<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/NCT03026140</url>
  </required_header>
  <id_info>
    <org_study_id>N16NCI</org_study_id>
    <nct_id>NCT03026140</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Immune Checkpoint Inhibition and Novel IO Combinations in Early-stage Colon Cancer</brief_title>
  <acronym>NICHE</acronym>
  <official_title>Neoadjuvant Immune Checkpoint Inhibition and Novel IO Combinations in Early-stage Colon Cancer (Amended Protocol of: Nivolumab, Ipilimumab and COX2-inhibition in Early Stage Colon Cancer: an Unbiased Approach for Signals of Sensitivity: The NICHE TRIAL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Netherlands Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>The Netherlands Cancer Institute</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>
      In this exploratory study, patients with stage 1-3 adenocarcinoma of the colon with no signs&#xD;
      of distant metastases will be treated with short-term immunotherapy + novel IO combinations&#xD;
      (i.e. anti-IL 8, COX2-inhibitors). This treatment will be given during the window period&#xD;
      until surgical resection of the tumor. The duration of treatment will be approximately 6&#xD;
      weeks.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this multi-center, open-label, exploratory study, the investigators will enroll 60&#xD;
      patients within two years, including 30 patients with MSS tumors and 30 patients with MSI&#xD;
      tumors. Patients with MSS tumors will be randomized to either group 1 or 2. Patients with MSI&#xD;
      tumors will all be allocated to group 1.&#xD;
&#xD;
      Patients in group 1 will be treated with a single dose of ipilimumab 1mg/kg on day 1 and two&#xD;
      cycles of nivolumab 3mg/kg on day 1 and 15, respectively.&#xD;
&#xD;
      Patients in group 2 will be treated with a single dose of ipilimumab 1mg/kg on day 1, two&#xD;
      cycles of nivolumab 3mg/kg one day 1 and 15 and celecoxib daily until the day before surgery.&#xD;
&#xD;
      The study was amended in May 2020 to enroll an additional 70 patients in the MSI cohort after&#xD;
      the first 30 patients, making a total of 100 patients with MSI tumors. A formal sample size&#xD;
      calculation and primary endpoint of 3-year disease-free-survival (DFS) for this group was&#xD;
      added.&#xD;
&#xD;
      The study was amended in July 2021 to add a new cohort, cohort 4, for patients with pMMR/MSS&#xD;
      tumors. Once accrual of 30 evaluable patients in group 2 was completed, a new cohort opened&#xD;
      in which patients will receive nivolumab plus anti-IL8 (BMS-986253).&#xD;
&#xD;
      The study was amended in November 2022 to add cohort 5 and 6, both in which patients will&#xD;
      receive nivolumab plus relatlimab (anti-LAG3). Patients with pMMR/MSS tumors will be&#xD;
      randomized 1:1 between cohort 4 and cohort 5, patients with dMMR/MSI tumors will be enrolled&#xD;
      in cohort 6.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 29, 2017</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of adverse events during the treatment and follow-up (safety)</measure>
    <time_frame>until 100 days after last patient last study drug treatment</time_frame>
    <description>Adverse events will be assessed (according to CTCAE v4.0) during treatment and follow-up.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Disease free survival</measure>
    <time_frame>until 5 years after diagnosis</time_frame>
    <description>To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Immune activating capacity of short-term pre-operative immunotherapy</measure>
    <time_frame>within 2 years after study completion</time_frame>
    <description>identify underlying potential escape mechanisms by comparing pre-treatment and post-treatment biopsies</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse free survival</measure>
    <time_frame>3-5 years after last patient inclusion.</time_frame>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Anticipated">268</enrollment>
  <condition>Colon Carcinoma</condition>
  <arm_group>
    <arm_group_label>group 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>group 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV) drug: celecoxib 200 mg daily (oral)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Anti-IL8 cohort 4 (pMMR/MSS tumors)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>drug: nivolumab 3 mg/kg day 1 and day 15 (IV) drug: BMS-986253 (anti-IL8) 2400mg on day 1 and day 15 (IV)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Relatlimab cohort 5 (pMMR/MSS tumors)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>drug: nivolumab 240mg IV on day 1 and day 15 drug: relatlimab 240mg IV on day 1 and day 15</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Relatlimab cohort 6 (dMMR/MSI tumors)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>drug: nivolumab 480mg IV on day 1 and day 29 drug: relatlimab 480mg IV on day 1 and day 29</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery</description>
    <arm_group_label>Anti-IL8 cohort 4 (pMMR/MSS tumors)</arm_group_label>
    <arm_group_label>Relatlimab cohort 5 (pMMR/MSS tumors)</arm_group_label>
    <arm_group_label>Relatlimab cohort 6 (dMMR/MSI tumors)</arm_group_label>
    <arm_group_label>group 1</arm_group_label>
    <arm_group_label>group 2</arm_group_label>
    <other_name>nivolumab (opdivo)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery</description>
    <arm_group_label>group 1</arm_group_label>
    <arm_group_label>group 2</arm_group_label>
    <other_name>Ipilimumab (Yervoy)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Celecoxib 200mg</intervention_name>
    <description>celecoxib will be administered starting day 1 until 1 day before surgery daily (if patient is randomized to group 2 (only applicable for patients with a MSS tumor)</description>
    <arm_group_label>group 2</arm_group_label>
    <other_name>Celebrex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BMS-986253</intervention_name>
    <description>BMS-986253 2400mg IV will be administered on day 1 and 15 (only applicable for patients with MSS tumors)</description>
    <arm_group_label>Anti-IL8 cohort 4 (pMMR/MSS tumors)</arm_group_label>
    <other_name>Anti-IL8</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BMS-986016</intervention_name>
    <description>Relatlimab will be administered IV, in cohort 5 240mg on day 1 and day 15, in cohort 6 480mg on day 1 and day 29</description>
    <arm_group_label>Relatlimab cohort 5 (pMMR/MSS tumors)</arm_group_label>
    <arm_group_label>Relatlimab cohort 6 (dMMR/MSI tumors)</arm_group_label>
    <other_name>Relatlimab</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
          -  Patients at least 18 years of age&#xD;
&#xD;
          -  Non-metastatic adenocarcinoma of the colon (and rectosigmoid considered as nonrectal&#xD;
             and not undergoing neoadjuvant treatment)&#xD;
&#xD;
               -  No signs of distant metastases on CT-scan and physical examination;&#xD;
&#xD;
               -  dMMR cohorts 3+6: &gt;cT3 and/or N+&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  No signs of distant metastases&#xD;
&#xD;
          -  No signs of obstruction or macroscopic bleeding or suspicion of perforation&#xD;
&#xD;
          -  Colonoscopy must be performed after registration to obtain study-specific biopsies. If&#xD;
             biopsies are not possible, patients cannot be included in the study&#xD;
&#xD;
          -  WHO performance status of 0 or 1&#xD;
&#xD;
          -  No previous treatment with immune checkpoint inhibitors targeting CTLA-4, PD-1 or&#xD;
             PD-L1&#xD;
&#xD;
          -  For patients with MSS tumors: no current use of NSAIDs or COX2-inhibitors at&#xD;
             registration and no active peptic ulcer, gastrointestinal bleeding, unstable ischemic&#xD;
             heart disease of thrombus etiology or significant established ischemic heart disease,&#xD;
             peripheral arterial disease and/or cerebrovascular disease&#xD;
&#xD;
          -  No radiotherapy prior to or planned post-surgery radiotherapy&#xD;
&#xD;
          -  No history of allergy to study drug components, severe hypersensitivity reaction to&#xD;
             any monoclonal antibody, allergy or severe hypersensitivity to NSAIDs or COX2-I (MSS&#xD;
             tumors)&#xD;
&#xD;
          -  No intercurrent illnesses, including but not limited to infections, unstable angina&#xD;
             pectoris&#xD;
&#xD;
          -  No positive test for hepatitis B virus surface antigen (HBsAg) or hepatitis C virus&#xD;
             ribonucleic acid (HCV antibody) indicating acute or chronic infection&#xD;
&#xD;
          -  No autoimmune disease&#xD;
&#xD;
          -  No conditions requiring systemic treatment with either corticosteroids (10 mg daily&#xD;
             prednisone or more and equivalents) or other immunosuppressive medications within 14&#xD;
             days of study drug administration&#xD;
&#xD;
          -  No live vaccines in the 4 weeks prior to inclusion&#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>Myriam Chalabi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Antoni van Leeuwenhoek</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Marieke van de Belt</last_name>
    <phone>+3120512</phone>
    <phone_ext>1926</phone_ext>
    <email>m.vd.belt@nki.nl</email>
  </overall_contact>
  <location>
    <facility>
      <name>Marieke van de Belt</name>
      <address>
        <city>Amsterdam</city>
        <zip>1066CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marieke van de Belt</last_name>
      <phone>+3120512</phone>
      <phone_ext>1926</phone_ext>
      <email>m.vd.belt@nki.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>OLVG</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>A van Lent</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Haga ziekenhuis</name>
      <address>
        <city>Den Haag</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>T Aukema</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Catharina Ziekenhuis</name>
      <address>
        <city>Eindhoven</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>P Burger</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Spaarne Ziekenhuis</name>
      <address>
        <city>Haarlem</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>S Oosterling</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Tergooi</name>
      <address>
        <city>Hilversum</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>E. Hendriks</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>December 15, 2016</study_first_submitted>
  <study_first_submitted_qc>January 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 20, 2017</study_first_posted>
  <last_update_submitted>January 23, 2023</last_update_submitted>
  <last_update_submitted_qc>January 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MSI tumors</keyword>
  <keyword>MSS tumors</keyword>
  <keyword>short-term immunotherapy</keyword>
  <keyword>surgical resection</keyword>
  <keyword>nivolumab</keyword>
  <keyword>ipilimumab</keyword>
  <keyword>COX2</keyword>
  <keyword>Anti-IL8</keyword>
  <keyword>Relatlimab</keyword>
  <keyword>Anti-LAG3</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colonic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Celecoxib</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
    <mesh_term>Relatlimab</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/NCT03026140
org study id: N16NCI
nct id: NCT03026140
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In this exploratory study, patients with stage 1-3 adenocarcinoma of the colon with no signs
      of distant metastases will be treated with short-term immunotherapy + novel IO combinations
      (i.e. anti-IL 8, COX2-inhibitors). This treatment will be given during the window period
      until surgical resection of the tumor. The duration of treatment will be approximately 6
      weeks.
In this multi-center, open-label, exploratory study, the investigators will enroll 60
      patients within two years, including 30 patients with MSS tumors and 30 patients with MSI
      tumors. Patients with MSS tumors will be randomized to either group 1 or 2. Patients with MSI
      tumors will all be allocated to group 1.

      Patients in group 1 will be treated with a single dose of ipilimumab 1mg/kg on day 1 and two
      cycles of nivolumab 3mg/kg on day 1 and 15, respectively.

      Patients in group 2 will be treated with a single dose of ipilimumab 1mg/kg on day 1, two
      cycles of nivolumab 3mg/kg one day 1 and 15 and celecoxib daily until the day before surgery.

      The study was amended in May 2020 to enroll an additional 70 patients in the MSI cohort after
      the first 30 patients, making a total of 100 patients with MSI tumors. A formal sample size
      calculation and primary endpoint of 3-year disease-free-survival (DFS) for this group was
      added.

      The study was amended in July 2021 to add a new cohort, cohort 4, for patients with pMMR/MSS
      tumors. Once accrual of 30 evaluable patients in group 2 was completed, a new cohort opened
      in which patients will receive nivolumab plus anti-IL8 (BMS-986253).

      The study was amended in November 2022 to add cohort 5 and 6, both in which patients will
      receive nivolumab plus relatlimab (anti-LAG3). Patients with pMMR/MSS tumors will be
      randomized 1:1 between cohort 4 and cohort 5, patients with dMMR/MSI tumors will be enrolled
      in cohort 6.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of adverse events during the treatment and follow-up (safety)
time frame: until 100 days after last patient last study drug treatment
description: Adverse events will be assessed (according to CTCAE v4.0) during treatment and follow-up.
measure: Disease free survival
time frame: until 5 years after diagnosis
description: To assess efficacy of neoadjuvant ipilimumab plus nivolumab in terms of disease-free survival
measure: Immune activating capacity of short-term pre-operative immunotherapy
time frame: within 2 years after study completion
description: identify underlying potential escape mechanisms by comparing pre-treatment and post-treatment biopsies
measure: Relapse free survival
time frame: 3-5 years after last patient inclusion.
arm group label: group 1
arm group type: Experimental
description: drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV)
arm group label: group 2
arm group type: Experimental
description: drug: ipilimumab 1 mg/kg day 1 (IV) drug: nivolumab 3 mg/kg on day 1 and day 15 (IV) drug: celecoxib 200 mg daily (oral)
arm group label: Anti-IL8 cohort 4 (pMMR/MSS tumors)
arm group type: Experimental
description: drug: nivolumab 3 mg/kg day 1 and day 15 (IV) drug: BMS-986253 (anti-IL8) 2400mg on day 1 and day 15 (IV)
arm group label: Relatlimab cohort 5 (pMMR/MSS tumors)
arm group type: Experimental
description: drug: nivolumab 240mg IV on day 1 and day 15 drug: relatlimab 240mg IV on day 1 and day 15
arm group label: Relatlimab cohort 6 (dMMR/MSI tumors)
arm group type: Experimental
description: drug: nivolumab 480mg IV on day 1 and day 29 drug: relatlimab 480mg IV on day 1 and day 29
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab 3mg/kg (day 1 and day 15), administered neoadjuvant before surgery
arm group label: Anti-IL8 cohort 4 (pMMR/MSS tumors)
arm group label: Relatlimab cohort 5 (pMMR/MSS tumors)
arm group label: Relatlimab cohort 6 (dMMR/MSI tumors)
arm group label: group 1
arm group label: group 2
other name: nivolumab (opdivo)
intervention type: Drug
intervention name: Ipilimumab
description: Ipilimumab 1 mg/kg (day 1) ,administered neoadjuvant before surgery
arm group label: group 1
arm group label: group 2
other name: Ipilimumab (Yervoy)
intervention type: Drug
intervention name: Celecoxib 200mg
description: celecoxib will be administered starting day 1 until 1 day before surgery daily (if patient is randomized to group 2 (only applicable for patients with a MSS tumor)
arm group label: group 2
other name: Celebrex
intervention type: Drug
intervention name: BMS-986253
description: BMS-986253 2400mg IV will be administered on day 1 and 15 (only applicable for patients with MSS tumors)
arm group label: Anti-IL8 cohort 4 (pMMR/MSS tumors)
other name: Anti-IL8
intervention type: Drug
intervention name: BMS-986016
description: Relatlimab will be administered IV, in cohort 5 240mg on day 1 and day 15, in cohort 6 480mg on day 1 and day 29
arm group label: Relatlimab cohort 5 (pMMR/MSS tumors)
arm group label: Relatlimab cohort 6 (dMMR/MSI tumors)
other name: Relatlimab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Myriam Chalabi, MD
role: Principal Investigator
affiliation: Antoni van Leeuwenhoek
last name: Marieke van de Belt
phone: +3120512
phone ext: 1926
email: m.vd.belt@nki.nl
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
country: Netherlands
responsible party type: Sponsor
mesh term: Colonic Neoplasms
mesh term: Celecoxib
mesh term: Nivolumab
mesh term: Ipilimumab
mesh term: Relatlimab
sharing ipd: No