverse
      events/serious adverse events). All analyses for outcome results will be based on evaluable
      subjects. Given the difference in the clinical behavior of PN in the adults and pediatric
      subjects, the adult and children stratum will be analyzed independently.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change from Baseline Target Tumor Volume at 12 months
time frame: Approximately 12 months
description: To determine the objective response defined as 20% or greater tumor volume reduction. Patients will undergo volumetric assays of their target PN using MRI.
measure: Incidence of Treatment-Emergent Adverse Events
time frame: Up to 24 months
description: To evaluate the toxicity of protracted binimetinib administration in this patient population. Subjects will be monitored continuously for adverse events and serious adverse events throughout the study.
arm group label: Open label study of Binimetinib (MEK162)
arm group type: Experimental
description: Subjects (≥ 18 years) (Stratum A) will receive a course of binimetinib by mouth twice a day (12 hours apart) of 45 mg/dose. Duration of each course is 4 weeks. After 8 courses, subjects will receive additional courses if MRI results showed at least 15% reduction in volume of the target tumor. Subjects can continue on therapy and will be evaluated at the end of 12 courses. Subjects who have ≥ 20% reduction in volume of the target tumor according to the MRI results can continue therapy up to an additional year (maximum of 24 total courses). Subjects who have not met the tumor reduction at the specified times will be removed from the study therapy. Subjects will be carefully monitored for toxicities associated with binimetinib.
Recruitment of subjects 1 - 17 years of age (Stratum B) is currently available. The pediatric maximum tolerated dose (MTD) of binimetinib the pediatric patients (Statum B) was established by a phase 1 study (NCT022).
intervention type: Drug
intervention name: Binimetinib
description: Adult subjects (18 years and older) will receive binimetinib by mouth twice daily of 45mg/dose. Pediatric subjects (1-17 years of age) are being treated on the pediatric MTD established by a phase I study (NCT02285439).
arm group label: Open label study of Binimetinib (MEK162)
criteria: 
gender: All
minimum age: 1 Year
maximum age: N/A
healthy volunteers: No
last name: Bruce Korf, MD, PhD
role: Study Chair
affiliation: University of Alabama at Birmingham
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country: United States
url: http://clinicaltrials.gov/show/NCT01362803
description: A phase 1 study of mitogen activated protein kinase (MEK) 1 inhibitor AZD6244 hydrogen sulfate (selumetinib sulfate) in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PN)
url: https://scholar.google.com
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PMID: 11708944
responsible party type: Principal Investigator
investigator affiliation: University of Alabama at Birmingham
investigator full name: Bruce Korf, MD
investigator title: Principal Investigator
mesh term: Neurofibromatoses
mesh term: Neurofibromatosis 1
mesh term: Neurofibroma
mesh term: Neurofibroma, Plexiform
sharing ipd: No