<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/NCT02978443</url>
  </required_header>
  <id_info>
    <org_study_id>2016-0420</org_study_id>
    <secondary_id>CA209-763</secondary_id>
    <nct_id>NCT02978443</nct_id>
  </id_info>
  <brief_title>A Biomarker Study in Advanced Mucosal or Acral Lentiginous Melanoma Receiving Nivolumab in Combination With Ipilimumab</brief_title>
  <official_title>A Study to Estimate the Anti-Tumor Activity and Identify Potential Predictors of Response in Patients With Advanced Mucosal or Acral Lentiginous Melanoma Receiving Standard Nivolumab in Combination With Ipilimumab Followed by Nivolumab Monotherapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Georgetown University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Melanoma Research Foundation Breakthrough Consortium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Colorado, Denver</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Vanderbilt University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Columbia University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Pittsburgh</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>M.D. Anderson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>H. Lee Moffitt Cancer Center and Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Memorial Sloan Kettering Cancer Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Northwestern University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Georgetown University</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>
      Participants with advanced or metastatic mucosal melanoma (cohort A) and acral lentiginous&#xD;
      melanoma (cohort B) eligible for treatment with nivolumab in combination with ipilimumab&#xD;
      followed by nivolumab therapy will submit tissue blocks from tumors of malignant melanoma for&#xD;
      histopathology review and immunohistochemistry analysis at Georgetown University-Lombardi&#xD;
      Comprehensive Cancer Center. Pretreatment blood will be drawn and stored in the Melanoma&#xD;
      Research Foundation Breakthrough Consortium Virtual Repository at each participating&#xD;
      institution. At the end of participation, samples will be sent to Georgetown&#xD;
      University-Lombardi Comprehensive Cancer Center for processing and storage. An optional&#xD;
      pretreatment biopsy of an accessible tumor lesion will be performed in a subset of enrolled&#xD;
      patients. Patients will receive nivolumab in combination with ipilimumab according to the&#xD;
      standard FDA approved treatment regimen.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Immunotherapy with HD-IL-2 has produced durable benefit in 10% of patients with metastatic&#xD;
      cutaneous melanoma. The antitumor activity of IL-2 has been limited at least in part by&#xD;
      immunosuppressive and immune-regulatory forces within the tumor microenvironment. Antibodies&#xD;
      against CTLA4 (e.g. ipilimumab), PD1 and its ligand (PD-L1) produced long-term benefit in&#xD;
      approximately 20-40% of patients with advanced melanoma. In addition, the combination of&#xD;
      ipilimumab with the anti-PD1 antibody, nivolumab, has shown tumor responses in up to 60% of&#xD;
      patients with advanced melanoma. These findings have led to FDA approval of ipilimumab and&#xD;
      nivolumab as an indication for treatment of patients with advanced melanoma and nivolumab for&#xD;
      other cancers. While these data are exciting, only a few patients enrolled to the prior&#xD;
      studies had metastatic MCM or ALM. There is no prospective immunotherapy studies conducted in&#xD;
      MCM or ALM-specific population. Therefore the activity of the ipilimumab + nivolumab&#xD;
      combination in these subsets or patients remains unknown&#xD;
&#xD;
      Reliable predictive biomarkers for the use of immune checkpoint inhibitors are needed to&#xD;
      identify pretreatment those patients most likely to respond and early on in treatment assays&#xD;
      could help identify mechanisms of tumor response and resistance necessary to improve therapy.&#xD;
      Although tumor PD-L1 expression in tumor confers higher treatment response rate, responses to&#xD;
      nivolumab or nivolumab + ipilimumab alone were noted in 55% and 41% of patients,&#xD;
      respectively, with PD-L1- tumors. Therefore, more reliable predictive biomarkers are needed.&#xD;
&#xD;
      Recently, extensive studies on metastatic colorectal cancer have demonstrated that a new&#xD;
      scoring system as well as density of immune cells infiltrates at the center of the tumor and&#xD;
      its invasive margin, described as Immunoscore, could accurately separate a group of patients&#xD;
      with high Immunoscore with improved DFS, and OS from those with low Immunoscore where the&#xD;
      histopathological staging system cannot. A recent study has also demonstrated relationship&#xD;
      between degree of pre-treatment CD8+ tumor infiltrating lymphocytes (TILs) infiltration and&#xD;
      PD-L1 expression at the invasive margin of the advanced cutaneous melanoma and improved&#xD;
      long-term clinical benefits in patients with advanced melanoma who received pembrolizumab&#xD;
      monotherapy. Further, there appeared to be an association between tumor response and&#xD;
      clonality of the immune infiltrate based on a next-generation sequencing method used to&#xD;
      evaluate T-cell receptor rearrangement pre- and in response to checkpoint inhibitor therapy.&#xD;
      Also, high mutational burden correlated with overall survival in patients with cutaneous&#xD;
      melanoma treated with ipilimumab or lung cancer treated with anti-PD1. However, the biology&#xD;
      of MCM and ALM are distinct from cutaneous melanoma at multiple levels. Consequently, the&#xD;
      utility of predictive biomarkers developed for cutaneous melanoma remains unknown.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">July 26, 2017</start_date>
  <completion_date type="Anticipated">December 2021</completion_date>
  <primary_completion_date type="Anticipated">December 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>Objective response rate (ORR) with mucosal melanoma (MCM)</measure>
    <time_frame>24 months</time_frame>
    <description>ORR, defined as complete response [CR] + partial response [PR] per RECIST 1.1 criteria and to compare this response rate to the response rate of patients with &quot;good&quot; molecular predictive features</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate with acral lentiginous melanoma (ALM)</measure>
    <time_frame>24 months</time_frame>
    <description>ORR, defined as complete response [CR] + partial response [PR] per RECIST 1.1 criteria and to compare this response rate to the response rate of patients with &quot;good&quot; molecular predictive features</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>36 months</time_frame>
    <description>PFS will be assessed for each cohort</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>36 months</time_frame>
    <description>OS will be assessed for each cohort</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Acral Lentiginous Melanoma</condition>
  <condition>Mucosal Melanoma</condition>
  <arm_group>
    <arm_group_label>Nivolumab-Ipilimumab Combination Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients will receive nivolumab administered IV over 60 minutes at 1 mg/kg combined with ipilimumab administered IV over 90 minutes at 3 mg/kg every 3 weeks for 4 treatment cycles (Induction) then continue with nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks until progression, intolerable toxicity, or a maximum of 48 weeks, whichever comes first (Maintenance). Patients exhibiting complete response (CR) should continue nivolumab monotherapy at least 12 weeks beyond documentation of CR, if possible.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>nivolumab administered IV over 60 minutes at 1 mg/kg every 3 weeks for 4 treatment cycles (Induction) then continue with nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks</description>
    <arm_group_label>Nivolumab-Ipilimumab Combination Therapy</arm_group_label>
    <other_name>BMS-936558</other_name>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>ipilimumab administered IV over 90 minutes at 3 mg/kg every 3 weeks for 4 treatment cycles (Induction)</description>
    <arm_group_label>Nivolumab-Ipilimumab Combination Therapy</arm_group_label>
    <other_name>BMS-734016</other_name>
    <other_name>Yervoy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically confirmed MCM or ALM that is metastatic or&#xD;
             unresectable.&#xD;
&#xD;
          -  Patients must be eligible to receive nivolumab in combination with ipilimumab&#xD;
             treatment per institutional guidelines.&#xD;
&#xD;
          -  Patients must have a tissue block (or 20 unstained slides) available with adequate&#xD;
             tumor to perform multiplex immunohistochemistry and nucleic acids analyses ( i.e.&#xD;
             whole exome sequencing) Patients with only a previous fine-needle aspirate are&#xD;
             ineligible for enrollment.&#xD;
&#xD;
          -  Patients must be willing to donate a small amount of whole blood prior to treatment&#xD;
             and during treatment for laboratory analysis.&#xD;
&#xD;
          -  Patients must give informed consent prior to initiation of therapy.&#xD;
&#xD;
          -  Patients must be ambulatory with good performance status (ECOG 0 or 1)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who do not have available tissue for immunohistochemistry and nucleic acids&#xD;
             analyses.&#xD;
&#xD;
          -  Patients who have received prior immunotherapy for unresectable or metastatic disease.&#xD;
&#xD;
          -  Patients with untreated brain metastases, leptomeningeal disease, or seizure disorders&#xD;
             are ineligible. Patients with a history of brain metastases must have completed&#xD;
             treatment (i.e. surgery or radiation) 1 month prior to enrollment and have no evidence&#xD;
             of disease or edema on brain CT or head MRI.&#xD;
&#xD;
          -  Patients with inadequate tissue for analysis.&#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_official>
    <last_name>Suthee Rapisuwon, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Lombardi Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lombardi Comprehensive Cancer Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20007</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington Cancer Institute at MedStar Washington Hospital Center</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>H. Lee Moffitt Cancer Center and Research Institute</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>John Theurer Cacner Center at Hackensack University Medical Center</name>
      <address>
        <city>Hackensack</city>
        <state>New Jersey</state>
        <zip>07601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2020</verification_date>
  <study_first_submitted>November 23, 2016</study_first_submitted>
  <study_first_submitted_qc>November 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 1, 2016</study_first_posted>
  <last_update_submitted>January 7, 2020</last_update_submitted>
  <last_update_submitted_qc>January 7, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Melanoma</keyword>
  <keyword>Mucosal</keyword>
  <keyword>Acral Lentiginous</keyword>
  <keyword>Ipilimumab</keyword>
  <keyword>Nivolumab</keyword>
  <keyword>Anti-tumor</keyword>
  <keyword>Potential Predictors</keyword>
  <keyword>Opdivo</keyword>
  <keyword>Yervoy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</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>
  <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/NCT02978443
org study id: 2016-0420
secondary id: CA209-763
nct id: NCT02978443
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Participants with advanced or metastatic mucosal melanoma (cohort A) and acral lentiginous
      melanoma (cohort B) eligible for treatment with nivolumab in combination with ipilimumab
      followed by nivolumab therapy will submit tissue blocks from tumors of malignant melanoma for
      histopathology review and immunohistochemistry analysis at Georgetown University-Lombardi
      Comprehensive Cancer Center. Pretreatment blood will be drawn and stored in the Melanoma
      Research Foundation Breakthrough Consortium Virtual Repository at each participating
      institution. At the end of participation, samples will be sent to Georgetown
      University-Lombardi Comprehensive Cancer Center for processing and storage. An optional
      pretreatment biopsy of an accessible tumor lesion will be performed in a subset of enrolled
      patients. Patients will receive nivolumab in combination with ipilimumab according to the
      standard FDA approved treatment regimen.
Immunotherapy with HD-IL-2 has produced durable benefit in 10% of patients with metastatic
      cutaneous melanoma. The antitumor activity of IL-2 has been limited at least in part by
      immunosuppressive and immune-regulatory forces within the tumor microenvironment. Antibodies
      against CTLA4 (e.g. ipilimumab), PD1 and its ligand (PD-L1) produced long-term benefit in
      approximately 20-40% of patients with advanced melanoma. In addition, the combination of
      ipilimumab with the anti-PD1 antibody, nivolumab, has shown tumor responses in up to 60% of
      patients with advanced melanoma. These findings have led to FDA approval of ipilimumab and
      nivolumab as an indication for treatment of patients with advanced melanoma and nivolumab for
      other cancers. While these data are exciting, only a few patients enrolled to the prior
      studies had metastatic MCM or ALM. There is no prospective immunotherapy studies conducted in
      MCM or ALM-specific population. Therefore the activity of the ipilimumab + nivolumab
      combination in these subsets or patients remains unknown

      Reliable predictive biomarkers for the use of immune checkpoint inhibitors are needed to
      identify pretreatment those patients most likely to respond and early on in treatment assays
      could help identify mechanisms of tumor response and resistance necessary to improve therapy.
      Although tumor PD-L1 expression in tumor confers higher treatment response rate, responses to
      nivolumab or nivolumab + ipilimumab alone were noted in 55% and 41% of patients,
      respectively, with PD-L1- tumors. Therefore, more reliable predictive biomarkers are needed.

      Recently, extensive studies on metastatic colorectal cancer have demonstrated that a new
      scoring system as well as density of immune cells infiltrates at the center of the tumor and
      its invasive margin, described as Immunoscore, could accurately separate a group of patients
      with high Immunoscore with improved DFS, and OS from those with low Immunoscore where the
      histopathological staging system cannot. A recent study has also demonstrated relationship
      between degree of pre-treatment CD8+ tumor infiltrating lymphocytes (TILs) infiltration and
      PD-L1 expression at the invasive margin of the advanced cutaneous melanoma and improved
      long-term clinical benefits in patients with advanced melanoma who received pembrolizumab
      monotherapy. Further, there appeared to be an association between tumor response and
      clonality of the immune infiltrate based on a next-generation sequencing method used to
      evaluate T-cell receptor rearrangement pre- and in response to checkpoint inhibitor therapy.
      Also, high mutational burden correlated with overall survival in patients with cutaneous
      melanoma treated with ipilimumab or lung cancer treated with anti-PD1. However, the biology
      of MCM and ALM are distinct from cutaneous melanoma at multiple levels. Consequently, the
      utility of predictive biomarkers developed for cutaneous melanoma remains unknown.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective response rate (ORR) with mucosal melanoma (MCM)
time frame: 24 months
description: ORR, defined as complete response [CR] + partial response [PR] per RECIST 1.1 criteria and to compare this response rate to the response rate of patients with "good" molecular predictive features
measure: Objective response rate with acral lentiginous melanoma (ALM)
time frame: 24 months
description: ORR, defined as complete response [CR] + partial response [PR] per RECIST 1.1 criteria and to compare this response rate to the response rate of patients with "good" molecular predictive features
measure: Progression-free survival (PFS)
time frame: 36 months
description: PFS will be assessed for each cohort
measure: Overall survival (OS)
time frame: 36 months
description: OS will be assessed for each cohort
arm group label: Nivolumab-Ipilimumab Combination Therapy
arm group type: Experimental
description: All patients will receive nivolumab administered IV over 60 minutes at 1 mg/kg combined with ipilimumab administered IV over 90 minutes at 3 mg/kg every 3 weeks for 4 treatment cycles (Induction) then continue with nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks until progression, intolerable toxicity, or a maximum of 48 weeks, whichever comes first (Maintenance). Patients exhibiting complete response (CR) should continue nivolumab monotherapy at least 12 weeks beyond documentation of CR, if possible.
intervention type: Drug
intervention name: Nivolumab
description: nivolumab administered IV over 60 minutes at 1 mg/kg every 3 weeks for 4 treatment cycles (Induction) then continue with nivolumab administered IV over 60 minutes at 3 mg/kg every 2 weeks
arm group label: Nivolumab-Ipilimumab Combination Therapy
other name: BMS-936558
other name: Opdivo
intervention type: Drug
intervention name: Ipilimumab
description: ipilimumab administered IV over 90 minutes at 3 mg/kg every 3 weeks for 4 treatment cycles (Induction)
arm group label: Nivolumab-Ipilimumab Combination Therapy
other name: BMS-734016
other name: Yervoy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Suthee Rapisuwon, MD
role: Study Chair
affiliation: Lombardi Comprehensive Cancer Center
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: No