<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/NCT01679405</url>
  </required_header>
  <id_info>
    <org_study_id>BIBW 2992</org_study_id>
    <nct_id>NCT01679405</nct_id>
  </id_info>
  <brief_title>BIBW 2992 as add-on to Gem/Cis in Advanced Biliary Tract Cancer</brief_title>
  <official_title>Open-label, Uncontrolled, Multicenter Phase I/Ib Trial to Investigate Safety and Efficacy of BIBW 2992 and Standard Gemcitabine/Cisplatin in Chemo-naïve Patients With Advanced Biliary Tract Adenocarcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johannes Gutenberg University Mainz</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Johannes Gutenberg University Mainz</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      An open-label, uncontrolled, multicenter phase I/Ib trial to investigate safety and efficacy&#xD;
      of BIBW 2992 added to the standard therapy of Gemcitabine/Cisplatin in chemo-naïve patients&#xD;
      with advanced and/or metastatic adenocarcinoma of the biliary tract&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary objective is safety and toxicity, including maximum tolerated dose, of BIBW 2992&#xD;
      when given as add-on therapy to Gem/Cis.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    No sufficient clinical or molecular signals for efficacy were observed.&#xD;
  </why_stopped>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">April 2016</completion_date>
  <primary_completion_date type="Actual">April 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>For Part A of the study a standard 3+3 design was used. The recruitment was carried out in cohorts. Subjects were not allowed to participate in both cohorts. If the maximum tolerated dose was found there should be additional patients recruited to confirm the maximum tolerated dose (part B)</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Adverse Events</measure>
    <time_frame>Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period.</time_frame>
    <description>In part A the maximum tolerated dose (MTD) of BIBW 2992 administered continuously to the standard therapy of Gemcitabine / Cisplatin (Gem/Cis) (administered together on day 1 and 8 of a three-week cycle) will be evaluated in a 2 step dose escalation.&#xD;
Safety and toxicity will be evaluated as described and considered primary for part B of the study.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Progress (TTP)</measure>
    <time_frame>Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period.</time_frame>
    <description>Median time to progress (according to RECIST 1.1 criteria) including the 95% confidence intervals were determined using Kaplan-Meier estimates. Time from start of treatment to first documentation of objective tumour progression. Deaths were censored at the time of death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Time from start of treatment to death due to any cause. Time to last observation will be used if a patient has not died and OS for the patient will be considered censored. Estimated time period: up to 76 weeks</time_frame>
    <description>Median overall survival time including the 95% confidence interval were determined using Kaplan-Meier estimates.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>Treatment period: up to eight cycles (maximum 8 months).</time_frame>
    <description>Response was assessed by means of RECIST 1.1 criteria for target lesions, non-target lesions and the appearance of new lesions. Objective response was defined as the CR, PR or SD at end of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tumor Control Rate</measure>
    <time_frame>Treatment period: up to eight cycles (maximum 8 months).</time_frame>
    <description>Tumor control rate is defined as the best tumour response (confirmed partial or complete response, stable disease) that is achieved until end of treatment according to Recist 1.1.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Metastatic Disease</condition>
  <arm_group>
    <arm_group_label>Dose level 1 (Part A)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>30 mg BIBW 2992, Gemcitabin (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dose level -1 (Part A)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>30 mg BIBW 2992, Gemcitabin (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BIBW 2992</intervention_name>
    <description>once daily per os</description>
    <arm_group_label>Dose level -1 (Part A)</arm_group_label>
    <arm_group_label>Dose level 1 (Part A)</arm_group_label>
    <other_name>Gemcitabine and Cisplatin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male and female patients aged ≥ 18 years&#xD;
&#xD;
          -  Signed and dated written informed consent,&#xD;
&#xD;
          -  Histologically confirmed adenocarcinoma of the gallbladder or intrahepatic bile ducts&#xD;
             or extrahepatic bile ducts (metastasized) or histologically proven hepatic metastases&#xD;
             of an earlier resected and histologically proven biliary tract cancer or a Klatskin&#xD;
             tumour (hilar cholangiocarcinoma)&#xD;
&#xD;
               -  with pain and biliary obstruction controlled&#xD;
&#xD;
               -  adequate biliary drainage, no uncontrolled infection&#xD;
&#xD;
               -  ECOG Performance Status of 0-1&#xD;
&#xD;
               -  LFTs: bilirubin (total) ≤ 1.5 x ULN, ALT/ AST/ alkaline phosphatase ≤ 3 2.5 x ULN&#xD;
                  (≤ 5 x ULN if liver metastases are present)&#xD;
&#xD;
               -  No prior systemic treatment i) previous adjuvant chemotherapy is allowed&#xD;
                  (completed ≥ 6 months if containing Gemcitabine or platinum salts); ii) previous&#xD;
                  irradiation (external radiotherapy, brachytherapy, chemoembolization) and PDT are&#xD;
                  allowed, provided that there is still at least one unidimensionally measurable&#xD;
                  target lesion in an untreated area&#xD;
&#xD;
          -  Resolution of all side effects of prior surgical procedures to CTCAE grade ≤ 1 (except&#xD;
             for the laboratory values specified below)&#xD;
&#xD;
          -  At least 4 weeks from any major surgery (at first dose of study drug)&#xD;
&#xD;
          -  Life expectancy of at least 12 weeks.&#xD;
&#xD;
          -  Cardiac left ventricular function with resting ejection fraction (LVEF) ≥ 50%&#xD;
&#xD;
          -  Adequate bone marrow, liver and renal function as assessed by the following laboratory&#xD;
             requirements to be conducted within 7 days prior to start of therapy:&#xD;
&#xD;
               -  Haemoglobin &gt; 10.0 g/dl (=6.2 mmol/l), blood transfusion is allowed&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt; 1,500/mm3 (=1.5x 109/L)&#xD;
&#xD;
               -  Platelet count ≥ 100,000/μl (=100x 109/L)&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 times the upper limit of normal&#xD;
&#xD;
               -  ALT and AST ≤ 2.5 x institutional upper limit of normal (in case of liver&#xD;
                  metastases: ALT and AST ≤ 5 x institutional upper limit of normal)&#xD;
&#xD;
               -  Prothrombin rate &gt; 60% or INR &lt; 1.5&#xD;
&#xD;
        Main exclusion criteria&#xD;
&#xD;
          -  Large surgery (except diagnostic biopsy) or smaller surgical procedures, external&#xD;
             radiotherapy, brachytherapy, or PDT within 30 days prior to start of treatment.&#xD;
&#xD;
          -  Other tumor type than adenocarcinoma (e.g. leiomyosarcoma, lymphoma) or a second&#xD;
             cancer except in patients with squamous or basal cell carcinoma of the skin or&#xD;
             carcinoma in situ of the cervix which has been effectively treated.&#xD;
&#xD;
          -  History of acute cardiac disease: congestive heart failure &gt; NYHA class 2; active CAD&#xD;
             (MI more than 6 months prior to study entry is allowed);&#xD;
&#xD;
          -  Patients on immunosuppressant therapy or with known HIV infection&#xD;
&#xD;
          -  Active clinically serious infections (&gt; grade 2 NCI-CTC version 3.0)&#xD;
&#xD;
          -  History of organ allograft&#xD;
&#xD;
          -  Pregnant or breast-feeding patients.&#xD;
&#xD;
          -  Substance abuse, medical, psychological or social conditions that may interfere with&#xD;
             the patient's participation&#xD;
&#xD;
          -  Any condition that is unstable or could jeopardize the safety of the patient and their&#xD;
             compliance in the study&#xD;
&#xD;
          -  Gastrointestinal (GI) tract disease resulting in an inability to take oral medication&#xD;
             or a requirement for IV alimentation, prior surgical procedures affecting absorption,&#xD;
             or active peptic ulcer disease&#xD;
&#xD;
          -  History of pre-existing interstitial lung disease (ILD)&#xD;
&#xD;
          -  Patients with untreated or symptomatic brain metastases.&#xD;
&#xD;
          -  Persistent Grade 2 or greater neurotoxicity / neuropathy from any cause&#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>Markus Moehler, Prof. Dr. med.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Medical Center of the Johannes Gutenberg-University Mainz</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>I. Medizinische Klinik und Poliklinik der Universitätsmedizin</name>
      <address>
        <city>Mainz</city>
        <zip>55131</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>August 17, 2012</study_first_submitted>
  <study_first_submitted_qc>August 31, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 6, 2012</study_first_posted>
  <results_first_submitted>February 27, 2017</results_first_submitted>
  <results_first_submitted_qc>August 9, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">January 22, 2019</results_first_posted>
  <last_update_submitted>August 26, 2019</last_update_submitted>
  <last_update_submitted_qc>August 26, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Johannes Gutenberg University Mainz</investigator_affiliation>
    <investigator_full_name>PD Dr Markus Möhler</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>metastatic biliary tract cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Gemcitabine</mesh_term>
    <mesh_term>Afatinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Dose Level 1</title>
          <description>30 mg BIBW 2992, Gemcitabine (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)</description>
        </group>
        <group group_id="P2">
          <title>Dose Level -1</title>
          <description>30 mg BIBW 2992, Gemcitabine (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Dose Level 1</title>
          <description>30 mg BIBW 2992, Gemcitabine (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)</description>
        </group>
        <group group_id="B2">
          <title>Dose Level -1</title>
          <description>30 mg BIBW 2992, Gemcitabine (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
            <count group_id="B2" value="6"/>
            <count group_id="B3" value="9"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62.00" spread="21.63"/>
                    <measurement group_id="B2" value="60.17" spread="7.31"/>
                    <measurement group_id="B3" value="60.78" spread="12.30"/>
                  </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 group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" 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>Germany</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Adverse Events</title>
        <description>In part A the maximum tolerated dose (MTD) of BIBW 2992 administered continuously to the standard therapy of Gemcitabine / Cisplatin (Gem/Cis) (administered together on day 1 and 8 of a three-week cycle) will be evaluated in a 2 step dose escalation.&#xD;
Safety and toxicity will be evaluated as described and considered primary for part B of the study.</description>
        <time_frame>Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1</title>
            <description>30 mg BIBW 2992, Gemcitabine (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1</title>
            <description>30 mg BIBW 2992, Gemcitabine (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Adverse Events</title>
          <description>In part A the maximum tolerated dose (MTD) of BIBW 2992 administered continuously to the standard therapy of Gemcitabine / Cisplatin (Gem/Cis) (administered together on day 1 and 8 of a three-week cycle) will be evaluated in a 2 step dose escalation.&#xD;
Safety and toxicity will be evaluated as described and considered primary for part B of the study.</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="3"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Progress (TTP)</title>
        <description>Median time to progress (according to RECIST 1.1 criteria) including the 95% confidence intervals were determined using Kaplan-Meier estimates. Time from start of treatment to first documentation of objective tumour progression. Deaths were censored at the time of death.</description>
        <time_frame>Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1</title>
            <description>30 mg BIBW 2992, Gemcitabine (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1</title>
            <description>30 mg BIBW 2992, Gemcitabine (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Progress (TTP)</title>
          <description>Median time to progress (according to RECIST 1.1 criteria) including the 95% confidence intervals were determined using Kaplan-Meier estimates. Time from start of treatment to first documentation of objective tumour progression. Deaths were censored at the time of death.</description>
          <units>days</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="159" lower_limit="134" upper_limit="184"/>
                    <measurement group_id="O2" value="NA" lower_limit="49" upper_limit="NA">Median and upper confidence limit could not be calculated, because of too few events.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>Median overall survival time including the 95% confidence interval were determined using Kaplan-Meier estimates.</description>
        <time_frame>Time from start of treatment to death due to any cause. Time to last observation will be used if a patient has not died and OS for the patient will be considered censored. Estimated time period: up to 76 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1</title>
            <description>30 mg BIBW 2992, Gemcitabine (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1</title>
            <description>30 mg BIBW 2992, Gemcitabine (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>Median overall survival time including the 95% confidence interval were determined using Kaplan-Meier estimates.</description>
          <units>days</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="163" lower_limit="79" upper_limit="NA">Upper confidence limit could not be calculated, because of too few events.</measurement>
                    <measurement group_id="O2" value="260" lower_limit="75" upper_limit="NA">Upper confidence limit could not be calculated, because of too few events.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response Rate</title>
        <description>Response was assessed by means of RECIST 1.1 criteria for target lesions, non-target lesions and the appearance of new lesions. Objective response was defined as the CR, PR or SD at end of treatment</description>
        <time_frame>Treatment period: up to eight cycles (maximum 8 months).</time_frame>
        <population>For one patient, there was no CT assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1</title>
            <description>30 mg BIBW 2992, Gemcitabine (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1</title>
            <description>30 mg BIBW 2992, Gemcitabine (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate</title>
          <description>Response was assessed by means of RECIST 1.1 criteria for target lesions, non-target lesions and the appearance of new lesions. Objective response was defined as the CR, PR or SD at end of treatment</description>
          <population>For one patient, there was no CT assessment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tumor Control Rate</title>
        <description>Tumor control rate is defined as the best tumour response (confirmed partial or complete response, stable disease) that is achieved until end of treatment according to Recist 1.1.</description>
        <time_frame>Treatment period: up to eight cycles (maximum 8 months).</time_frame>
        <population>For one patient there was no CT assessment.</population>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1</title>
            <description>30 mg BIBW 2992, Gemcitabine (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1</title>
            <description>30 mg BIBW 2992, Gemcitabine (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)</description>
          </group>
        </group_list>
        <measure>
          <title>Tumor Control Rate</title>
          <description>Tumor control rate is defined as the best tumour response (confirmed partial or complete response, stable disease) that is achieved until end of treatment according to Recist 1.1.</description>
          <population>For one patient there was no CT assessment.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Dose Level 1</title>
          <description>30 mg BIBW 2992, Gemcitabine (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)</description>
        </group>
        <group group_id="E2">
          <title>Dose Level -1</title>
          <description>30 mg BIBW 2992, Gemcitabine (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (11.0)</default_vocab>
        <default_assessment>Non-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="3"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>diarrhea, hypokaliemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Progression of disease (fatal)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>liver failure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>sepsis, chronic kidney disease (worsening), platelet count decreased, worsening of anemia, diarrhea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Infection unknown origin, platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>&quot;infection unknown origin, worsening of chronic kidney disease, platelet count decreased, leukocytop</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Biliary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>infection, unknown origin, pulmonary embolism both sides, deep vein thrombosis both leg</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>thrombocytopenia, anaemia, hypokaliemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>worsening of pleural effusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>pulmonary embolism</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (11.0)</default_vocab>
        <default_assessment>Non-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="3" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </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="7" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="8" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>nausea</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="9" subjects_affected="5" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>diarrhoea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="25" subjects_affected="5" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>stomatitis</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="8" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>fatigue</sub_title>
                <counts group_id="E1" events="11" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="19" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>paronychia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>weight loss</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="9" subjects_affected="6" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>neutropenia</sub_title>
                <counts group_id="E1" events="11" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="9" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>thrombocytopenia</sub_title>
                <counts group_id="E1" events="17" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="20" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>hypokalemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="6" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>paresthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" events="9" subjects_affected="4" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>epistaxis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>rash</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" events="10" subjects_affected="4" subjects_at_risk="6"/>
              </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>Prof. Dr. Markus Moehler</name_or_title>
      <organization>University Medical Center Mainz</organization>
      <phone>0049613117 ext 7275</phone>
      <email>Markus.Moehler@unimedizin-mainz.de</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/NCT01679405
org study id: BIBW 2992
nct id: NCT01679405
lead sponsor: 
has dmc: No
An open-label, uncontrolled, multicenter phase I/Ib trial to investigate safety and efficacy
      of BIBW 2992 added to the standard therapy of Gemcitabine/Cisplatin in chemo-naïve patients
      with advanced and/or metastatic adenocarcinoma of the biliary tract
The primary objective is safety and toxicity, including maximum tolerated dose, of BIBW 2992
      when given as add-on therapy to Gem/Cis.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: For Part A of the study a standard 3+3 design was used. The recruitment was carried out in cohorts. Subjects were not allowed to participate in both cohorts. If the maximum tolerated dose was found there should be additional patients recruited to confirm the maximum tolerated dose (part B)
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Adverse Events
time frame: Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period.
description: In part A the maximum tolerated dose (MTD) of BIBW 2992 administered continuously to the standard therapy of Gemcitabine / Cisplatin (Gem/Cis) (administered together on day 1 and 8 of a three-week cycle) will be evaluated in a 2 step dose escalation.
Safety and toxicity will be evaluated as described and considered primary for part B of the study.
measure: Time to Progress (TTP)
time frame: Treatment period: up to eight cycles (maximum 8 months). 12 months follow-up period.
description: Median time to progress (according to RECIST 1.1 criteria) including the 95% confidence intervals were determined using Kaplan-Meier estimates. Time from start of treatment to first documentation of objective tumour progression. Deaths were censored at the time of death.
measure: Overall Survival (OS)
time frame: Time from start of treatment to death due to any cause. Time to last observation will be used if a patient has not died and OS for the patient will be considered censored. Estimated time period: up to 76 weeks
description: Median overall survival time including the 95% confidence interval were determined using Kaplan-Meier estimates.
measure: Objective Response Rate
time frame: Treatment period: up to eight cycles (maximum 8 months).
description: Response was assessed by means of RECIST 1.1 criteria for target lesions, non-target lesions and the appearance of new lesions. Objective response was defined as the CR, PR or SD at end of treatment
measure: Tumor Control Rate
time frame: Treatment period: up to eight cycles (maximum 8 months).
description: Tumor control rate is defined as the best tumour response (confirmed partial or complete response, stable disease) that is achieved until end of treatment according to Recist 1.1.
arm group label: Dose level 1 (Part A)
arm group type: Experimental
description: 30 mg BIBW 2992, Gemcitabin (1.000 mg/m² BSA i.v.)/Cisplatin (25 mg/m² BSA i.v.)
arm group label: Dose level -1 (Part A)
arm group type: Experimental
description: 30 mg BIBW 2992, Gemcitabin (800 mg/m² BSA i.v.)/Cisplatin (20 mg/m² BSA i.v.)
intervention type: Drug
intervention name: BIBW 2992
description: once daily per os
arm group label: Dose level -1 (Part A)
arm group label: Dose level 1 (Part A)
other name: Gemcitabine and Cisplatin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Markus Moehler, Prof. Dr. med.
role: Principal Investigator
affiliation: University Medical Center of the Johannes Gutenberg-University Mainz
facility: 
country: Germany
responsible party type: Principal Investigator
investigator affiliation: Johannes Gutenberg University Mainz
investigator full name: PD Dr Markus Möhler
investigator title: Principal Investigator
mesh term: Neoplasm Metastasis
mesh term: Cisplatin
mesh term: Gemcitabine
mesh term: Afatinib
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 