<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/NCT02979977</url>
  </required_header>
  <id_info>
    <org_study_id>1608018260</org_study_id>
    <nct_id>NCT02979977</nct_id>
  </id_info>
  <brief_title>Dual Inhibition of EGFR With Afatinib and Cetuximab in the Treatment of Advanced Squamous Cell Cancers of the Head and Neck</brief_title>
  <official_title>Single-Arm Phase II Trial of Dual Inhibition of EGFR With Afatinib and Cetuximab With Correlative Studies in the Treatment of Advanced Squamous Cell Cancers of the Head and Neck</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Comprehensive Cancer Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Yale 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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single arm Phase II study for patients with recurrent or metastatic squamous cell&#xD;
      carcinoma of the head and neck, who are previously treated with a platinum based regimen or&#xD;
      with an immune checkpoint inhibitor. The primary objective is to evaluate the efficacy of the&#xD;
      combination of cetuximab and afatinib.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will be a multicenter, single-arm, open-label Phase II trial. Patients with&#xD;
      advanced squamous cell carcinoma of the head and neck, who are previously treated with a&#xD;
      platinum based regimen or with immune checkpoint inhibitor therapy or both, will be eligible&#xD;
      for participation on the study. After a baseline evaluation and biopsy (where feasible), they&#xD;
      will be treated with weekly/bi-weekly intravenous cetuximab and daily oral afatinib. Biopsy&#xD;
      will be repeated where feasible after 4 weeks (window of +1 week) on therapy and again at&#xD;
      disease progression or end of treatment.&#xD;
&#xD;
      Treatment will continue until disease progression or development of Grade 3 or higher drug&#xD;
      related toxicities that fail to resolve to Grade 2 despite appropriate supportive care.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 24, 2017</start_date>
  <completion_date type="Anticipated">January 2025</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>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>Tumor shrinkage</measure>
    <time_frame>Disease progression or end of treatment (up to 2 years)</time_frame>
    <description>Objective Response Rate (Complete Response + Partial Response), defined by tumor shrinkage (mm), per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival in weeks</measure>
    <time_frame>1 year follow-up</time_frame>
    <description>We will use Kaplan-Meier survival analysis to estimate the median PFS in the cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival in months</measure>
    <time_frame>1 year follow-up</time_frame>
    <description>Measured by a monthly phone calls. We will use Kaplan-Meier survival analysis to estimate the median and OS in the cohort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response in weeks</measure>
    <time_frame>1 year follow-up</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity assessed with National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</measure>
    <time_frame>Up to 2.5 years</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Exploratory biomarker analysis</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Analysis of tumor-tissue from biopsies obtained at baseline, after four weeks of treatment with the combination, and again at disease progression or end of treatment</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Squamous Cell Cancers of the Head and Neck</condition>
  <arm_group>
    <arm_group_label>All subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Advanced squamous cell carcinoma of the head and neck region, having previously been treated on a platinum based regimen or with an immune checkpoint inhibitor. Subjects will receive Afatinib dose 30 mg per day and weekly/bi-weekly intravenous cetuximab.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>cetuximab</intervention_name>
    <description>30-60 minutes after the recommended pre-medications, cetuximab will be administered intravenously at a dose of 400mg/m2 on cycle 1, day 1 of treatment (loading dose) and at a dose of 250mg/m2 every 7 days (+/- 1 day) thereafter. Alternatively, patients can be treated at a dose of 500mg/m2 every 14 days (+/- 2 days).</description>
    <arm_group_label>All subjects</arm_group_label>
    <other_name>Erbitux</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>afatinib</intervention_name>
    <description>Patients will take a single oral dose of afatinib each day at a dose of 30 mg. Afatinib dose will not be escalated beyond the 30 mg daily oral dose; dose reductions of afatinib can occur to manage treatment related adverse events.</description>
    <arm_group_label>All subjects</arm_group_label>
    <other_name>GIOTRIF or GILOTRIF</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed squamous cell carcinoma of the head and neck that is&#xD;
             metastatic, recurrent or locally advanced and not treatable with curative intent.&#xD;
&#xD;
          -  Previous treatment with a platinum-based regimen or immune checkpoint inhibitor or&#xD;
             both.2-week washout period prior to treatment start will be required.&#xD;
&#xD;
          -  Patients who have experienced progression of disease within 6 months following&#xD;
             completion of a platinum-based chemoradiation in the definitive or adjuvant setting&#xD;
             will be permitted.&#xD;
&#xD;
          -  Prior cetuximab permitted if it was given as part of multi-modality therapy for&#xD;
             initial treatment of locally advanced disease.&#xD;
&#xD;
          -  Measurable disease based on RECIST v 1.1. Baseline measurements and evaluations must&#xD;
             be obtained within 4 weeks of enrollment. Disease in previously irradiated sites is&#xD;
             considered measurable if there has been unequivocal disease progression or&#xD;
             biopsy-proven residual carcinoma following radiation therapy.&#xD;
&#xD;
          -  ECOG performance status ≤2&#xD;
&#xD;
          -  Adequate organ function, defined as all of the following:&#xD;
&#xD;
          -  Hemoglobin ≥ 8 g/dl.&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) ≥1000 / mm3.&#xD;
&#xD;
          -  Platelet count ≥75,000 / mm3.&#xD;
&#xD;
          -  Estimated creatinine clearance &gt; 45ml / min.&#xD;
&#xD;
          -  Total Bilirubin ≤ 1.5 times upper limit of (institutional/central) normal (Patients&#xD;
             with Gilbert's syndrome total bilirubin must be ≤4 times institutional upper limit of&#xD;
             normal).&#xD;
&#xD;
          -  Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ three times the&#xD;
             upper limit of (institutional/central) normal (ULN) (if related to liver metastases ≤&#xD;
             five times ULN).&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent that is&#xD;
             consistent with ICH-GCP guidelines.&#xD;
&#xD;
          -  Negative urine or serum pregnancy test for women of childbearing potential&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior erlotinib, gefitinib or lapatinib therapy or prior exposure to any&#xD;
             investigational EGFR or panErbB reversible or irreversible inhibitor or any prior&#xD;
             panitumumab or investigational EGFR-directed monoclonal antibody.&#xD;
&#xD;
          -  Radiotherapy within 2 weeks prior to enrollment. Palliative radiation to target organs&#xD;
             may be allowed up to 2 weeks prior to enrollment, as long as there are other target&#xD;
             lesions that can be monitored for response to study treatment.&#xD;
&#xD;
          -  Known hypersensitivity to afatinib or its excipients&#xD;
&#xD;
          -  Women of child-bearing potential (WOCBP) and men who are able to father a child,&#xD;
             unwilling to be abstinent or use highly effective methods of birth control prior to&#xD;
             study entry, for the duration of study participation and for at least 4 weeks after&#xD;
             treatment has ended.&#xD;
&#xD;
          -  Women who are pregnant, nursing, or who plan to become pregnant while in the trial.&#xD;
&#xD;
          -  Any history of or concomitant condition that, in the opinion of the Investigator,&#xD;
             would compromise the patient's ability to comply with the study or interfere with the&#xD;
             evaluation of the efficacy and safety of the test drug.&#xD;
&#xD;
          -  Concomitant malignancies at other sites that are being actively treated with systemic&#xD;
             therapy&#xD;
&#xD;
          -  Requiring treatment with any of the prohibited concomitant medications that cannot be&#xD;
             stopped for the duration of trial participation.&#xD;
&#xD;
          -  Clinically significant interstitial lung disease.&#xD;
&#xD;
          -  Known history of untreated viral hepatitis or HIV.&#xD;
&#xD;
          -  Patients with parenchymal brain metastases are not eligible, unless they have&#xD;
             completed local therapy&#xD;
&#xD;
          -  Leptomeningeal carcinomatosis&#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>Aarti Bhatia, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cindy Voghell</last_name>
    <phone>203-737-4784</phone>
    <email>cynthia.voghell@yale.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Yale Cancer Center</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520-8028</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Clinical Trials Office</last_name>
      <phone>203-785-5702</phone>
    </contact>
    <investigator>
      <last_name>Aarti Bhatia, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>November 29, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 2, 2016</study_first_posted>
  <last_update_submitted>January 10, 2023</last_update_submitted>
  <last_update_submitted_qc>January 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 11, 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>Neoplasms, Squamous Cell</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <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>Cetuximab</mesh_term>
    <mesh_term>Afatinib</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/NCT02979977
org study id: 1608018260
nct id: NCT02979977
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a single arm Phase II study for patients with recurrent or metastatic squamous cell
      carcinoma of the head and neck, who are previously treated with a platinum based regimen or
      with an immune checkpoint inhibitor. The primary objective is to evaluate the efficacy of the
      combination of cetuximab and afatinib.
This study will be a multicenter, single-arm, open-label Phase II trial. Patients with
      advanced squamous cell carcinoma of the head and neck, who are previously treated with a
      platinum based regimen or with immune checkpoint inhibitor therapy or both, will be eligible
      for participation on the study. After a baseline evaluation and biopsy (where feasible), they
      will be treated with weekly/bi-weekly intravenous cetuximab and daily oral afatinib. Biopsy
      will be repeated where feasible after 4 weeks (window of +1 week) on therapy and again at
      disease progression or end of treatment.

      Treatment will continue until disease progression or development of Grade 3 or higher drug
      related toxicities that fail to resolve to Grade 2 despite appropriate supportive care.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Tumor shrinkage
time frame: Disease progression or end of treatment (up to 2 years)
description: Objective Response Rate (Complete Response + Partial Response), defined by tumor shrinkage (mm), per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
measure: Progression-free survival in weeks
time frame: 1 year follow-up
description: We will use Kaplan-Meier survival analysis to estimate the median PFS in the cohort.
measure: Overall survival in months
time frame: 1 year follow-up
description: Measured by a monthly phone calls. We will use Kaplan-Meier survival analysis to estimate the median and OS in the cohort.
measure: Duration of response in weeks
time frame: 1 year follow-up
measure: Toxicity assessed with National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
time frame: Up to 2.5 years
measure: Exploratory biomarker analysis
time frame: Up to 2 years
description: Analysis of tumor-tissue from biopsies obtained at baseline, after four weeks of treatment with the combination, and again at disease progression or end of treatment
arm group label: All subjects
arm group type: Experimental
description: Advanced squamous cell carcinoma of the head and neck region, having previously been treated on a platinum based regimen or with an immune checkpoint inhibitor. Subjects will receive Afatinib dose 30 mg per day and weekly/bi-weekly intravenous cetuximab.
intervention type: Drug
intervention name: cetuximab
description: 30-60 minutes after the recommended pre-medications, cetuximab will be administered intravenously at a dose of 400mg/m2 on cycle 1, day 1 of treatment (loading dose) and at a dose of 250mg/m2 every 7 days (+/- 1 day) thereafter. Alternatively, patients can be treated at a dose of 500mg/m2 every 14 days (+/- 2 days).
arm group label: All subjects
other name: Erbitux
intervention type: Drug
intervention name: afatinib
description: Patients will take a single oral dose of afatinib each day at a dose of 30 mg. Afatinib dose will not be escalated beyond the 30 mg daily oral dose; dose reductions of afatinib can occur to manage treatment related adverse events.
arm group label: All subjects
other name: GIOTRIF or GILOTRIF
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Aarti Bhatia, MD, MPH
role: Principal Investigator
affiliation: Yale University
last name: Cindy Voghell
phone: 203-737-4784
email: cynthia.voghell@yale.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Neoplasms, Squamous Cell
mesh term: Carcinoma, Squamous Cell
mesh term: Head and Neck Neoplasms
mesh term: Cetuximab
mesh term: Afatinib
sharing ipd: No