<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/NCT01663259</url>
  </required_header>
  <id_info>
    <org_study_id>UMCC 2009.078</org_study_id>
    <secondary_id>HUM00032219</secondary_id>
    <nct_id>NCT01663259</nct_id>
    <nct_alias>NCT01649414</nct_alias>
  </id_info>
  <brief_title>Reduced-intensity Therapy for Oropharyngeal Cancer in Non-smoking HPV-16 Positive Patients</brief_title>
  <official_title>Reduced-intensity Therapy for Advanced Oropharyngeal Cancer in Non-smoking Human Papilloma Virus (HPV)-16 Positive Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan Rogel Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Michigan Rogel Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Taking into account the excellent prognosis of patients with HPV-positive oropharyngeal&#xD;
      cancer with &lt; 10 pack-year smoking, the investigators hypothesize that reducing the intensity&#xD;
      of therapy for these patients will reduce treatment sequelae, notably long-term dysphagia,&#xD;
      without affecting their cure rates. The main Aim is to assess whether reducing treatment&#xD;
      intensity, by replacing concurrent chemotherapy with cetuximab, will indeed achieve improved&#xD;
      long-term toxicity.&#xD;
&#xD;
      The primary objectives include the following: to confirm that reducing treatment intensity in&#xD;
      patients with HPV-related oropharyngeal cancer and &lt; 10 pack-year smoking history by&#xD;
      replacing concurrent chemotherapy with concurrent cetuximab, does not significantly increase&#xD;
      the proportion of patients whose tumors recur, compared to our previous experience in similar&#xD;
      patients receiving chemo-RT and to compare the toxicity in patients receiving cetuximab-RT to&#xD;
      similar patients treated with 7 weeks of chemotherapy concurrent with RT (&quot;standard therapy&quot;)&#xD;
      in UMCC 2-21.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators have shown in past experience a high success in getting rid of&#xD;
      oropharyngeal cancer (tonsil or base of tongue cancer) using chemotherapy and radiation&#xD;
      therapy in patients who have not smoked, or only smoked a minimal amount of cigarettes or&#xD;
      equivalent. In these patients, the cancer is thought to be caused by a virus (Human Papilloma&#xD;
      Virus, or HPV). HPV is a virus that infects the epidermis (outermost layer of skin) and&#xD;
      mucous membranes of humans. In general, patients with HPV-related cancer such as yours have a&#xD;
      better prognosis compared with patients whose tumors are smoking-related. Taking into account&#xD;
      the good prognosis, it is possible that reducing the intensity of therapy will not affect the&#xD;
      high rate of tumor control, while reducing the side-effects of therapy. In this study, the&#xD;
      investigators plan to reduce the intensity of treatment by replacing the currently used&#xD;
      chemotherapy drugs with an FDA approved drug, cetuximab, which is a monoclonal antibody to a&#xD;
      growth factor which helps cancer cells grow. By opposing the effect of the growth factor,&#xD;
      cetuximab may help radiotherapy kill cancer cells without a lot of effect on the normal&#xD;
      tissue. It differs from chemotherapy in its more selective activity against tumors compared&#xD;
      to normal tissue Cetuximab has the chance to preserve the high rate of success in killing the&#xD;
      tumor but may reduce the side effects and complications of therapy in comparison to&#xD;
      chemotherapy drugs.&#xD;
&#xD;
      The investigators would also like to know if taking cetuximab has any effect on certain&#xD;
      cancer-related molecules in the cancer and the normal cells inside the cheek. They would like&#xD;
      to test this by taking a small biopsy of the tumor, as well as a swab of the inside of the&#xD;
      cheek, before and shortly after the start of therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2011</start_date>
  <completion_date type="Actual">September 2019</completion_date>
  <primary_completion_date type="Actual">September 2019</primary_completion_date>
  <phase>N/A</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>Rate of Recurrence</measure>
    <time_frame>2 years</time_frame>
    <description>Number of patients whose tumors recur (includes local, regional, and distant recurrence; and second primaries).&#xD;
Note: Research indicates that freedom from local and regional progression (FFLRP) is a more meaningful measure. Therefore, the percentage of patients with FFLRP is included below as a Post-Hoc measure.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events</measure>
    <time_frame>3 years</time_frame>
    <description>In order to evaluate the toxicity in patients receiving cetuximab-RT, adverse events were clustered into three categories: None, Mild-Moderate (grade 1 or 2), and Severe (grade 3 or 4). Graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment Related Toxicities</measure>
    <time_frame>3 years</time_frame>
    <description>Toxicities are measured by number of participants who experience one or more types or indicator of toxicity, shown as all grades and grades 3-4. As each participant could have multiple toxicities, the number of incidents outnumbers the number of participants. Toxicities graded according to the CTCAE v4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Tumor Epidermal Growth Factor Receptor (EGFR)</measure>
    <time_frame>Day 7</time_frame>
    <description>The ratio (fold change) of tumor EGFR post/pre loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Tumor Phosphorylated EGFR (pEGFR)</measure>
    <time_frame>Day 7</time_frame>
    <description>The ratio (fold change) of tumor pEGFR post/pre loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Tumor EGFR Level Relative to EGFR in Normal Mucosa</measure>
    <time_frame>Day 7</time_frame>
    <description>Normal mucosa EGFR was assessed for comparison with EGFR in tumor sample. The fold change in tumor EGFR level post/pre loading dose of cetuximab, relative to fold change in normal mucosa EGFR level post/pre loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal EGFR.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">43</enrollment>
  <condition>Squamous Cell Carcinoma of the Oropharynx</condition>
  <condition>HPV</condition>
  <arm_group>
    <arm_group_label>Cetuximab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cetuximab</intervention_name>
    <description>Before Radiotherapy patients you will receive a single loading dose of cetuximab. Patients will also have two additional biopsies before and after cetuximab to determine how the tumor is affected. A Cetuximab infusion will also be delivered once a week during radiotherapy.Radiation will be started (70 Gy in 35 fractions over 7 weeks to the gross tumor, 50-60 Gy to subclinical target volumes) five days a week until the total dose of radiation prescribed by the doctor is reached. Radiation will be delivered concurrent with weekly cetuximab 250 mg/m2, delivered on Monday or Tuesday each week. In order to evaluate swallowing problems from radiotherapy, patients will undergo an evaluation of swallowing by videofluoroscopy (VF). Quality of Life questionnaires will be given before therapy and periodically up to 36 months after therapy. In order to assess if the tumor was completely eradicated, CT-PET scan will be performed 3 months after the completion of therapy.</description>
    <arm_group_label>Cetuximab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiotherapy</intervention_name>
    <description>Radiation will be started (70 Gy in 35 fractions over 7 weeks to the gross tumor, 50-60 Gy to subclinical target volumes) five days a week until the total dose of radiation prescribed by the doctor is reached. Radiation will be delivered concurrent with weekly cetuximab 250 mg/m2, delivered on Monday or Tuesday each week.</description>
    <arm_group_label>Cetuximab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have pathologically-confirmed, previously untreated,stage&#xD;
             III-IV(excluding N3 or T4) squamous cell carcinoma of the oropharynx, without evidence&#xD;
             of distant metastasis&#xD;
&#xD;
          -  Pretreatment tumor biopsy with sufficient tumor for HPV or p16 analysis is required.&#xD;
             The tumor must be HPV(+) or p16(+)&#xD;
&#xD;
        Smoking history &lt;10 pack-year or equivalent (including cigarettes, cigars, pipes, chewing&#xD;
        tobacco, and/or marijuana). One cannabis joint is equivalent to 5 cigarettes. (Aldington&#xD;
        etal, Thorax 2007; 62:1058-1063). Smoking status definitions (National Health Interview&#xD;
        Survey and Behavioral Risk Factor Surveillance System (Nelson DE etal al, Am J Pub Health&#xD;
        2003;93:1335):&#xD;
&#xD;
          -  Smokers: smoking now every day or some days in past month&#xD;
&#xD;
          -  Quitters: at least 100 cigarettes/lifetime and not smoking in the past 1-12 months&#xD;
&#xD;
          -  Former smoker: at least 100 cigarettes/lifetime and not smoking &gt;12 months&#xD;
&#xD;
          -  Never smokers: &lt;100 cigarettes (or equivalent)/lifetime&#xD;
&#xD;
               -  KPS &gt; 80 (see Appendix A)&#xD;
&#xD;
               -  Patients must undergo pre-treatment endoscopic tumor staging and PET-CT scanning&#xD;
&#xD;
               -  Laboratory criteria:&#xD;
&#xD;
          -  WBC &gt; 3500/ul&#xD;
&#xD;
          -  granulocyte &gt; 1500/ul&#xD;
&#xD;
          -  Platelet count &gt; 100,000/ul&#xD;
&#xD;
          -  Total Bilirubin &lt; 1.5 X ULN&#xD;
&#xD;
          -  AST and ALT &lt; 2.5 X ULN&#xD;
&#xD;
               -  Creatinine clearance &gt;30 cc/min&#xD;
&#xD;
               -  Patients must sign study specific informed consent&#xD;
&#xD;
               -  Patients must have, in the opinion of a treating physician, tumor that is&#xD;
                  accessible to biopsy in the clinic.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior head and neck malignancy or history of other prior non-head and neck malignancy&#xD;
             (excluding skin cancer and early stage treated prostate cancer) within the past 3&#xD;
             years&#xD;
&#xD;
          -  Prior head and neck radiation or chemotherapy&#xD;
&#xD;
          -  Any medical or psychiatric illness, which in the opinion of the principal&#xD;
             investigator, would compromise the patient's ability to tolerate this treatment or&#xD;
             limit compliance with study requirements&#xD;
&#xD;
          -  Patients residing in prison&#xD;
&#xD;
          -  Patients with prior anti-epidermal growth-factor receptor antibody therapy (antibody&#xD;
             or small molecule)&#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>Michelle Mierzwa, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan Rogel Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Radiation Oncology , University of Michigan Health System</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>July 23, 2012</study_first_submitted>
  <study_first_submitted_qc>August 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2012</study_first_posted>
  <results_first_submitted>September 30, 2020</results_first_submitted>
  <results_first_submitted_qc>September 30, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">October 26, 2020</results_first_posted>
  <last_update_submitted>December 23, 2020</last_update_submitted>
  <last_update_submitted_qc>December 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">January 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Oropharyngeal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cetuximab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 20, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/59/NCT01663259/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>43 patients consented, but one never began treatment.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Cetuximab + Radiotherapy</title>
          <description>Patients received a single loading dose public) of cetuximab 400 mg/m (Day 0), then weekly cetuximab 250 mg/m concurrent with radiation. Within approximately 4 days after first (loading) dose of cetuximab, patients received radiation administered as 70 Gy in 35 fractions to the gross tumor, 50-60 Gy to subclinical target volumes.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="42"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="42"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Cetuximab + Radiotherapy</title>
          <description>Patients received a single loading dose public) of cetuximab 400 mg/m (Day 0), then weekly cetuximab 250 mg/m concurrent with radiation. Within approximately 4 days after first (loading) dose of cetuximab, patients received radiation administered as 70 Gy in 35 fractions to the gross tumor, 50-60 Gy to subclinical target volumes.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="42"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="58" lower_limit="48" upper_limit="76"/>
                  </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="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                  </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="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                  </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="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="41"/>
                  </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="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Smoking</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Yes, current</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Yes, past</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cancer Location</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Oropharynx</title>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Oral Cavity</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Auditory Canal</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Hypopharynx</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown Primary</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>HPV Status</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Positive</title>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Negative</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Rate of Recurrence</title>
        <description>Number of patients whose tumors recur (includes local, regional, and distant recurrence; and second primaries).&#xD;
Note: Research indicates that freedom from local and regional progression (FFLRP) is a more meaningful measure. Therefore, the percentage of patients with FFLRP is included below as a Post-Hoc measure.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cetuximab + Radiotherapy</title>
            <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Recurrence</title>
          <description>Number of patients whose tumors recur (includes local, regional, and distant recurrence; and second primaries).&#xD;
Note: Research indicates that freedom from local and regional progression (FFLRP) is a more meaningful measure. Therefore, the percentage of patients with FFLRP is included below as a Post-Hoc measure.</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="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events</title>
        <description>In order to evaluate the toxicity in patients receiving cetuximab-RT, adverse events were clustered into three categories: None, Mild-Moderate (grade 1 or 2), and Severe (grade 3 or 4). Graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4).</description>
        <time_frame>3 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cetuximab + Radiotherapy</title>
            <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events</title>
          <description>In order to evaluate the toxicity in patients receiving cetuximab-RT, adverse events were clustered into three categories: None, Mild-Moderate (grade 1 or 2), and Severe (grade 3 or 4). Graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4).</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="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>None</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Mild-Moderate</title>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Severe</title>
                  <measurement_list>
                    <measurement group_id="O1" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Treatment Related Toxicities</title>
        <description>Toxicities are measured by number of participants who experience one or more types or indicator of toxicity, shown as all grades and grades 3-4. As each participant could have multiple toxicities, the number of incidents outnumbers the number of participants. Toxicities graded according to the CTCAE v4.</description>
        <time_frame>3 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cetuximab + Radiotherapy</title>
            <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Treatment Related Toxicities</title>
          <description>Toxicities are measured by number of participants who experience one or more types or indicator of toxicity, shown as all grades and grades 3-4. As each participant could have multiple toxicities, the number of incidents outnumbers the number of participants. Toxicities graded according to the CTCAE v4.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>All Grades : Cutaneous Toxicity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>All Grades : Mucositis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>All Grades : Dysphagia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>All Grades : Hematologic Toxicity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grades 3-4 : Cutaneous Toxicity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grades 3-4 : Mucositis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grades 3-4 : Dysphagia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grades 3-4 : Hematologic Toxicity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Tumor Epidermal Growth Factor Receptor (EGFR)</title>
        <description>The ratio (fold change) of tumor EGFR post/pre loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.</description>
        <time_frame>Day 7</time_frame>
        <population>8 participants had a sample size sufficient for EGFR analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Cetuximab + Radiotherapy</title>
            <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Tumor Epidermal Growth Factor Receptor (EGFR)</title>
          <description>The ratio (fold change) of tumor EGFR post/pre loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.</description>
          <population>8 participants had a sample size sufficient for EGFR analysis.</population>
          <units>fold change</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.2" lower_limit="0.1" upper_limit="2.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Tumor Phosphorylated EGFR (pEGFR)</title>
        <description>The ratio (fold change) of tumor pEGFR post/pre loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.</description>
        <time_frame>Day 7</time_frame>
        <population>2 participants had a sample size sufficient for pEGFR analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Cetuximab + Radiotherapy</title>
            <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Tumor Phosphorylated EGFR (pEGFR)</title>
          <description>The ratio (fold change) of tumor pEGFR post/pre loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.</description>
          <population>2 participants had a sample size sufficient for pEGFR analysis.</population>
          <units>fold change</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.55" lower_limit="0.5" upper_limit="0.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Tumor EGFR Level Relative to EGFR in Normal Mucosa</title>
        <description>Normal mucosa EGFR was assessed for comparison with EGFR in tumor sample. The fold change in tumor EGFR level post/pre loading dose of cetuximab, relative to fold change in normal mucosa EGFR level post/pre loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal EGFR.</description>
        <time_frame>Day 7</time_frame>
        <population>7 participants had a sample size sufficient for EGFR analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Cetuximab + Radiotherapy</title>
            <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Tumor EGFR Level Relative to EGFR in Normal Mucosa</title>
          <description>Normal mucosa EGFR was assessed for comparison with EGFR in tumor sample. The fold change in tumor EGFR level post/pre loading dose of cetuximab, relative to fold change in normal mucosa EGFR level post/pre loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal EGFR.</description>
          <population>7 participants had a sample size sufficient for EGFR analysis.</population>
          <units>ratio</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <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>
                  <measurement_list>
                    <measurement group_id="O1" value="1.31" lower_limit="0.1" upper_limit="2.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Post-Hoc</type>
        <title>Disease Free Survival Rate</title>
        <description>Percentage of participants who survived without recurrent disease, from the time of enrollment to 1 and 2 years.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cetuximab + Radiotherapy</title>
            <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Disease Free Survival Rate</title>
          <description>Percentage of participants who survived without recurrent disease, from the time of enrollment to 1 and 2 years.</description>
          <units>Percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>1 year</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85.7" lower_limit="75.8" upper_limit="97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 year</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="81" lower_limit="69.9" upper_limit="93.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <other_analysis_desc>Estimates of proportion event-free at 1 and 2 years calculated using Kaplan-Meier methods, and the 2-sided, 95% confidence intervals were calculated by the Greenwood method. All analyses were performed using SAS v9.4 software and R version 3.5.2.</other_analysis_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Post-Hoc</type>
        <title>Overall Survival Rate</title>
        <description>Percentage of participants alive at 1 and 2 years after enrollment.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cetuximab + Radiotherapy</title>
            <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival Rate</title>
          <description>Percentage of participants alive at 1 and 2 years after enrollment.</description>
          <units>Percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>1 year</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="97.6" lower_limit="93.1" upper_limit="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 year</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95.2" lower_limit="89" upper_limit="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <other_analysis_desc>Survival proportion estimates at 1 and 2 years were calculated using Kaplan-Meier methods, and the 2-sided, 95% confidence intervals calculated by the Greenwood method. All analyses were performed using SAS v9.4 software and R version 3.5.2.</other_analysis_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Post-Hoc</type>
        <title>Freedom From Local Regional Progression (FFLRP)</title>
        <description>Percentage of participants without first local or regional recurrence at one and at two years from the time of enrollment. Local recurrence refers to mouth or throat; regional recurrence refers to nearby lymph nodes.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cetuximab + Radiotherapy</title>
            <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</description>
          </group>
        </group_list>
        <measure>
          <title>Freedom From Local Regional Progression (FFLRP)</title>
          <description>Percentage of participants without first local or regional recurrence at one and at two years from the time of enrollment. Local recurrence refers to mouth or throat; regional recurrence refers to nearby lymph nodes.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>1 year</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="87.9" lower_limit="75.8" upper_limit="97"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="87.9" lower_limit="69.9" upper_limit="93.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <other_analysis_desc>Estimates of proportion LRP event-free at 1 and 2 years were calculated using Kaplan-Meier methods, and the 2-sided, 95% confidence intervals calculated by the Greenwood method. All analyses were performed using SAS v9.4 software and R version 3.5.2.</other_analysis_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>3 years</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Cetuximab</title>
          <description>Patients received a single loading dose of cetuximab and a Cetuximab infusion delivered once a week during radiotherapy.</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="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - other</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cognitive disturbance</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Aspiration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="42" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Lymph node pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>External ear inflammation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="92" subjects_affected="40" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="96" subjects_affected="40" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Esophagitis</sub_title>
                <counts group_id="E1" events="84" subjects_affected="41" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other</sub_title>
                <counts group_id="E1" events="51" subjects_affected="21" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="115" subjects_affected="42" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="46" subjects_affected="24" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" events="15" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Salivary duct inflammation</sub_title>
                <counts group_id="E1" events="18" subjects_affected="12" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="16" subjects_affected="9" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Facial pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="45" subjects_affected="26" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Dermatitis radiation</sub_title>
                <counts group_id="E1" events="64" subjects_affected="38" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="13" subjects_affected="9" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="43" subjects_affected="14" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Urine output decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="14" subjects_affected="11" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="8" subjects_affected="4" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="31" subjects_affected="18" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="11" subjects_affected="7" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Trismus</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Akathisia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="91" subjects_affected="42" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Myelitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Urine discoloration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Laryngeal hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Laryngeal inflammation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pharyngolaryngeal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Fat atrophy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Nail loss</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Nail ridging</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pain of skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" events="59" subjects_affected="35" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Scalp pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Skin atrophy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Superficial thrombophlebitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>
    <point_of_contact>
      <name_or_title>Michelle Mierzwa</name_or_title>
      <organization>University of Michigan Rogel Cancer Center</organization>
      <phone>734-936-7810</phone>
      <email>mmierzwa@umich.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/NCT01663259
org study id: UMCC 2009.078
secondary id: HUM00032219
nct id: NCT01663259
nct alias: NCT01649414
lead sponsor: 
has dmc: Yes
Taking into account the excellent prognosis of patients with HPV-positive oropharyngeal
      cancer with < 10 pack-year smoking, the investigators hypothesize that reducing the intensity
      of therapy for these patients will reduce treatment sequelae, notably long-term dysphagia,
      without affecting their cure rates. The main Aim is to assess whether reducing treatment
      intensity, by replacing concurrent chemotherapy with cetuximab, will indeed achieve improved
      long-term toxicity.

      The primary objectives include the following: to confirm that reducing treatment intensity in
      patients with HPV-related oropharyngeal cancer and < 10 pack-year smoking history by
      replacing concurrent chemotherapy with concurrent cetuximab, does not significantly increase
      the proportion of patients whose tumors recur, compared to our previous experience in similar
      patients receiving chemo-RT and to compare the toxicity in patients receiving cetuximab-RT to
      similar patients treated with 7 weeks of chemotherapy concurrent with RT ("standard therapy")
      in UMCC 2-21.
The investigators have shown in past experience a high success in getting rid of
      oropharyngeal cancer (tonsil or base of tongue cancer) using chemotherapy and radiation
      therapy in patients who have not smoked, or only smoked a minimal amount of cigarettes or
      equivalent. In these patients, the cancer is thought to be caused by a virus (Human Papilloma
      Virus, or HPV). HPV is a virus that infects the epidermis (outermost layer of skin) and
      mucous membranes of humans. In general, patients with HPV-related cancer such as yours have a
      better prognosis compared with patients whose tumors are smoking-related. Taking into account
      the good prognosis, it is possible that reducing the intensity of therapy will not affect the
      high rate of tumor control, while reducing the side-effects of therapy. In this study, the
      investigators plan to reduce the intensity of treatment by replacing the currently used
      chemotherapy drugs with an FDA approved drug, cetuximab, which is a monoclonal antibody to a
      growth factor which helps cancer cells grow. By opposing the effect of the growth factor,
      cetuximab may help radiotherapy kill cancer cells without a lot of effect on the normal
      tissue. It differs from chemotherapy in its more selective activity against tumors compared
      to normal tissue Cetuximab has the chance to preserve the high rate of success in killing the
      tumor but may reduce the side effects and complications of therapy in comparison to
      chemotherapy drugs.

      The investigators would also like to know if taking cetuximab has any effect on certain
      cancer-related molecules in the cancer and the normal cells inside the cheek. They would like
      to test this by taking a small biopsy of the tumor, as well as a swab of the inside of the
      cheek, before and shortly after the start of therapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of Recurrence
time frame: 2 years
description: Number of patients whose tumors recur (includes local, regional, and distant recurrence; and second primaries).
Note: Research indicates that freedom from local and regional progression (FFLRP) is a more meaningful measure. Therefore, the percentage of patients with FFLRP is included below as a Post-Hoc measure.
measure: Number of Participants With Adverse Events
time frame: 3 years
description: In order to evaluate the toxicity in patients receiving cetuximab-RT, adverse events were clustered into three categories: None, Mild-Moderate (grade 1 or 2), and Severe (grade 3 or 4). Graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4).
measure: Treatment Related Toxicities
time frame: 3 years
description: Toxicities are measured by number of participants who experience one or more types or indicator of toxicity, shown as all grades and grades 3-4. As each participant could have multiple toxicities, the number of incidents outnumbers the number of participants. Toxicities graded according to the CTCAE v4.
measure: Mean Change in Tumor Epidermal Growth Factor Receptor (EGFR)
time frame: Day 7
description: The ratio (fold change) of tumor EGFR post/pre loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.
measure: Mean Change in Tumor Phosphorylated EGFR (pEGFR)
time frame: Day 7
description: The ratio (fold change) of tumor pEGFR post/pre loading dose of cetuximab. Reported as the mean of fold changes across all participants who had an evaluable tumor sample.
measure: Change in Tumor EGFR Level Relative to EGFR in Normal Mucosa
time frame: Day 7
description: Normal mucosa EGFR was assessed for comparison with EGFR in tumor sample. The fold change in tumor EGFR level post/pre loading dose of cetuximab, relative to fold change in normal mucosa EGFR level post/pre loading dose of cetuximab was summarized across all participants who had an evaluable tumor sample and normal mucosa sample. The value reported is the ratio of fold change in tumor/fold change in buccal EGFR.
arm group label: Cetuximab
arm group type: Experimental
intervention type: Drug
intervention name: Cetuximab
description: Before Radiotherapy patients you will receive a single loading dose of cetuximab. Patients will also have two additional biopsies before and after cetuximab to determine how the tumor is affected. A Cetuximab infusion will also be delivered once a week during radiotherapy.Radiation will be started (70 Gy in 35 fractions over 7 weeks to the gross tumor, 50-60 Gy to subclinical target volumes) five days a week until the total dose of radiation prescribed by the doctor is reached. Radiation will be delivered concurrent with weekly cetuximab 250 mg/m2, delivered on Monday or Tuesday each week. In order to evaluate swallowing problems from radiotherapy, patients will undergo an evaluation of swallowing by videofluoroscopy (VF). Quality of Life questionnaires will be given before therapy and periodically up to 36 months after therapy. In order to assess if the tumor was completely eradicated, CT-PET scan will be performed 3 months after the completion of therapy.
arm group label: Cetuximab
intervention type: Radiation
intervention name: Radiotherapy
description: Radiation will be started (70 Gy in 35 fractions over 7 weeks to the gross tumor, 50-60 Gy to subclinical target volumes) five days a week until the total dose of radiation prescribed by the doctor is reached. Radiation will be delivered concurrent with weekly cetuximab 250 mg/m2, delivered on Monday or Tuesday each week.
arm group label: Cetuximab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michelle Mierzwa, MD
role: Principal Investigator
affiliation: University of Michigan Rogel Cancer Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Oropharyngeal Neoplasms
mesh term: Cetuximab
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 