<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/NCT03247712</url>
  </required_header>
  <id_info>
    <org_study_id>NIRT-HNC</org_study_id>
    <nct_id>NCT03247712</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Immunoradiotherapy in Head &amp; Neck Cancer</brief_title>
  <official_title>Neoadjuvant Immunoradiotherapy: Head &amp; Neck Cancer (NIRT-HNC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Providence Health &amp; Services</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Providence Cancer Center, Earle A. Chiles Research Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Providence Health &amp; Services</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to test the safety of neoadjuvant immunoradiotherapy as a safe&#xD;
      means of down-staging Head and Neck Squamous Cell Carcinoma (HNSCC) prior to surgical&#xD;
      resection.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This clinical trial uses nivolumab and radiotherapy prior to definitive surgical resection of&#xD;
      tumors in patients with Head and Neck Squamous Cell Carcinoma (OHNSCC) with the primary&#xD;
      objective of determining the safety and feasibility of preoperative immunoradiotherapy. In&#xD;
      addition, tumor tissue, microbiome samples, and peripheral blood will be obtained for&#xD;
      exploratory immunologic end points including measurements of tumor infiltrating immune cell&#xD;
      populations based on flow cytometry and immunohistochemistry as well as circulating&#xD;
      immunological parameters. This is the first study to evaluate the safety and efficacy of&#xD;
      neoadjuvant radiation + PD-1 blockade in patients with HNSCC.&#xD;
&#xD;
      Estimated duration of 20 weeks: neoadjuvant immunoradiotherapy +/- surgery, followed by 6&#xD;
      doses of nivolumab 480mg IV q4wks +/- risk-adapted adjuvant therapy, per standard of care.&#xD;
&#xD;
      Phase I safety lead-in study (n = 6) evaluating the safety of neoadjuvant immunoradiotherapy&#xD;
      in HNSCC, followed by phase II efficacy study (n = 28, total) to assess rate of down-staging&#xD;
      after neoadjuvant immunoradiotherapy using Simon's two-stage design (futility assessment at n&#xD;
      = 12).&#xD;
&#xD;
      The phase 1 portion of this study will require 6 patients and is therefore expected to&#xD;
      complete in 6 months. Although non-surgical patients are eligible to enroll, they will not be&#xD;
      counted toward accrual for either the primary safety endpoint, (as by definition, unplanned&#xD;
      delay of surgery cannot exist); nor the secondary efficacy endpoint, as potential for&#xD;
      surgical staging is absent.&#xD;
&#xD;
      So long as 2 or fewer surgical delays are observed (primary safety endpoint), the phase 2&#xD;
      portion of study will proceed (secondary efficacy endpoint). Patients will be followed for&#xD;
      disease free and overall survival at 5 years.&#xD;
&#xD;
      Eligible patients may be enrolled unless a rate of unplanned surgical delay attributed to&#xD;
      immunoradiotherapy is found to exceed 33% after enrollment of the first 6 patients. We&#xD;
      estimate 10 to 20 patients per year will be enrolled.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 15, 2018</start_date>
  <completion_date type="Anticipated">December 2026</completion_date>
  <primary_completion_date type="Anticipated">December 2025</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>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with an Unplanned Delay to Surgery [Safety and Tolerability of Neoadjuvant Treatment]</measure>
    <time_frame>6 weeks</time_frame>
    <description>Safety endpoint: Number of patients with an Unplanned Delay to Surgery defined as any change to scheduled surgery date considered to be at least possibly related to neoadjuvant treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with decrease in tumor size or number of lymph nodes involved [Efficacy of Neoadjuvant Treatment]</measure>
    <time_frame>6 weeks</time_frame>
    <description>Efficacy endpoint: Number of patients with decrease in tumor size of greater than 10% or decrease in the number of lymph nodes involved by 10% by week 6.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Head and Neck Cancer</condition>
  <condition>Head and Neck Squamous Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab administration (3 doses) and radiation (5 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab administration (3 doses) and radiation (3 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment Cohort 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Radiation (3 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment Cohort 4</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab administration (3 doses) and radiation (3 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab 240mg IV q2wks or 480mg IV q4wks</description>
    <arm_group_label>Treatment Cohort 1</arm_group_label>
    <arm_group_label>Treatment Cohort 2</arm_group_label>
    <arm_group_label>Treatment Cohort 3</arm_group_label>
    <arm_group_label>Treatment Cohort 4</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Surgical Resection</intervention_name>
    <description>Surgical Resection of Tumor</description>
    <arm_group_label>Treatment Cohort 1</arm_group_label>
    <arm_group_label>Treatment Cohort 2</arm_group_label>
    <arm_group_label>Treatment Cohort 3</arm_group_label>
    <arm_group_label>Treatment Cohort 4</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiation (5 days)</intervention_name>
    <description>8Gy x 5 (Mon-Fri) GTV+3mm</description>
    <arm_group_label>Treatment Cohort 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiation (3 days)</intervention_name>
    <description>8Gy x 3 (Monday, Wednesday, Friday) GTV+3mm</description>
    <arm_group_label>Treatment Cohort 2</arm_group_label>
    <arm_group_label>Treatment Cohort 3</arm_group_label>
    <arm_group_label>Treatment Cohort 4</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients with squamous cell carcinoma of the head and neck region, (including&#xD;
             mucosal,cutaneous, or nodal) who are planned for surgical resection and in the opinion&#xD;
             of the investigator are able to safely undergo neoadjuvant anti-PD-1 and radiation. In&#xD;
             addition, the following are eligible (but will not contribute toward total accrual):&#xD;
             non-surgical cases that are planned for palliative RT or that refuse or are unfit for&#xD;
             definitive concurrent chemotherapy.&#xD;
&#xD;
          2. HPV status as determined by p16 immunostain&#xD;
&#xD;
          3. Cohort 3: HPV-positive patients only&#xD;
&#xD;
          4. Cohort 4: HPV-negative patients only&#xD;
&#xD;
          5. Age 18 years or above with ability to give informed consent, comply with the protocol,&#xD;
             and sign a study-specific consent document. Patients with history of psychiatric&#xD;
             illness must be judged by the investigator as able to understand the investigational&#xD;
             nature and risks associated with the therapy.&#xD;
&#xD;
          6. Eastern Cooperative Oncology Group (ECOG) performance status deemed suitable by&#xD;
             investigator for study requirements.&#xD;
&#xD;
          7. Laboratory values (most recent), must be within 6 weeks of week 0 on study:&#xD;
&#xD;
               -  WBC ≥ 2000/uL, ANC ≥ 1000/uL&#xD;
&#xD;
               -  Hgb &gt; 8g/dL (patients may be transfused to reach this level)&#xD;
&#xD;
               -  Platelets &gt; 50,000 cells/mm3&#xD;
&#xD;
               -  Creatinine ≤ 3 x ULN&#xD;
&#xD;
               -  AST/ALT ≤ 5 x ULN for subjects without liver metastasis; or ≤ 8 x ULN for&#xD;
                  subjects with liver metastasis, [per investigator brochure]&#xD;
&#xD;
               -  Total bilirubin ≤ 3 x ULN, (except subjects with Gilbert's Syndrome, who must&#xD;
                  have a total bilirubin less than 3.0 mg/dL)&#xD;
&#xD;
               -  Negative pregnancy test (bHCG urine or serum, women of childbearing potential&#xD;
                  only)&#xD;
&#xD;
          8. Women of child-bearing potential (WOCBP) must agree to follow adequate contraceptive&#xD;
             practices to avoid pregnancy for the duration of treatment with nivolumab plus 5&#xD;
             half-lives of nivolumab (75 days) plus 30 days (duration of ovulatory cycle) for a&#xD;
             total of 105 days post-treatment completion.&#xD;
&#xD;
          9. Males who are sexually active with WOCBP must agree to follow adequate contraceptive&#xD;
             practices to avoid pregnancy for the duration of treatment with study drug (s) plus 5&#xD;
             half lives of the study drug (75 days) plus 90 days (duration of sperm turnover) for a&#xD;
             total of 165 days post-treatment completion.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any clinical factors such as bleeding, active infection, or psychiatric factors that&#xD;
             in the judgment of the investigator would preclude safe participation and compliance&#xD;
             with study procedures.&#xD;
&#xD;
          2. HNSCC for which radiation is not indicated during normal treatment course.&#xD;
&#xD;
          3. Need for chronic maintenance with oral steroids ≥20mg daily prednisone equivalent;&#xD;
             inhaled, topical or non-absorbed steroids are acceptable.&#xD;
&#xD;
          4. History of or current active autoimmune disease, [e.g. including but not limited to&#xD;
             inflammatory bowel diseases [IBD], rheumatoid arthritis, autoimmune hepatitis,&#xD;
             systemic sclerosis (scleroderma and variants), systemic lupus erythematosus,&#xD;
             autoimmune vasculitis, autoimmune neuropathies (such as Guillain-Barre syndrome)],&#xD;
             which in the judgment of the investigator poses an active and significant morbidity&#xD;
             risk. Vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism&#xD;
             are not exclusionary. Patient and investigator may opt to accept risk of autoimmune&#xD;
             disease flare, based on shared-decision making with consideration of risk/benefit.&#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>Rom Leidner, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Providence Health and Services</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Providence Portland Medical Center</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://oregon.providence.org/our-services/p/providence-cancer-center/</url>
    <description>Providence Cancer Center</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>August 8, 2017</study_first_submitted>
  <study_first_submitted_qc>August 10, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 14, 2017</study_first_posted>
  <last_update_submitted>June 2, 2023</last_update_submitted>
  <last_update_submitted_qc>June 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HNSCC</keyword>
  <keyword>radiation</keyword>
  <keyword>surgery</keyword>
  <keyword>phase 1</keyword>
  <keyword>immunotherapy</keyword>
  <keyword>nivolumab</keyword>
  <keyword>antibodies</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Head and Neck Neoplasms</mesh_term>
    <mesh_term>Squamous Cell Carcinoma of Head and Neck</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</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/NCT03247712
org study id: NIRT-HNC
nct id: NCT03247712
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The purpose of this study is to test the safety of neoadjuvant immunoradiotherapy as a safe
      means of down-staging Head and Neck Squamous Cell Carcinoma (HNSCC) prior to surgical
      resection.
This clinical trial uses nivolumab and radiotherapy prior to definitive surgical resection of
      tumors in patients with Head and Neck Squamous Cell Carcinoma (OHNSCC) with the primary
      objective of determining the safety and feasibility of preoperative immunoradiotherapy. In
      addition, tumor tissue, microbiome samples, and peripheral blood will be obtained for
      exploratory immunologic end points including measurements of tumor infiltrating immune cell
      populations based on flow cytometry and immunohistochemistry as well as circulating
      immunological parameters. This is the first study to evaluate the safety and efficacy of
      neoadjuvant radiation + PD-1 blockade in patients with HNSCC.

      Estimated duration of 20 weeks: neoadjuvant immunoradiotherapy +/- surgery, followed by 6
      doses of nivolumab 480mg IV q4wks +/- risk-adapted adjuvant therapy, per standard of care.

      Phase I safety lead-in study (n = 6) evaluating the safety of neoadjuvant immunoradiotherapy
      in HNSCC, followed by phase II efficacy study (n = 28, total) to assess rate of down-staging
      after neoadjuvant immunoradiotherapy using Simon's two-stage design (futility assessment at n
      = 12).

      The phase 1 portion of this study will require 6 patients and is therefore expected to
      complete in 6 months. Although non-surgical patients are eligible to enroll, they will not be
      counted toward accrual for either the primary safety endpoint, (as by definition, unplanned
      delay of surgery cannot exist); nor the secondary efficacy endpoint, as potential for
      surgical staging is absent.

      So long as 2 or fewer surgical delays are observed (primary safety endpoint), the phase 2
      portion of study will proceed (secondary efficacy endpoint). Patients will be followed for
      disease free and overall survival at 5 years.

      Eligible patients may be enrolled unless a rate of unplanned surgical delay attributed to
      immunoradiotherapy is found to exceed 33% after enrollment of the first 6 patients. We
      estimate 10 to 20 patients per year will be enrolled.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients with an Unplanned Delay to Surgery [Safety and Tolerability of Neoadjuvant Treatment]
time frame: 6 weeks
description: Safety endpoint: Number of patients with an Unplanned Delay to Surgery defined as any change to scheduled surgery date considered to be at least possibly related to neoadjuvant treatment.
measure: Number of patients with decrease in tumor size or number of lymph nodes involved [Efficacy of Neoadjuvant Treatment]
time frame: 6 weeks
description: Efficacy endpoint: Number of patients with decrease in tumor size of greater than 10% or decrease in the number of lymph nodes involved by 10% by week 6.
arm group label: Treatment Cohort 1
arm group type: Experimental
description: Nivolumab administration (3 doses) and radiation (5 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).
arm group label: Treatment Cohort 2
arm group type: Experimental
description: Nivolumab administration (3 doses) and radiation (3 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).
arm group label: Treatment Cohort 3
arm group type: Experimental
description: Radiation (3 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).
arm group label: Treatment Cohort 4
arm group type: Experimental
description: Nivolumab administration (3 doses) and radiation (3 days) therapy prior to restaging and surgical resection followed by additional administration of nivolumab (3 doses).
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab 240mg IV q2wks or 480mg IV q4wks
arm group label: Treatment Cohort 1
arm group label: Treatment Cohort 2
arm group label: Treatment Cohort 3
arm group label: Treatment Cohort 4
other name: Opdivo
intervention type: Procedure
intervention name: Surgical Resection
description: Surgical Resection of Tumor
arm group label: Treatment Cohort 1
arm group label: Treatment Cohort 2
arm group label: Treatment Cohort 3
arm group label: Treatment Cohort 4
intervention type: Radiation
intervention name: Radiation (5 days)
description: 8Gy x 5 (Mon-Fri) GTV+3mm
arm group label: Treatment Cohort 1
intervention type: Radiation
intervention name: Radiation (3 days)
description: 8Gy x 3 (Monday, Wednesday, Friday) GTV+3mm
arm group label: Treatment Cohort 2
arm group label: Treatment Cohort 3
arm group label: Treatment Cohort 4
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rom Leidner, MD
role: Principal Investigator
affiliation: Providence Health and Services
facility: 
country: United States
url: http://oregon.providence.org/our-services/p/providence-cancer-center/
description: Providence Cancer Center
responsible party type: Sponsor
mesh term: Head and Neck Neoplasms
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Nivolumab
sharing ipd: No