<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/NCT01732640</url>
  </required_header>
  <id_info>
    <org_study_id>J1266</org_study_id>
    <secondary_id>NA_00074085</secondary_id>
    <nct_id>NCT01732640</nct_id>
  </id_info>
  <brief_title>A Phase I/II Study Afatinib/Carboplatin/Paclitaxel Induction Chemotherapy In HPV-Negative HNSCC.</brief_title>
  <official_title>A Phase I/II Study Afatinib/Carboplatin/Paclitaxel Induction Chemotherapy Followed By Standard Chemoradiation In HPV-Negative or High-risk HPV-Positive Locally Advanced Stage III/IVa/IVb HNSCC</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Vanderbilt-Ingram Cancer Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Comprehensive Cancer Network</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Trial Objectives:&#xD;
&#xD;
      The objective is to investigate the efficacy and safety of afatinib with induction&#xD;
      chemotherapy in primary unresected patients with locally advanced, HPV-negative, stage III or&#xD;
      IVa/b HNSCC including oral cavity, oropharynx, hypopharynx, or larynx.&#xD;
&#xD;
      Primary Objective Phase I The primary objective of the phase I portion of the trial is to&#xD;
      determine the maximum tolerated dose (MTD) or the recommended phase II dose of daily oral&#xD;
      afatinib that is safe in combination with carboplatin AUC 6 and paclitaxel 175mg/m2 q 21 days&#xD;
      as an induction regimen.&#xD;
&#xD;
      Primary Objective Phase 2 The primary objective of the phase 2 portion of the trial is to&#xD;
      estimate the objective tumor response rate and toxicity with induction therapy in patients&#xD;
      treated on the afatinib dose determined in Phase I.&#xD;
&#xD;
      Secondary Objectives The secondary objective of phase II is to estimate: 1) the overall&#xD;
      response to entire treatment after completion of CRT, 2) progression-free survival (PFS) rate&#xD;
      at 2 years, and 3) overall survival (OS) at 2 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a phase I/phase II prospective multicenter trial to investigate the efficacy and&#xD;
      safety of afatinib with induction chemotherapy in primary unresected patients with&#xD;
      HPV-negative locally advanced SCC stage III or IVa/b of oral cavity, oropharynx, hypopharynx,&#xD;
      or larynx. The primary endpoint is overall response rate after the completion of induction&#xD;
      chemotherapy.&#xD;
&#xD;
      Eligible patients will begin with a 14 day lead-in period with afatinib alone. This will be&#xD;
      followed immediately by 2 cycles of induction chemotherapy with carboplatin AUC 6 IV,&#xD;
      paclitaxel 175mg/m2 day 1, and afatinib as a continuous daily dosing. Each cycle is repeated&#xD;
      every 21 days. All patients will receive concurrent chemoradiotherapy beginning 2-3 weeks&#xD;
      after the completion of the second cycle of induction chemotherapy (Refer to Study Schema in&#xD;
      page 8 of the protocol).&#xD;
&#xD;
      During the period of induction chemotherapy, a complete history and physical (including&#xD;
      weight) and tumor assessment by physical examination on Day 1 of each cycle will be performed&#xD;
      and documented. Complete blood count with differential and a comprehensive metabolic profile&#xD;
      will be performed weekly. After completion of induction chemotherapy, reassessment with blood&#xD;
      work, physical exam, CT/MRI of neck and nasopharyngolaryngoscopy will be performed. After the&#xD;
      completion of CRT, the patient will have a MRI, CT, or FDG PET approximately 12 weeks after&#xD;
      CRT. Follow-up will be standard of care from this point onwards.&#xD;
&#xD;
      Physical exam, blood work and AE assessments will also be frequently performed during entire&#xD;
      treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Slow accrual and high levels of toxicity lead to early termination.&#xD;
  </why_stopped>
  <start_date>December 2012</start_date>
  <completion_date type="Actual">January 2017</completion_date>
  <primary_completion_date type="Actual">November 2016</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>Maximum Tolerated Dose (MTD) of Afatinib</measure>
    <time_frame>1 Year (Average)</time_frame>
    <description>The maximally tolerated dose (MTD) was defined as the dose of afatinib in which &lt;2 of 6 patients experience a DLT with the next higher dose having at least 2 of up to 6 patients experiencing a DLT. No dose escalations or de-escalations are permitted within each subject's treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective Tumor Response</measure>
    <time_frame>After completion of 2 cycles of induction chemotherapy (at least 8 weeks)</time_frame>
    <description>Patients were accessed for response by CT/MRI and clinical exam. Partial response was defined as a greater than 30 % reduction in tumor size.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Dose Limiting Toxicities</measure>
    <time_frame>1 year (average)</time_frame>
    <description>Grade 3 or 4 neutropenia (ie. absolute neutrophil count &lt;1000 cells/mm^3) that was associated with a fever&gt;38.5 degrees C or lasting longer than 5 days, grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia, and any grade 3 or 4 non-hematologic toxicity per CTCAE criteria which were probably or definitely related to study therapy. During the chemoradiation, an event of stomatitis, pharyngitis, mucositis, or dermatitis was not considered to be a dose limiting toxicity unless it was a grade 4 that did resolve to &lt;grade 2 with a radiation treatment break (not to exceed 10 days) or with withholding chemotherapy (not to exceed 2 weekly doses).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response After Chemoradiation</measure>
    <time_frame>5 Years</time_frame>
    <description>To estimate the overall response rate after completion of chemoradiation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>2 Year Progression Free Survival (PFS)</measure>
    <time_frame>2 Years</time_frame>
    <description>To estimate the 2 year progression free survival.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Overall Survival at 2 Years</measure>
    <time_frame>2 Years</time_frame>
    <description>To estimate the median overall survival.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biological Marker Activity of Afatinib</measure>
    <time_frame>5 Years</time_frame>
    <description>To estimate the biological marker activity of afatinib by serial sampling of tumor and blood samples from patients, and correlate with clinical and pathological response and outcomes. On- and off-target effects of afatinib will be assessed for the biological marker activity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Activity of Afatinib Based on Serial FLT-PET/CT and DW-MRI</measure>
    <time_frame>5 Years</time_frame>
    <description>To estimate the activity of afatinib by obtaining serial FLT-PET/CT and DW-MRI, And compare to standard of care CT images (which will be acquired at baseline and at the completion of treatment, and categorized per RECIST criteria) and correlated with response.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlate Standard Imaging Pre and Post Treatment</measure>
    <time_frame>5 Years</time_frame>
    <description>To correlate the response with standard imaging CT/MRI and FDG PET pre and post treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response After Chemoradiation</measure>
    <time_frame>5 years</time_frame>
    <description>To estimate the overall response rate after completion of chemoradiation</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Squamous Cell Carcinoma of the Head and Neck</condition>
  <arm_group>
    <arm_group_label>Study Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Afatinib</intervention_name>
    <description>Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 20, 30, or 40 mg. Tablets will be supplied in HDPE, child-resistant, tamper-evident bottles.</description>
    <arm_group_label>Study Arm</arm_group_label>
    <other_name>N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paclitaxel</intervention_name>
    <description>Induction chemotherapy: 175 mg/m2 day 1 every 21 days for 2 cycles (IV infusion as per institutional standard).</description>
    <arm_group_label>Study Arm</arm_group_label>
    <other_name>TaxolR</other_name>
    <other_name>NSC 673089</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 150 mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and mannitol. Commercial supplies of carboplatin will be used in this trial.</description>
    <arm_group_label>Study Arm</arm_group_label>
    <other_name>cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Concurrent chemotherapy: 40 mg/m2 once weekly for 7 cycles (IV infusion as per institutional standard).</description>
    <arm_group_label>Study Arm</arm_group_label>
    <other_name>Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II)</other_name>
    <other_name>diaminedichloroplatinum</other_name>
    <other_name>cis-platinum</other_name>
    <other_name>platinum</other_name>
    <other_name>Platinol</other_name>
    <other_name>Platinol-AQ</other_name>
    <other_name>DDP</other_name>
    <other_name>CDDP</other_name>
    <other_name>DACP</other_name>
    <other_name>NSC 119875 R R</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Intensity Modulated Radiation Therapy</intervention_name>
    <description>Standard Fractionation 70 Gy /35 fractions at 2 Gy/day for 5 days per week.</description>
    <arm_group_label>Study Arm</arm_group_label>
    <other_name>IMRT</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients must have a histologically confirmed diagnosis of squamous cell carcinoma,&#xD;
             operable or inoperable tumors, stage III (T3N0-1) and IVA-B (T1-4 N2-3M0 or T4N0-1M0)&#xD;
             of oral cavity, oropharynx, hypopharynx and larynx. For patients with oropharynx&#xD;
             primary, either HPV negative or HPV positive with a &gt; 10 pack year tobacco history or&#xD;
             current smokers are eligible. HPV status should be determined before the enrollment in&#xD;
             only non-smokers with oropharynx primary by HPV in-situ hybridization and/or p16&#xD;
             immunostain.&#xD;
&#xD;
          2. Patients must have measurable disease of primary, nodes or both by clinical and&#xD;
             radiographic methods per RECIST v1.1..&#xD;
&#xD;
          3. No prior therapy, including surgery with curative intent, chemotherapy, radiation&#xD;
             therapy, immunotherapy, EGFR targeted therapies, or any other investigational agents.&#xD;
&#xD;
          4. Age &gt;= 18 years.&#xD;
&#xD;
          5. ECOG performance status 0-1.&#xD;
&#xD;
          6. Patients must have normal hepatic, renal and bone marrow function.&#xD;
&#xD;
               -  Absolute neutrophil count &gt;=1,000/ mm3 Count&#xD;
&#xD;
               -  Platelets &gt;= 100,000/mm3 Count&#xD;
&#xD;
               -  Total serum bilirubin =&lt; 1.5mg/dL Level:&#xD;
&#xD;
               -  AST and ALT =&lt; 2.5 X ULN&#xD;
&#xD;
               -  Alkaline Phosphatase =&lt; 2.5 X ULN&#xD;
&#xD;
               -  Total calculated creatinine clearance &gt;= 60 mL/min&#xD;
&#xD;
          7. Patients with a history of a curatively treated malignancy must be disease-free for at&#xD;
             least two years except for carcinoma in situ of cervix and/or non-melanomatous skin&#xD;
             cancer.&#xD;
&#xD;
          8. Patients with the following within the last 6 months prior to pre-registration must be&#xD;
             evaluated by a cardiologist and/or neurologist prior to entry into the study.&#xD;
&#xD;
               -  Congestive heart failure &gt; NYHA Class II&#xD;
&#xD;
               -  CVA/TIA&#xD;
&#xD;
               -  Unstable angina&#xD;
&#xD;
               -  Myocardial infarction (with or without ST elevation)&#xD;
&#xD;
          9. Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any prior radiation above the clavicles.&#xD;
&#xD;
          2. Any prior invasive malignancy (unless non-melanomatous resectable skin or the DFS is 2&#xD;
             years or more).&#xD;
&#xD;
          3. History of allergic reactions attributed to compounds of similar chemical or&#xD;
             biological composition to afatinib, or other agents used in study.&#xD;
&#xD;
          4. Cardiac left ventricular dysfunction with resting ejection fraction of less than&#xD;
             institutional lower limit of normal ( if no lower limit of normal is defined in the&#xD;
             institution, the lower limit is 50%)&#xD;
&#xD;
          5. Gastrointestinal tract disease resulting in an inability to take or absorb oral or&#xD;
             enteral medication.&#xD;
&#xD;
          6. Baseline significant gastrointestinal symptoms with diarrhoea as a major symptom or a&#xD;
             CTCAE Grade &gt;1 diarrhoea of any etiology.&#xD;
&#xD;
          7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          8. Women of childbearing potential and sexually active males are strongly advised to use&#xD;
             an accepted and effective method of contraception.&#xD;
&#xD;
          9. Known pre-existing interstitial lung disease (ILD)&#xD;
&#xD;
         10. Pregnant women are excluded.&#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>Christine Chung, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins Sidney Kimmel Comprehensive Cancer Center</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt Ingram Cancer Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Chung CH, Rudek MA, Kang H, Marur S, John P, Tsottles N, Bonerigo S, Veasey A, Kiess A, Quon H, Cmelak A, Murphy BA, Gilbert J. A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally advanced stage III/IVa/IVb head and neck squamous cell carcinoma. Oral Oncol. 2016 Feb;53:54-9. doi: 10.1016/j.oraloncology.2015.11.020. Epub 2015 Dec 17.</citation>
    <PMID>26705063</PMID>
  </results_reference>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>November 12, 2012</study_first_submitted>
  <study_first_submitted_qc>November 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 26, 2012</study_first_posted>
  <results_first_submitted>July 28, 2017</results_first_submitted>
  <results_first_submitted_qc>June 29, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">July 26, 2018</results_first_posted>
  <last_update_submitted>June 29, 2018</last_update_submitted>
  <last_update_submitted_qc>June 29, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 26, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Squamous cell carcinoma of the head and neck</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Squamous Cell</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>Paclitaxel</mesh_term>
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Afatinib</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>20 mg Afatinib</title>
          <description>Eligible patients will begin a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
        </group>
        <group group_id="P2">
          <title>30 mg Afatinib</title>
          <description>Eligible patients will begin a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>All Study Participants</title>
          <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="9"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ECOG Status</title>
          <description>ECOG of 0 is best value; Normal, no complaints. ECOG of 1 is second best value; Able to carry on normal activities. Minor signs or symptoms of disease.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>0</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Disease Site</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Larynx</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Oropharynx</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Oral Cavity</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of Afatinib</title>
        <description>The maximally tolerated dose (MTD) was defined as the dose of afatinib in which &lt;2 of 6 patients experience a DLT with the next higher dose having at least 2 of up to 6 patients experiencing a DLT. No dose escalations or de-escalations are permitted within each subject's treatment.</description>
        <time_frame>1 Year (Average)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of Afatinib</title>
          <description>The maximally tolerated dose (MTD) was defined as the dose of afatinib in which &lt;2 of 6 patients experience a DLT with the next higher dose having at least 2 of up to 6 patients experiencing a DLT. No dose escalations or de-escalations are permitted within each subject's treatment.</description>
          <units>mg</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Objective Tumor Response</title>
        <description>Patients were accessed for response by CT/MRI and clinical exam. Partial response was defined as a greater than 30 % reduction in tumor size.</description>
        <time_frame>After completion of 2 cycles of induction chemotherapy (at least 8 weeks)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>All Study Particpants</title>
            <description>Eligible patients will begin with a 4-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Tumor Response</title>
          <description>Patients were accessed for response by CT/MRI and clinical exam. Partial response was defined as a greater than 30 % reduction in tumor size.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Partial Response</title>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Stable Disease</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Dose Limiting Toxicities</title>
        <description>Grade 3 or 4 neutropenia (ie. absolute neutrophil count &lt;1000 cells/mm^3) that was associated with a fever&gt;38.5 degrees C or lasting longer than 5 days, grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia, and any grade 3 or 4 non-hematologic toxicity per CTCAE criteria which were probably or definitely related to study therapy. During the chemoradiation, an event of stomatitis, pharyngitis, mucositis, or dermatitis was not considered to be a dose limiting toxicity unless it was a grade 4 that did resolve to &lt;grade 2 with a radiation treatment break (not to exceed 10 days) or with withholding chemotherapy (not to exceed 2 weekly doses).</description>
        <time_frame>1 year (average)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>20 mg Afatinib</title>
            <description>Eligible patients will begin a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
          <group group_id="O2">
            <title>30 mg Afatinib</title>
            <description>Eligible patients will begin a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Dose Limiting Toxicities</title>
          <description>Grade 3 or 4 neutropenia (ie. absolute neutrophil count &lt;1000 cells/mm^3) that was associated with a fever&gt;38.5 degrees C or lasting longer than 5 days, grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia, and any grade 3 or 4 non-hematologic toxicity per CTCAE criteria which were probably or definitely related to study therapy. During the chemoradiation, an event of stomatitis, pharyngitis, mucositis, or dermatitis was not considered to be a dose limiting toxicity unless it was a grade 4 that did resolve to &lt;grade 2 with a radiation treatment break (not to exceed 10 days) or with withholding chemotherapy (not to exceed 2 weekly doses).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response After Chemoradiation</title>
        <description>To estimate the overall response rate after completion of chemoradiation.</description>
        <time_frame>5 Years</time_frame>
        <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Study Arm</title>
            <description>14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.&#xD;
Afatinib: Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 20, 30, or 40 mg. Tablets will be supplied in HDPE, child-resistant, tamper-evident bottles.&#xD;
Paclitaxel: Induction chemotherapy: 175 mg/m2 day 1 every 21 days for</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response After Chemoradiation</title>
          <description>To estimate the overall response rate after completion of chemoradiation.</description>
          <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>2 Year Progression Free Survival (PFS)</title>
        <description>To estimate the 2 year progression free survival.</description>
        <time_frame>2 Years</time_frame>
        <population>Patients were taken off study before the full 2 years could be completed, therefore data was not collected for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
        </group_list>
        <measure>
          <title>2 Year Progression Free Survival (PFS)</title>
          <description>To estimate the 2 year progression free survival.</description>
          <population>Patients were taken off study before the full 2 years could be completed, therefore data was not collected for this outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Overall Survival at 2 Years</title>
        <description>To estimate the median overall survival.</description>
        <time_frame>2 Years</time_frame>
        <population>Patients were taken off study before the full 2 years could be completed, therefore data was not collected for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Overall Survival at 2 Years</title>
          <description>To estimate the median overall survival.</description>
          <population>Patients were taken off study before the full 2 years could be completed, therefore data was not collected for this outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Biological Marker Activity of Afatinib</title>
        <description>To estimate the biological marker activity of afatinib by serial sampling of tumor and blood samples from patients, and correlate with clinical and pathological response and outcomes. On- and off-target effects of afatinib will be assessed for the biological marker activity.</description>
        <time_frame>5 Years</time_frame>
        <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
        </group_list>
        <measure>
          <title>Biological Marker Activity of Afatinib</title>
          <description>To estimate the biological marker activity of afatinib by serial sampling of tumor and blood samples from patients, and correlate with clinical and pathological response and outcomes. On- and off-target effects of afatinib will be assessed for the biological marker activity.</description>
          <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Activity of Afatinib Based on Serial FLT-PET/CT and DW-MRI</title>
        <description>To estimate the activity of afatinib by obtaining serial FLT-PET/CT and DW-MRI, And compare to standard of care CT images (which will be acquired at baseline and at the completion of treatment, and categorized per RECIST criteria) and correlated with response.</description>
        <time_frame>5 Years</time_frame>
        <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
        </group_list>
        <measure>
          <title>Activity of Afatinib Based on Serial FLT-PET/CT and DW-MRI</title>
          <description>To estimate the activity of afatinib by obtaining serial FLT-PET/CT and DW-MRI, And compare to standard of care CT images (which will be acquired at baseline and at the completion of treatment, and categorized per RECIST criteria) and correlated with response.</description>
          <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Correlate Standard Imaging Pre and Post Treatment</title>
        <description>To correlate the response with standard imaging CT/MRI and FDG PET pre and post treatment.</description>
        <time_frame>5 Years</time_frame>
        <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
        </group_list>
        <measure>
          <title>Correlate Standard Imaging Pre and Post Treatment</title>
          <description>To correlate the response with standard imaging CT/MRI and FDG PET pre and post treatment.</description>
          <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response After Chemoradiation</title>
        <description>To estimate the overall response rate after completion of chemoradiation</description>
        <time_frame>5 years</time_frame>
        <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>All Study Participants</title>
            <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response After Chemoradiation</title>
          <description>To estimate the overall response rate after completion of chemoradiation</description>
          <population>Patients were taken off study before the full 5 years could be completed, therefore data was not collected for this outcome measure.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <desc>Only Grade 3-5 Serious Adverse Events were monitored and assessed.</desc>
      <group_list>
        <group group_id="E1">
          <title>20 mg Afatinib</title>
          <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
        </group>
        <group group_id="E2">
          <title>30 mg Afatinib</title>
          <description>Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Gr. 4 Neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gr. 3 Elevated ALT</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gr. 3 Pancytopenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gr. 3 Abdominal Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gr. 3 Diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Gr. 3 Urinary Tract Infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gr. 4 Sepsis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gr. 3 Pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Slow accrual and high levels of toxicity lead to early termination.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Hao Wang</name_or_title>
      <organization>Johns Hopkins University</organization>
      <phone>410-614-3426</phone>
      <email>hwang76@jhmi.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01732640
org study id: J1266
secondary id: NA_00074085
nct id: NCT01732640
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
Trial Objectives:

      The objective is to investigate the efficacy and safety of afatinib with induction
      chemotherapy in primary unresected patients with locally advanced, HPV-negative, stage III or
      IVa/b HNSCC including oral cavity, oropharynx, hypopharynx, or larynx.

      Primary Objective Phase I The primary objective of the phase I portion of the trial is to
      determine the maximum tolerated dose (MTD) or the recommended phase II dose of daily oral
      afatinib that is safe in combination with carboplatin AUC 6 and paclitaxel 175mg/m2 q 21 days
      as an induction regimen.

      Primary Objective Phase 2 The primary objective of the phase 2 portion of the trial is to
      estimate the objective tumor response rate and toxicity with induction therapy in patients
      treated on the afatinib dose determined in Phase I.

      Secondary Objectives The secondary objective of phase II is to estimate: 1) the overall
      response to entire treatment after completion of CRT, 2) progression-free survival (PFS) rate
      at 2 years, and 3) overall survival (OS) at 2 years.
This is a phase I/phase II prospective multicenter trial to investigate the efficacy and
      safety of afatinib with induction chemotherapy in primary unresected patients with
      HPV-negative locally advanced SCC stage III or IVa/b of oral cavity, oropharynx, hypopharynx,
      or larynx. The primary endpoint is overall response rate after the completion of induction
      chemotherapy.

      Eligible patients will begin with a 14 day lead-in period with afatinib alone. This will be
      followed immediately by 2 cycles of induction chemotherapy with carboplatin AUC 6 IV,
      paclitaxel 175mg/m2 day 1, and afatinib as a continuous daily dosing. Each cycle is repeated
      every 21 days. All patients will receive concurrent chemoradiotherapy beginning 2-3 weeks
      after the completion of the second cycle of induction chemotherapy (Refer to Study Schema in
      page 8 of the protocol).

      During the period of induction chemotherapy, a complete history and physical (including
      weight) and tumor assessment by physical examination on Day 1 of each cycle will be performed
      and documented. Complete blood count with differential and a comprehensive metabolic profile
      will be performed weekly. After completion of induction chemotherapy, reassessment with blood
      work, physical exam, CT/MRI of neck and nasopharyngolaryngoscopy will be performed. After the
      completion of CRT, the patient will have a MRI, CT, or FDG PET approximately 12 weeks after
      CRT. Follow-up will be standard of care from this point onwards.

      Physical exam, blood work and AE assessments will also be frequently performed during entire
      treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) of Afatinib
time frame: 1 Year (Average)
description: The maximally tolerated dose (MTD) was defined as the dose of afatinib in which <2 of 6 patients experience a DLT with the next higher dose having at least 2 of up to 6 patients experiencing a DLT. No dose escalations or de-escalations are permitted within each subject's treatment.
measure: Objective Tumor Response
time frame: After completion of 2 cycles of induction chemotherapy (at least 8 weeks)
description: Patients were accessed for response by CT/MRI and clinical exam. Partial response was defined as a greater than 30 % reduction in tumor size.
measure: Number of Participants With Dose Limiting Toxicities
time frame: 1 year (average)
description: Grade 3 or 4 neutropenia (ie. absolute neutrophil count <1000 cells/mm^3) that was associated with a fever>38.5 degrees C or lasting longer than 5 days, grade 3 thrombocytopenia with bleeding or grade 4 thrombocytopenia, and any grade 3 or 4 non-hematologic toxicity per CTCAE criteria which were probably or definitely related to study therapy. During the chemoradiation, an event of stomatitis, pharyngitis, mucositis, or dermatitis was not considered to be a dose limiting toxicity unless it was a grade 4 that did resolve to <grade 2 with a radiation treatment break (not to exceed 10 days) or with withholding chemotherapy (not to exceed 2 weekly doses).
measure: Overall Response After Chemoradiation
time frame: 5 Years
description: To estimate the overall response rate after completion of chemoradiation.
measure: 2 Year Progression Free Survival (PFS)
time frame: 2 Years
description: To estimate the 2 year progression free survival.
measure: Median Overall Survival at 2 Years
time frame: 2 Years
description: To estimate the median overall survival.
measure: Biological Marker Activity of Afatinib
time frame: 5 Years
description: To estimate the biological marker activity of afatinib by serial sampling of tumor and blood samples from patients, and correlate with clinical and pathological response and outcomes. On- and off-target effects of afatinib will be assessed for the biological marker activity.
measure: Activity of Afatinib Based on Serial FLT-PET/CT and DW-MRI
time frame: 5 Years
description: To estimate the activity of afatinib by obtaining serial FLT-PET/CT and DW-MRI, And compare to standard of care CT images (which will be acquired at baseline and at the completion of treatment, and categorized per RECIST criteria) and correlated with response.
measure: Correlate Standard Imaging Pre and Post Treatment
time frame: 5 Years
description: To correlate the response with standard imaging CT/MRI and FDG PET pre and post treatment.
measure: Overall Response After Chemoradiation
time frame: 5 years
description: To estimate the overall response rate after completion of chemoradiation
arm group label: Study Arm
arm group type: Experimental
description: Eligible patients will begin with a 14-day lead-in period with afatinib alone. This will be followed immediately by 2 cycles of induction chemotherapy (IC) with carboplatin AUC 6 IV Day 1, paclitaxel 175mg/m2 IV Day 1, and oral afatinib as a continuous daily dosing. Each cycle is repeated every 21 days. After completion of 2 cycles of IC, patients will be assessed for response by CT/MRI and clinical exam. After the induction, all patients will receive Intensity Modulated Radiation Therapy (IMRT) with weekly cisplatin 40mg/m2 IV. Chemoradiotherapy (CRT) will begin 2-3 weeks after the completion of the second cycle of IC. The patients will be evaluated with a MRI or CT, and FDG PET approximately 12 weeks after completion of CRT.
intervention type: Drug
intervention name: Afatinib
description: Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 20, 30, or 40 mg. Tablets will be supplied in HDPE, child-resistant, tamper-evident bottles.
arm group label: Study Arm
other name: N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide
intervention type: Drug
intervention name: Paclitaxel
description: Induction chemotherapy: 175 mg/m2 day 1 every 21 days for 2 cycles (IV infusion as per institutional standard).
arm group label: Study Arm
other name: TaxolR
other name: NSC 673089
intervention type: Drug
intervention name: Carboplatin
description: Carboplatin is available as a sterile lyophilized powder in single-dose vials containing 50 mg, 150 mg, or 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and mannitol. Commercial supplies of carboplatin will be used in this trial.
arm group label: Study Arm
other name: cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II)
intervention type: Drug
intervention name: Cisplatin
description: Concurrent chemotherapy: 40 mg/m2 once weekly for 7 cycles (IV infusion as per institutional standard).
arm group label: Study Arm
other name: Cis-diaminedichloroplatinum Cis-diaminedichloroplatinum (II)
other name: diaminedichloroplatinum
other name: cis-platinum
other name: platinum
other name: Platinol
other name: Platinol-AQ
other name: DDP
other name: CDDP
other name: DACP
other name: NSC 119875 R R
intervention type: Radiation
intervention name: Intensity Modulated Radiation Therapy
description: Standard Fractionation 70 Gy /35 fractions at 2 Gy/day for 5 days per week.
arm group label: Study Arm
other name: IMRT
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Christine Chung, MD
role: Principal Investigator
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
facility: 
facility: 
country: United States
citation: Chung CH, Rudek MA, Kang H, Marur S, John P, Tsottles N, Bonerigo S, Veasey A, Kiess A, Quon H, Cmelak A, Murphy BA, Gilbert J. A phase I study afatinib/carboplatin/paclitaxel induction chemotherapy followed by standard chemoradiation in HPV-negative or high-risk HPV-positive locally advanced stage III/IVa/IVb head and neck squamous cell carcinoma. Oral Oncol. 2016 Feb;53:54-9. doi: 10.1016/j.oraloncology.2015.11.020. Epub 2015 Dec 17.
PMID: 26705063
responsible party type: Sponsor
mesh term: Carcinoma, Squamous Cell
mesh term: Squamous Cell Carcinoma of Head and Neck
mesh term: Paclitaxel
mesh term: Cisplatin
mesh term: Carboplatin
mesh term: Afatinib
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Slow accrual and high levels of toxicity lead to early termination.
point of contact: 