<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/NCT03016091</url>
  </required_header>
  <id_info>
    <org_study_id>MK-3475-415</org_study_id>
    <nct_id>NCT03016091</nct_id>
  </id_info>
  <brief_title>A Trial of Pembrolizumab for Refractory Atypical and Anaplastic Meningioma</brief_title>
  <official_title>A Phase II, Open-label, Single Arm Trial of Pembrolizumab for Refractory Atypical and Anaplastic Meningioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rabin Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rabin Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A Phase II, Open-label, Single Arm Trial of Pembrolizumab for Refractory Atypical and&#xD;
      Anaplastic Meningioma&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multicenter, prospective, single arm, open label, interventional study. The goal of&#xD;
      this study, is to evaluate feasibility and efficacy of pembrolizumab for the treatment of&#xD;
      recurrent or progressive meningioma (WHO grades II-III) or hemangiopericytoma (HPC). All&#xD;
      patients will receive IV pembrolizumab, at a dose of 200mg, every 3 weeks. Patients will be&#xD;
      treated until disease progression or intolerable toxicity. Treatment can be stopped after one&#xD;
      year of treatment in case of stable disease or completer response, with re-initiation of&#xD;
      treatment upon progression. Expression of PD1 and PD-L1 will be tested, on tumor cells, using&#xD;
      IHC staining on biopsy material obtained from previous surgeries.&#xD;
&#xD;
      All patients will have a baseline neurologic and clinical exam, MRI scan, a brain dedicated&#xD;
      CT-PET scan, a baseline cognitive exam and QOL assessment with a dedicated questionnaire.&#xD;
      Patients will have a clinical and neurological exam every treatment cycle. MRI scan will be&#xD;
      repeated after 2 months from the beginning of the trial drug administration and then every&#xD;
      2-3 months. There are no designated and specific criteria for response assessment in the&#xD;
      treatment of meningioma. Therefore, response evaluation will be made using the RECIST 1.1&#xD;
      criteria, as used for solid tumors. The trial will allow the continuation of pembrolizumab in&#xD;
      case of stable or improved clinical response, when pseudo-progression is suspected in the&#xD;
      MRI. In addition, response assessment will also be made according to the RANO criteria, as&#xD;
      used for high grade glioma. This will be compared to the RECIST evaluation, but will not be&#xD;
      used for treatment decision making.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 20, 2018</start_date>
  <completion_date type="Anticipated">February 2022</completion_date>
  <primary_completion_date type="Anticipated">February 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <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>progression free survival (PFS)</measure>
    <time_frame>6 months</time_frame>
    <description>To determine the 6 months progression free survival (PFS) rate for patients with recurrent or progressive meningioma on pembrolizumab therapy, using the RECIST 1.1 criteria.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>progression free survival (PFS)</measure>
    <time_frame>12 months</time_frame>
    <description>To determine the 12 months progression free survival (PFS) rate for patients with recurrent or progressive meningioma on pembrolizumab therapy, using the RECIST 1.1 criteria.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>4 years</time_frame>
    <description>To determine OS of patients with recurrent or progressive meningioma treated with pembrolizumab.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">25</enrollment>
  <condition>Atypical Meningioma</condition>
  <condition>Anaplastic Meningioma</condition>
  <condition>Hemangiopericytoma</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>IV Pembrolizumab 200mg, given every 3 weeks until disease progression or intolerable toxicity</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>anti PD-L1</description>
    <arm_group_label>Arm 1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Be willing and able to provide written informed consent/assent for the trial.&#xD;
&#xD;
          2. Be 18 years of age on day of signing informed consent.&#xD;
&#xD;
          3. Have measurable disease based on RECIST 1.1.&#xD;
&#xD;
          4. Histologically, previously proven, grade II or III meningioma, HPC or classic&#xD;
             radiographic features of a recurrent surgically inaccessible atypical or anaplastic&#xD;
             meningioma.&#xD;
&#xD;
          5. All patients would have to have recurrence despite radiotherapy, unless radiotherapy&#xD;
             is contraindicated.&#xD;
&#xD;
          6. No limit on the number of prior surgeries, radiation or radiosurgery treatments.&#xD;
&#xD;
          7. No limit on prior systemic therapies - chemotherapy or biological agents.&#xD;
&#xD;
          8. Patients who received stereotactic radiosurgery (SRS) are eligible without histologic&#xD;
             documentation of recurrence if at least 6 months have passed from previous SRS&#xD;
             treatment, and preferably, but not necessarily a 2-ﬂuoro-2-deoxy-D-glucose PET imaging&#xD;
             demonstrated hypermetabolism.&#xD;
&#xD;
          9. KPS≥50%&#xD;
&#xD;
         10. At least 4 weeks since any prior therapy.&#xD;
&#xD;
         11. Life expectancy of at least 4 months.&#xD;
&#xD;
         12. Dexamethasone use will be allowed up to a dose of 2mg per day. Steroids dose should be&#xD;
             reduced or stopped 7 days prior to treatment with study drug.&#xD;
&#xD;
         13. Demonstrate adequate organ function as defined in Table 1, all screening labs should&#xD;
             be performed within 10 days of treatment initiation.&#xD;
&#xD;
             Table 1 Adequate Organ Function Laboratory Values&#xD;
&#xD;
             Hematological Absolute neutrophil count (ANC)≥1,500 /mcL Platelets≥100,000 / mcL&#xD;
             Hemoglobin≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days&#xD;
             of assessment) Renal Serum creatinine OR Measured or calculated creatinine clearance&#xD;
             (GFR can also be used in place of creatinine or CrCl)≤1.5 X upper limit of normal&#xD;
             (ULN) OR&#xD;
&#xD;
             ≥60 mL/min for subject with creatinine levels &gt; 1.5 X institutional ULN Hepatic Serum&#xD;
             total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total&#xD;
             bilirubin levels &gt; 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR&#xD;
&#xD;
             ≤ 5 X ULN for subjects with liver metastases Albumin &gt;2.5 mg/dL Coagulation&#xD;
             International Normalized Ratio (INR) or Prothrombin Time (PT)&#xD;
&#xD;
             Activated Partial Thromboplastin Time (aPTT)≤1.5 X ULN unless subject is receiving&#xD;
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use&#xD;
             of anticoagulants&#xD;
&#xD;
             ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is&#xD;
             within therapeutic range of intended use of anticoagulants a Creatinine clearance&#xD;
             should be calculated per institutional standard.&#xD;
&#xD;
         14. Female subject of childbearing potential should have a negative urine or serum&#xD;
             pregnancy within 72 hours prior to receiving the first dose of study medication. If&#xD;
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test&#xD;
             will be required.&#xD;
&#xD;
         15. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an&#xD;
             adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the&#xD;
             course of the study through 120 days after the last dose of study medication.&#xD;
&#xD;
             Note: Abstinence is acceptable if this is the usual lifestyle and preferred&#xD;
             contraception for the subject.&#xD;
&#xD;
         16. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate&#xD;
             method of contraception as outlined in Section 5.7.1- Contraception, starting with the&#xD;
             first dose of study therapy through 120 days after the last dose of study therapy.&#xD;
&#xD;
        Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception&#xD;
        for the subject.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Is currently participating and receiving study therapy or has participated in a study&#xD;
             of an investigational agent and received study therapy or used an investigational&#xD;
             device within 4 weeks of the first dose of treatment.&#xD;
&#xD;
          2. Has a diagnosis of immunodeficiency or is receiving other form of immunosuppressive&#xD;
             therapy within 7 days prior to the first dose of trial treatment.&#xD;
&#xD;
          3. Patients who are steroid dependent and cannot reduce the dexamethasone dose to a&#xD;
             maximal dose of 2mg per day.&#xD;
&#xD;
          4. Has a known history of active TB (Bacillus Tuberculosis)&#xD;
&#xD;
          5. Hypersensitivity to pembrolizumab or any of its excipients.&#xD;
&#xD;
          6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study&#xD;
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events&#xD;
             due to agents administered more than 4 weeks earlier.&#xD;
&#xD;
          7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy&#xD;
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at&#xD;
             baseline) from adverse events due to a previously administered agent.&#xD;
&#xD;
               -  Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and&#xD;
                  may qualify for the study.&#xD;
&#xD;
               -  Note: If subject received major surgery, they must have recovered adequately from&#xD;
                  the toxicity and/or complications from the intervention prior to starting&#xD;
                  therapy.&#xD;
&#xD;
          8. Has a known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the&#xD;
             skin that has undergone potentially curative therapy or in situ cervical cancer.&#xD;
&#xD;
          9. Has known active central nervous system (CNS) metastases and/or carcinomatous&#xD;
             meningitis.&#xD;
&#xD;
         10. Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment.&#xD;
&#xD;
         11. Has known history of, or any evidence of active, non-infectious pneumonitis.&#xD;
&#xD;
         12. Has an active infection requiring systemic therapy.&#xD;
&#xD;
         13. Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the subject's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating investigator.&#xD;
&#xD;
         14. Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
         15. Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the pre-screening or screening visit&#xD;
             through 120 days after the last dose of trial treatment.&#xD;
&#xD;
         16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.&#xD;
&#xD;
         17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).&#xD;
&#xD;
         18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA&#xD;
             [qualitative] is detected).&#xD;
&#xD;
         19. Has received a live vaccine within 30 days of planned start of study therapy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Dror Limon, Dr</last_name>
    <phone>972-54-3009451</phone>
    <email>drorlim@tlvmc.gov.il</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Shlomit Yust-Katz, Dr</last_name>
    <phone>972-58-7454567</phone>
    <email>shlomit2@clalit.org.il</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Rabin Medical Center</name>
      <address>
        <city>Petach Tikva</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Shlomit Yust-Katz, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Tel Aviv Medical Center</name>
      <address>
        <city>Tel Aviv</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Dror Limon, MD</last_name>
    </contact>
    <investigator>
      <last_name>Dror Limon, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>January 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 10, 2017</study_first_posted>
  <last_update_submitted>April 16, 2019</last_update_submitted>
  <last_update_submitted_qc>April 16, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Meningioma</mesh_term>
    <mesh_term>Hemangiopericytoma</mesh_term>
    <mesh_term>Solitary Fibrous Tumors</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03016091
org study id: MK-3475-415
nct id: NCT03016091
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
A Phase II, Open-label, Single Arm Trial of Pembrolizumab for Refractory Atypical and
      Anaplastic Meningioma
This is a multicenter, prospective, single arm, open label, interventional study. The goal of
      this study, is to evaluate feasibility and efficacy of pembrolizumab for the treatment of
      recurrent or progressive meningioma (WHO grades II-III) or hemangiopericytoma (HPC). All
      patients will receive IV pembrolizumab, at a dose of 200mg, every 3 weeks. Patients will be
      treated until disease progression or intolerable toxicity. Treatment can be stopped after one
      year of treatment in case of stable disease or completer response, with re-initiation of
      treatment upon progression. Expression of PD1 and PD-L1 will be tested, on tumor cells, using
      IHC staining on biopsy material obtained from previous surgeries.

      All patients will have a baseline neurologic and clinical exam, MRI scan, a brain dedicated
      CT-PET scan, a baseline cognitive exam and QOL assessment with a dedicated questionnaire.
      Patients will have a clinical and neurological exam every treatment cycle. MRI scan will be
      repeated after 2 months from the beginning of the trial drug administration and then every
      2-3 months. There are no designated and specific criteria for response assessment in the
      treatment of meningioma. Therefore, response evaluation will be made using the RECIST 1.1
      criteria, as used for solid tumors. The trial will allow the continuation of pembrolizumab in
      case of stable or improved clinical response, when pseudo-progression is suspected in the
      MRI. In addition, response assessment will also be made according to the RANO criteria, as
      used for high grade glioma. This will be compared to the RECIST evaluation, but will not be
      used for treatment decision making.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: progression free survival (PFS)
time frame: 6 months
description: To determine the 6 months progression free survival (PFS) rate for patients with recurrent or progressive meningioma on pembrolizumab therapy, using the RECIST 1.1 criteria.
measure: progression free survival (PFS)
time frame: 12 months
description: To determine the 12 months progression free survival (PFS) rate for patients with recurrent or progressive meningioma on pembrolizumab therapy, using the RECIST 1.1 criteria.
measure: Overall survival (OS)
time frame: 4 years
description: To determine OS of patients with recurrent or progressive meningioma treated with pembrolizumab.
arm group label: Arm 1
arm group type: Experimental
description: IV Pembrolizumab 200mg, given every 3 weeks until disease progression or intolerable toxicity
intervention type: Drug
intervention name: Pembrolizumab
description: anti PD-L1
arm group label: Arm 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Dror Limon, Dr
phone: 972-54-3009451
email: drorlim@tlvmc.gov.il
last name: Shlomit Yust-Katz, Dr
phone: 972-58-7454567
email: shlomit2@clalit.org.il
facility: 
status: Recruiting
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
country: Israel
responsible party type: Sponsor
mesh term: Meningioma
mesh term: Hemangiopericytoma
mesh term: Solitary Fibrous Tumors
mesh term: Pembrolizumab