<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/NCT03003637</url>
  </required_header>
  <id_info>
    <org_study_id>N16IMC</org_study_id>
    <nct_id>NCT03003637</nct_id>
  </id_info>
  <brief_title>ImmunoModulation by the Combination of Ipilimumab and Nivolumab Neoadjuvant to Surgery In Advanced or Recurrent Head and Neck Carcinoma</brief_title>
  <acronym>IMCISION</acronym>
  <official_title>ImmunoModulation by the Combination of Ipilimumab and Nivolumab Neoadjuvant to Surgery In Advanced Or Recurrent Head and Neck Carcinoma. Subtitle: Hypoxia as a Determinant for the Effect of Nivolumab With or Without Ipilimumab on Intra-tumoral T Cell Capacity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Netherlands Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Netherlands Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This is a phase IB/II trial to examine feasibility and safety of checkpoint blockade (aPD1&#xD;
      with or without aCTLA4) neoadjuvant to standard of care (SOC) in advanced stage head and neck&#xD;
      squamous cell carcinoma (HNSCC), a patient population in need for improved clinical outcome&#xD;
      and in tumors likely to respond to neoadjuvant aPD1 and aCTLA4. In addition, with this&#xD;
      research protocol the potential impact of intratumoral hypoxia on tumor infiltrating&#xD;
      lymphocyte (TIL) abundance, differentiation and effector function will be assessed, and the&#xD;
      potentially divergent effects of T cell checkpoint blockade in areas of hypoxia and normoxia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The phase Ib is designed as 3 + 3, with primary objective feasibility and toxicity.&#xD;
&#xD;
      Of Note: endpoints must be reached in all 6 patients of cohort 1 and 2, before start of the&#xD;
      next cohort.&#xD;
&#xD;
      The phase II is designed as a single arm design with primary endpoint efficacy.&#xD;
&#xD;
      In phase Ib, two cohorts will be used (cohort 1: nivolumab only and cohort 2: nivolumab and&#xD;
      ipilimumab neoadjuvant to surgery) to define which neoadjuvant immunotherapy regimen will be&#xD;
      taken towards the expansion cohort 3.&#xD;
&#xD;
      Thirty-two patients will be treated with nivolumab (240 mg flat dose, week 1 and week 3,&#xD;
      twice in total) as a single agent OR the combination of ipilimumab (1 mg/kg) + nivolumab&#xD;
      (240mg flat dose) in week 1, and nivolumab 240mg flat dose in week 3, neoadjuvant to SOC&#xD;
      (surgery with or without adjuvant (C)RT).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 28, 2017</start_date>
  <completion_date type="Actual">February 12, 2021</completion_date>
  <primary_completion_date type="Actual">October 12, 2019</primary_completion_date>
  <phase>Phase 1/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>Phase Ib: the number of patients that will not endure a delay in surgery due to neoadjuvant immunotherapy related toxicity OR toxicity due to the treatment of immunotherapy related toxicity.</measure>
    <time_frame>2.5 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II: Tumor response to neoadjuvant IT in terms of tumor tissue pathological response at time of surgery compared to RECIST 1.1 (FDG-PET and perfusion and diffusion weighted MRI).</measure>
    <time_frame>2.5 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase Ib/II: the potential impact of local tumor hypoxia on tumor T-cell abundance and capacity before and after neo-adjuvant immunotherapy, through HX4-PET-guided tumor biopsies from hypoxic and normoxic tumor regions.</measure>
    <time_frame>2.5 years</time_frame>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Immunotherapy</condition>
  <condition>Head and Neck Neoplasms</condition>
  <arm_group>
    <arm_group_label>Nivolumab with or without Ipilimumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>First dose scheme will be 2x nivolumab 240 mg flat dose, weeks 1 and 3. When feasible and safe, the next patients will be treated with the following dose scheme: the combination of 1x ipilimumab 1 mg/kg + nivolumab 240 mg flat dose in week 1 and nivolumab mono-therapy 240 mg flat dose in week 3</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab (240 mg flat dose, week 1 and week 3, twice in total) monotherapy, neoadjuvant to SOC (surgery with or without adjuvant (C)RT).</description>
    <arm_group_label>Nivolumab with or without Ipilimumab</arm_group_label>
    <other_name>Nivolumab (Opdivo) BMS-936558-01</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Ipilimumab (1 mg/kg) only in week 1, in combination with nivolumab (240 mg flat dose, week 1 and week 3, twice in total), neoadjuvant to SOC (surgery with or without adjuvant (C)RT).</description>
    <arm_group_label>Nivolumab with or without Ipilimumab</arm_group_label>
    <other_name>Ipilimumab (Yervoy) BMS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults age 18 years and older&#xD;
&#xD;
          -  Patients with histologically confirmed T3-4N0-3M0 HNSCC (with soft tissue infiltration&#xD;
             depth of ≥ 1 cm) of the oral cavity, oropharynx, hypopharynx or supraglottic larynx,&#xD;
             eligible for curative surgery as primary treatment or salvage surgery after failed&#xD;
             (chemo)radiation.&#xD;
&#xD;
          -  Performance Status ECOG 0 or 1&#xD;
&#xD;
          -  No immunosuppressive medications within 6 months prior study inclusion&#xD;
&#xD;
          -  Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L,&#xD;
             Neutrophils ≥ 1.5x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 5.5 mmol/L, Creatinine ≤&#xD;
             1.5x ULN, AST ≤ 3 x ULN, ALT ≤ 3 x ULN, Total Bilirubin ≤1.5 X ULN (except subjects&#xD;
             with Gilbert Syndrome, who can have total bilirubin &lt; 3.0 mg/dL)&#xD;
&#xD;
          -  No hard-drug abuse.&#xD;
&#xD;
          -  Women of childbearing potential (WOCBP) must use appropriate method(s) of&#xD;
             contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30&#xD;
             days plus the time required for nivolumab to undergo five half-lives after the last&#xD;
             dose of investigational drug.&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the&#xD;
             start of nivolumab w/wo ipilimumab.&#xD;
&#xD;
          -  Men who are sexually active with WOCBP must use any contraceptive method with a&#xD;
             failure rate of less than 1% per year Men receiving nivolumab w/wo ipilimumab and who&#xD;
             are sexually active with WOCBP will be instructed to adhere to contraception for a&#xD;
             period of 31 weeks after the last dose of investigational product.&#xD;
&#xD;
          -  Women who are not of childbearing potential (i.e., who are postmenopausal or&#xD;
             surgically sterile) as well as azoospermic men do not require contraception.&#xD;
&#xD;
          -  All subjects must have signed and dated the written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Distant metastasis&#xD;
&#xD;
          -  Active, known or suspected autoimmune disease. Subjects are permitted to enroll if&#xD;
             they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to&#xD;
             autoimmune condition only requiring hormone replacement, psoriasis not requiring&#xD;
             systemic treatment, or conditions not expected to recur in the absence of an external&#xD;
             trigger.&#xD;
&#xD;
          -  Patients should be excluded if they have a condition requiring systemic treatment with&#xD;
             either corticosteroids (&gt; 10 mg daily prednisone equivalents) or other&#xD;
             immunosuppressive medications within 14 days of study drug administration. Inhaled or&#xD;
             topical corticosteroids and adrenal replacement doses &gt; 10 mg daily prednisone&#xD;
             equivalents are permitted in the absence of active autoimmune disease.&#xD;
&#xD;
          -  Prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4&#xD;
             antibody, or any other antibody or drug specifically targeting T-cell costimulation or&#xD;
             immune checkpoint pathways;&#xD;
&#xD;
          -  Patients will be excluded if they are positive test for hepatitis B virus surface&#xD;
             antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating&#xD;
             acute or chronic infection;&#xD;
&#xD;
          -  Patients will be excluded if they have known history of testing positive for human&#xD;
             immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);&#xD;
&#xD;
          -  Allergies and Adverse Drug Reaction: history of allergy to study drug components,&#xD;
             history of severe hypersensitivity reaction to any monoclonal antibody.&#xD;
&#xD;
          -  Underlying medical conditions that, in the Investigator's opinion, will make the&#xD;
             administration of study drug hazardous or obscure the interpretation of toxicity&#xD;
             determination or adverse events;&#xD;
&#xD;
          -  Concurrent medical condition requiring the use of immunosuppressive medications, or&#xD;
             immunosuppressive doses of systemic or absorbable topical corticosteroids;&#xD;
&#xD;
          -  Use of other investigational drugs before study drug administration 30 days and 5 half&#xD;
             times before study inclusion;&#xD;
&#xD;
          -  Pregnant or nursing.&#xD;
&#xD;
          -  As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab&#xD;
             combinations, drugs with a predisposition to hepatotoxicity should be used with&#xD;
             caution in patients treated with nivolumab-containing regimen.&#xD;
&#xD;
          -  In those patients who have a contraindication for cisplatin chemotherapy, Cetuximab&#xD;
             might be used as a radiosensitizer for radiotherapy if adjuvant treatment is deemed&#xD;
             necessary.&#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>Lotje Zuur, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NKI-AvL</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>NKI-AVL</name>
      <address>
        <city>Amsterdam</city>
        <state>Noord-Holland</state>
        <zip>1066CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>December 22, 2016</study_first_submitted>
  <study_first_submitted_qc>December 22, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 28, 2016</study_first_posted>
  <last_update_submitted>February 12, 2021</last_update_submitted>
  <last_update_submitted_qc>February 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2021</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>Head and Neck Neoplasms</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/NCT03003637
org study id: N16IMC
nct id: NCT03003637
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a phase IB/II trial to examine feasibility and safety of checkpoint blockade (aPD1
      with or without aCTLA4) neoadjuvant to standard of care (SOC) in advanced stage head and neck
      squamous cell carcinoma (HNSCC), a patient population in need for improved clinical outcome
      and in tumors likely to respond to neoadjuvant aPD1 and aCTLA4. In addition, with this
      research protocol the potential impact of intratumoral hypoxia on tumor infiltrating
      lymphocyte (TIL) abundance, differentiation and effector function will be assessed, and the
      potentially divergent effects of T cell checkpoint blockade in areas of hypoxia and normoxia.
The phase Ib is designed as 3 + 3, with primary objective feasibility and toxicity.

      Of Note: endpoints must be reached in all 6 patients of cohort 1 and 2, before start of the
      next cohort.

      The phase II is designed as a single arm design with primary endpoint efficacy.

      In phase Ib, two cohorts will be used (cohort 1: nivolumab only and cohort 2: nivolumab and
      ipilimumab neoadjuvant to surgery) to define which neoadjuvant immunotherapy regimen will be
      taken towards the expansion cohort 3.

      Thirty-two patients will be treated with nivolumab (240 mg flat dose, week 1 and week 3,
      twice in total) as a single agent OR the combination of ipilimumab (1 mg/kg) + nivolumab
      (240mg flat dose) in week 1, and nivolumab 240mg flat dose in week 3, neoadjuvant to SOC
      (surgery with or without adjuvant (C)RT).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase Ib: the number of patients that will not endure a delay in surgery due to neoadjuvant immunotherapy related toxicity OR toxicity due to the treatment of immunotherapy related toxicity.
time frame: 2.5 years
measure: Phase II: Tumor response to neoadjuvant IT in terms of tumor tissue pathological response at time of surgery compared to RECIST 1.1 (FDG-PET and perfusion and diffusion weighted MRI).
time frame: 2.5 years
measure: Phase Ib/II: the potential impact of local tumor hypoxia on tumor T-cell abundance and capacity before and after neo-adjuvant immunotherapy, through HX4-PET-guided tumor biopsies from hypoxic and normoxic tumor regions.
time frame: 2.5 years
arm group label: Nivolumab with or without Ipilimumab
arm group type: Experimental
description: First dose scheme will be 2x nivolumab 240 mg flat dose, weeks 1 and 3. When feasible and safe, the next patients will be treated with the following dose scheme: the combination of 1x ipilimumab 1 mg/kg + nivolumab 240 mg flat dose in week 1 and nivolumab mono-therapy 240 mg flat dose in week 3
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab (240 mg flat dose, week 1 and week 3, twice in total) monotherapy, neoadjuvant to SOC (surgery with or without adjuvant (C)RT).
arm group label: Nivolumab with or without Ipilimumab
other name: Nivolumab (Opdivo) BMS-936558-01
intervention type: Drug
intervention name: Ipilimumab
description: Ipilimumab (1 mg/kg) only in week 1, in combination with nivolumab (240 mg flat dose, week 1 and week 3, twice in total), neoadjuvant to SOC (surgery with or without adjuvant (C)RT).
arm group label: Nivolumab with or without Ipilimumab
other name: Ipilimumab (Yervoy) BMS
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lotje Zuur, MD, PhD
role: Principal Investigator
affiliation: NKI-AvL
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Head and Neck Neoplasms
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: No