<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/NCT04465643</url>
  </required_header>
  <id_info>
    <org_study_id>J20112</org_study_id>
    <secondary_id>IRB00215437</secondary_id>
    <nct_id>NCT04465643</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Nivolumab Plus Ipilimumab for Newly Diagnosed Malignant Peripheral Nerve Sheath Tumor</brief_title>
  <official_title>Neoadjuvant Nivolumab Plus Ipilimumab for Newly Diagnosed Malignant Peripheral Nerve Sheath Tumor</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</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>
      The purpose of the study is to evaluate safety and feasibility of neoadjuvant nivolumab plus&#xD;
      ipilimumab prior to standard therapy (surgery, chemotherapy or radiation therapy) in patients&#xD;
      with Neurofibromatosis Type 1 (NF1) and newly diagnosed pre-malignant and malignant&#xD;
      peripheral nerve sheath tumors (MPNST) for whom surgery for resection of tumor is indicated.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 8, 2021</start_date>
  <completion_date type="Anticipated">August 2026</completion_date>
  <primary_completion_date type="Anticipated">June 2025</primary_completion_date>
  <phase>Phase 1</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>Safety of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) as determined by number of participants with dose limiting toxicities (DLT)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Maximum tolerated dose will be determined by the maximum dose at which the least number of participants experience dose-limiting toxicity. The dose limiting toxicity is defined using the Common Terminology Criteria for Adverse Events (CTCAE).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who achieve a response</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Number of participants who achieve a response (improved progression free survival).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety as assessed by number of treatment-emergent adverse events in patients on combination nivolumab and ipilimumab with NF1, standard low, or high grade MPNST therapy</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>Up to 2 years.</time_frame>
    <description>Proportion of participants with measurable disease at baseline and have been re-evaluated after at least 1 cycle of therapy with observed reduction in tumor burden as defined by RECIST and iRECIST criteria after 2 doses of nivolumab and ipilimumab.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in pain levels in relation to target tumor as assessed by the Numeric Rating Scale</measure>
    <time_frame>Baseline, Week 6, 4 months, and 8 months</time_frame>
    <description>Evaluate pain levels in participants related to target tumor via the Numeric Rating Scale. Assessment to be performed at baseline, Week 6, 4 months, and 8 months via numeric grading scale (0 through 10) recorded by participant via survey in order to determine an improvement or worsening of pain throughout treatment. Lower scores indicate no pain or decreased levels of pain while higher score indicate increased levels of pain.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in pain levels in relation to target tumor as assessed by the Pain Interference Index</measure>
    <time_frame>Baseline, Week 6, 4 months, and 8 months</time_frame>
    <description>Evaluate pain in participants related to target tumor via the Pain Interference Index (6-24 years). Assessment to be performed at baseline, Week 6, 4 months, and 8 months via numeric grading scale (0 through 6) recorded by participant via survey In order to determine an improvement or worsening of pain throughout treatment. Lower scores indicate no interference or decreased levels of interference in every day life while higher scores indicate increased interference in ever day life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in pain levels in relation to target tumor as assessed by the Patient-Reported Outcome Measurement Information System</measure>
    <time_frame>Baseline, Week 6, 4 months, and 8 months</time_frame>
    <description>Evaluate pain in participants related to target tumor via the Patient-Reported Outcome Measurement Information System (PROMIS). Assessment to be performed at at baseline, Week 6, 4 months, and 8 months via numeric grading scale (1 through 5) recorded by participant via survey in order to determine an improvement or worsening of pain throughout treatment. Higher scores indicate no to low difficulty in mobility while lower scores indicate increased difficulty or inability in mobility.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>At 4 months post intervention</time_frame>
    <description>Proportion of participants who had measurable disease at baseline and have been re-evaluated after at least 1 cycle of therapy with observed reduction in tumor burden as defined by RECIST and iRECIST criteria at 4 months.</description>
  </other_outcome>
  <other_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Proportion of participants who achieve progression free survival post treatment</description>
  </other_outcome>
  <other_outcome>
    <measure>Tumor Response as assessed by immune markers in tumor samples</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Analyses may include phosphorylated protines of signaling pathways and phenotypes of infiltrating immune cell populations including but not limited to CD3, CD4, FoxP3, CD25, CD8, CD45, CD11b, CD163, CD206, CD68, CD56, CD20, CD45RO and granzyme B. Pathologists will assign an intratumoral and peritumoral immune cell infiltrate grade of 0 through 3. Immunohistochemical analysis of exploratory markers will focus on areas including but not limited to: B7 family ligands PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, B7-H4, as well as inhibitory receptors on lymphocytes, including PD-1, 2B4, LAG-3, BTLA, Tim-3, CTLA-4, and TIGIT.</description>
  </other_outcome>
  <other_outcome>
    <measure>Pharmacodynamic activity as assessed by markers in blood samples</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>T cell subsets (including CD4, CD8, and Treg with CD25 and Foxp3) will be analyzed as well as co-stimulatory and co-inhibitory molecule expression and markers for T cell activation state (e.g., CD25, HLADR, CD45RO, LAP, PD-1, PD-L1, LAG-3, ICOS, OX40, 41BB). B cells (CD19, CD20, PD-1, PD-L1, PD-L2, ICOSL), dendritic cells and macrophages (CD68, CD83, CD1a, PD-L1, PD-L2, 4-1BB, 4-1BBL, ICOSL, HLA-DR) and natural killer cells (CD56) will be enumerated and characterized. Myeloid derived suppressor cells (MDSCs) will be enumerated by staining for CD14, CD11b, and HLADR expression.</description>
  </other_outcome>
  <other_outcome>
    <measure>CD3 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD3 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD4 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD4 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>FoxP3 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>FoxP3 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD25 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD25 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD8 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD8 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD45 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD45 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD11b Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD11b cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD163 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD163 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD206 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD206 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD68 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD68 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD56 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD56 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD20 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD20 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD45RO Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD45RO cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>Granzyme B Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Granzyme B cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>PD-L1 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>PD-L1 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>PD-L2 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>PD-L2 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>B7-H3 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>B7-H3 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>B7-H4 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>B7-H4 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>PD-1 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>PD-1 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>2B4 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>2B4 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>LAG-3 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>LAG-3 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>BTLA Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>BTLA cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>Tim-3 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Tim-3 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CTLA-4 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CTLA-4 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>TIGIT Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>TIGIT cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>HLA-DR Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>HLA-DR cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>LAP Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>LAP cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD14 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD14 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>ICOS Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>ICOS cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>OX40 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>OX40 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>4-1BB Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>4-1BB cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>4-1BBL Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>4-1BBL cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>ICOSL Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>ICOSL cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD19 Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD19 cell count in cells/mm^3</description>
  </other_outcome>
  <other_outcome>
    <measure>CD1a Cell Count</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>CD1a cell count in cells/mm^3</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Nerve Sheath Tumors</condition>
  <arm_group>
    <arm_group_label>Immunotherapy with Nivolumab and Ipilimumab</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Nivolumab 4.5 mg/kg every 3 weeks (Q3W) x 2 Ipilimumab 1 mg/kg Q3W x 2 Nivolumab monotherapy 4.5mg/kg Q3W concurrent with standard therapy Nivolumab monotherapy should be held for at least 2 weeks before and 2 weeks after surgery</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab 4.5 mg/kg Q3W x 2</description>
    <arm_group_label>Immunotherapy with Nivolumab and Ipilimumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Ipilimumab 1 mg/kg Q3W x 2</description>
    <arm_group_label>Immunotherapy with Nivolumab and Ipilimumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed diagnosis of atypical neurofibromatous neoplasms of uncertain&#xD;
             biologic potential (ANNUBP), low grade malignant peripheral nerve sheath tumor (MPNST)&#xD;
             or high grade MPNST in accordance with the Miettinen et al diagnostic criteria via&#xD;
             biopsy&#xD;
&#xD;
          -  Plexiform neurofibroma or other tumors such as optic pathway glioma, other low-grade&#xD;
             glioma or other neoplasm in addition to the ANNUBP, low grade MPNST or high grade&#xD;
             MPNST that is stable (has not required treatment in the last 12 months and is not&#xD;
             anticipated to need treatment in the next 12 months)&#xD;
&#xD;
          -  Measureable disease by RECIST criteria in at least one site.&#xD;
&#xD;
          -  Karnofsky Performance Scale ≥ 60%&#xD;
&#xD;
          -  No contraindications for Nivolumab or Ipilimumab&#xD;
&#xD;
          -  Normal organ and marrow function on routine laboratory tests&#xD;
&#xD;
          -  Evidence of post-menopausal status or negative urinary/serum pregnancy test for female&#xD;
             pre-menopausal subjects. Women will be considered post-menopausal if they have been&#xD;
             amenorrheic for 12 months without an alternative medical cause&#xD;
&#xD;
          -  Ability to understand and willingness of sign consent form&#xD;
&#xD;
          -  Willingness to comply with the protocol for the duration of the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Chemotherapy or other investigational agent for the current episode of newly diagnosed&#xD;
             atypical neurofibroma or MPNST&#xD;
&#xD;
          -  Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PDL-2 antibody&#xD;
&#xD;
          -  Known allergy to compounds of similar chemical or biologic composition to Nivolumab or&#xD;
             Ipilimumab&#xD;
&#xD;
          -  Pregnant or breastfeeding women&#xD;
&#xD;
          -  Known history of Human Immunodeficiency Virus&#xD;
&#xD;
          -  Active infection requiring therapy, including known positive tests for Hepatitis B&#xD;
             surface antigen or Hepatitis C ribonucleic acid (RNA)&#xD;
&#xD;
          -  Active autoimmune disease, history of autoimmune disease or history of syndrome that&#xD;
             required systemic steroids or immunosuppressive medications, e.g. organ, tissue, or&#xD;
             allogenic hematopoietic stem cell transplant (HSCT) recipients. Exceptions include&#xD;
             those with resolved childhood asthma/atopy. Subjects with asthma who require&#xD;
             intermittent use of bronchodilators (such as albuterol) will not be excluded from this&#xD;
             study. Subjects are also permitted to enroll if they have vitiligo, type I diabetes&#xD;
             mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone&#xD;
             replacement, psoriasis not requiring systemic treatment, or conditions not expected to&#xD;
             recur in the absence of an external trigger&#xD;
&#xD;
          -  A condition requiring systemic treatment with either corticosteroids (&gt; 10 mg daily&#xD;
             prednisone equivalents) or other immunosuppressive medications within 14 days of study&#xD;
             drug administration. Inhaled or topical steroids and adrenal replacement doses &gt; 10 mg&#xD;
             daily prednisone equivalents are permitted in the absence of active autoimmune&#xD;
             disease.&#xD;
&#xD;
          -  Use of any vaccines against infectious diseases (e.g. varicella, influenza, etc.) up&#xD;
             to 4 weeks (28 days) before receiving nivolumab and ipilimumab.&#xD;
&#xD;
          -  Prisoners or subjects who are compulsorily detained for treatment of either a&#xD;
             psychiatric or physical (e.g. infectious disease) illness&#xD;
&#xD;
          -  Prior radiation doses equivalent to, or greater than, 8000 centigray (cGy) to the&#xD;
             target lesions at 200 cGy fractions at any time point&#xD;
&#xD;
          -  Any radiation to the the target lesions within 6 months of enrollment&#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;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jaishri Blakeley, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jaishri Blakeley, MD</last_name>
    <phone>410-955-8837</phone>
    <email>jblakel3@jhmi.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Anthony Stanfield</last_name>
    <phone>410-502-1962</phone>
    <email>astanfi1@jhmi.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Johns Hopkins Medical Institution</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jaishri Blakeley, MD</last_name>
      <phone>410-955-8837</phone>
      <email>jblakel3@jhmi.edu</email>
    </contact>
    <contact_backup>
      <last_name>Anthony Stanfield</last_name>
      <phone>410-502-1962</phone>
      <email>astanfi1@jhmi.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 7, 2020</study_first_submitted>
  <study_first_submitted_qc>July 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 10, 2020</study_first_posted>
  <last_update_submitted>June 29, 2023</last_update_submitted>
  <last_update_submitted_qc>June 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 3, 2023</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>Nerve Sheath Neoplasms</mesh_term>
    <mesh_term>Neurofibrosarcoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</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/NCT04465643
org study id: J20112
secondary id: IRB00215437
nct id: NCT04465643
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of the study is to evaluate safety and feasibility of neoadjuvant nivolumab plus
      ipilimumab prior to standard therapy (surgery, chemotherapy or radiation therapy) in patients
      with Neurofibromatosis Type 1 (NF1) and newly diagnosed pre-malignant and malignant
      peripheral nerve sheath tumors (MPNST) for whom surgery for resection of tumor is indicated.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events
time frame: Up to 2 years
description: Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
measure: Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who experience adverse events
time frame: Up to 2 years
description: Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).
measure: Maximum Tolerated Dose (MTD) as determined by number of participants with dose limiting toxicities (DLT)
time frame: Up to 2 years
description: Maximum tolerated dose will be determined by the maximum dose at which the least number of participants experience dose-limiting toxicity. The dose limiting toxicity is defined using the Common Terminology Criteria for Adverse Events (CTCAE).
measure: Feasibility of combination nivolumab and ipilimumab as assessed by number of participants who achieve a response
time frame: Up to 2 years
description: Number of participants who achieve a response (improved progression free survival).
measure: Safety as assessed by number of treatment-emergent adverse events in patients on combination nivolumab and ipilimumab with NF1, standard low, or high grade MPNST therapy
time frame: Up to 2 years
description: Number of participants who experience grade 1 or higher adverse events, as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0)
measure: Objective response rate (ORR)
time frame: Up to 2 years.
description: Proportion of participants with measurable disease at baseline and have been re-evaluated after at least 1 cycle of therapy with observed reduction in tumor burden as defined by RECIST and iRECIST criteria after 2 doses of nivolumab and ipilimumab.
measure: Change in pain levels in relation to target tumor as assessed by the Numeric Rating Scale
time frame: Baseline, Week 6, 4 months, and 8 months
description: Evaluate pain levels in participants related to target tumor via the Numeric Rating Scale. Assessment to be performed at baseline, Week 6, 4 months, and 8 months via numeric grading scale (0 through 10) recorded by participant via survey in order to determine an improvement or worsening of pain throughout treatment. Lower scores indicate no pain or decreased levels of pain while higher score indicate increased levels of pain.
measure: Change in pain levels in relation to target tumor as assessed by the Pain Interference Index
time frame: Baseline, Week 6, 4 months, and 8 months
description: Evaluate pain in participants related to target tumor via the Pain Interference Index (6-24 years). Assessment to be performed at baseline, Week 6, 4 months, and 8 months via numeric grading scale (0 through 6) recorded by participant via survey In order to determine an improvement or worsening of pain throughout treatment. Lower scores indicate no interference or decreased levels of interference in every day life while higher scores indicate increased interference in ever day life.
measure: Change in pain levels in relation to target tumor as assessed by the Patient-Reported Outcome Measurement Information System
time frame: Baseline, Week 6, 4 months, and 8 months
description: Evaluate pain in participants related to target tumor via the Patient-Reported Outcome Measurement Information System (PROMIS). Assessment to be performed at at baseline, Week 6, 4 months, and 8 months via numeric grading scale (1 through 5) recorded by participant via survey in order to determine an improvement or worsening of pain throughout treatment. Higher scores indicate no to low difficulty in mobility while lower scores indicate increased difficulty or inability in mobility.
measure: Objective response rate (ORR)
time frame: At 4 months post intervention
description: Proportion of participants who had measurable disease at baseline and have been re-evaluated after at least 1 cycle of therapy with observed reduction in tumor burden as defined by RECIST and iRECIST criteria at 4 months.
measure: Progression Free Survival
time frame: Up to 2 years
description: Proportion of participants who achieve progression free survival post treatment
measure: Tumor Response as assessed by immune markers in tumor samples
time frame: Up to 2 years
description: Analyses may include phosphorylated protines of signaling pathways and phenotypes of infiltrating immune cell populations including but not limited to CD3, CD4, FoxP3, CD25, CD8, CD45, CD11b, CD163, CD206, CD68, CD56, CD20, CD45RO and granzyme B. Pathologists will assign an intratumoral and peritumoral immune cell infiltrate grade of 0 through 3. Immunohistochemical analysis of exploratory markers will focus on areas including but not limited to: B7 family ligands PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, B7-H4, as well as inhibitory receptors on lymphocytes, including PD-1, 2B4, LAG-3, BTLA, Tim-3, CTLA-4, and TIGIT.
measure: Pharmacodynamic activity as assessed by markers in blood samples
time frame: Up to 2 years
description: T cell subsets (including CD4, CD8, and Treg with CD25 and Foxp3) will be analyzed as well as co-stimulatory and co-inhibitory molecule expression and markers for T cell activation state (e.g., CD25, HLADR, CD45RO, LAP, PD-1, PD-L1, LAG-3, ICOS, OX40, 41BB). B cells (CD19, CD20, PD-1, PD-L1, PD-L2, ICOSL), dendritic cells and macrophages (CD68, CD83, CD1a, PD-L1, PD-L2, 4-1BB, 4-1BBL, ICOSL, HLA-DR) and natural killer cells (CD56) will be enumerated and characterized. Myeloid derived suppressor cells (MDSCs) will be enumerated by staining for CD14, CD11b, and HLADR expression.
measure: CD3 Cell Count
time frame: Up to 1 year
description: CD3 cell count in cells/mm^3
measure: CD4 Cell Count
time frame: Up to 1 year
description: CD4 cell count in cells/mm^3
measure: FoxP3 Cell Count
time frame: Up to 1 year
description: FoxP3 cell count in cells/mm^3
measure: CD25 Cell Count
time frame: Up to 1 year
description: CD25 cell count in cells/mm^3
measure: CD8 Cell Count
time frame: Up to 1 year
description: CD8 cell count in cells/mm^3
measure: CD45 Cell Count
time frame: Up to 1 year
description: CD45 cell count in cells/mm^3
measure: CD11b Cell Count
time frame: Up to 1 year
description: CD11b cell count in cells/mm^3
measure: CD163 Cell Count
time frame: Up to 1 year
description: CD163 cell count in cells/mm^3
measure: CD206 Cell Count
time frame: Up to 1 year
description: CD206 cell count in cells/mm^3
measure: CD68 Cell Count
time frame: Up to 1 year
description: CD68 cell count in cells/mm^3
measure: CD56 Cell Count
time frame: Up to 1 year
description: CD56 cell count in cells/mm^3
measure: CD20 Cell Count
time frame: Up to 1 year
description: CD20 cell count in cells/mm^3
measure: CD45RO Cell Count
time frame: Up to 1 year
description: CD45RO cell count in cells/mm^3
measure: Granzyme B Cell Count
time frame: Up to 1 year
description: Granzyme B cell count in cells/mm^3
measure: PD-L1 Cell Count
time frame: Up to 1 year
description: PD-L1 cell count in cells/mm^3
measure: PD-L2 Cell Count
time frame: Up to 1 year
description: PD-L2 cell count in cells/mm^3
measure: B7-H3 Cell Count
time frame: Up to 1 year
description: B7-H3 cell count in cells/mm^3
measure: B7-H4 Cell Count
time frame: Up to 1 year
description: B7-H4 cell count in cells/mm^3
measure: PD-1 Cell Count
time frame: Up to 1 year
description: PD-1 cell count in cells/mm^3
measure: 2B4 Cell Count
time frame: Up to 1 year
description: 2B4 cell count in cells/mm^3
measure: LAG-3 Cell Count
time frame: Up to 1 year
description: LAG-3 cell count in cells/mm^3
measure: BTLA Cell Count
time frame: Up to 1 year
description: BTLA cell count in cells/mm^3
measure: Tim-3 Cell Count
time frame: Up to 1 year
description: Tim-3 cell count in cells/mm^3
measure: CTLA-4 Cell Count
time frame: Up to 1 year
description: CTLA-4 cell count in cells/mm^3
measure: TIGIT Cell Count
time frame: Up to 1 year
description: TIGIT cell count in cells/mm^3
measure: HLA-DR Cell Count
time frame: Up to 1 year
description: HLA-DR cell count in cells/mm^3
measure: LAP Cell Count
time frame: Up to 1 year
description: LAP cell count in cells/mm^3
measure: CD14 Cell Count
time frame: Up to 1 year
description: CD14 cell count in cells/mm^3
measure: ICOS Cell Count
time frame: Up to 1 year
description: ICOS cell count in cells/mm^3
measure: OX40 Cell Count
time frame: Up to 1 year
description: OX40 cell count in cells/mm^3
measure: 4-1BB Cell Count
time frame: Up to 1 year
description: 4-1BB cell count in cells/mm^3
measure: 4-1BBL Cell Count
time frame: Up to 1 year
description: 4-1BBL cell count in cells/mm^3
measure: ICOSL Cell Count
time frame: Up to 1 year
description: ICOSL cell count in cells/mm^3
measure: CD19 Cell Count
time frame: Up to 1 year
description: CD19 cell count in cells/mm^3
measure: CD1a Cell Count
time frame: Up to 1 year
description: CD1a cell count in cells/mm^3
arm group label: Immunotherapy with Nivolumab and Ipilimumab
arm group type: Other
description: Nivolumab 4.5 mg/kg every 3 weeks (Q3W) x 2 Ipilimumab 1 mg/kg Q3W x 2 Nivolumab monotherapy 4.5mg/kg Q3W concurrent with standard therapy Nivolumab monotherapy should be held for at least 2 weeks before and 2 weeks after surgery
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab 4.5 mg/kg Q3W x 2
arm group label: Immunotherapy with Nivolumab and Ipilimumab
intervention type: Drug
intervention name: Ipilimumab
description: Ipilimumab 1 mg/kg Q3W x 2
arm group label: Immunotherapy with Nivolumab and Ipilimumab
criteria: 
gender: All
minimum age: 12 Years
maximum age: 100 Years
healthy volunteers: No
last name: Jaishri Blakeley, MD
role: Principal Investigator
affiliation: Johns Hopkins University
last name: Jaishri Blakeley, MD
phone: 410-955-8837
email: jblakel3@jhmi.edu
last name: Anthony Stanfield
phone: 410-502-1962
email: astanfi1@jhmi.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Sponsor
mesh term: Nerve Sheath Neoplasms
mesh term: Neurofibrosarcoma
mesh term: Nivolumab
mesh term: Ipilimumab