<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/NCT01728818</url>
  </required_header>
  <id_info>
    <org_study_id>2011-004063-77</org_study_id>
    <nct_id>NCT01728818</nct_id>
  </id_info>
  <brief_title>Afatinib as Cancer Therapy for Exocrine Pancreatic Tumours</brief_title>
  <acronym>ACCEPT</acronym>
  <official_title>Gemcitabine in Combination With the Oral Irreversible ErbB Inhibitor Afatinib Versus Gemcitabine Alone in Patients With Metastatic Pancreatic Cancer: an Explorative Randomized Phase II Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>PD Dr. med. Volker Heinemann</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Ludwig-Maximilians - University of Munich</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Single-agent gemcitabine is currently still regarded as one international standard of care&#xD;
      for patients with advanced pancreatic cancer (Burris 1997 [4]). The oral EGFR tyrosine kinase&#xD;
      inhibitor erlotinib received EMEA-approval for the treatment of patients with metastatic&#xD;
      pancreatic cancer in January 2007.&#xD;
&#xD;
      In the pivotal phase III trial, the combination of gemcitabine plus erlotinib was associated&#xD;
      with a statistically significant prolongation of OS (compared to single-agent gemcitabine),&#xD;
      however, the absolute survival benefit was - for the overall study population - clinically&#xD;
      moderate (median OS: 6.24 vs 5.91 months, 1-year OS rate: 23% vs 17%; HR = 0.82, p=0.038)&#xD;
      (Moore 2007 [19]).&#xD;
&#xD;
      The recently presented FOLFIRINOX regimen shows enhanced activity in metastatic pancreatic&#xD;
      cancer patients. This regimen is, however, limited to patients with good performance status&#xD;
      (ECOG 0-1), no major comorbidity, age &lt;75 years, and bilirubin &lt;1.5 ULN (Conroy 2011 [6]).&#xD;
      The majority of pancreatic cancer patients will therefore not be treated with this regimen.&#xD;
&#xD;
      Accordingly, novel treatment concepts are urgently needed in pancreatic cancer and&#xD;
      pre-clinical data indicate an important role of the EGFR1/erbB2 receptor signalling in the&#xD;
      pathogenesis of pancreatic adenocarcinoma (Yeh 2007 [24]). A recent publication (Larbouret&#xD;
      2010 [16]) indicates that the combination of cetuximab and trastuzumab induced superior&#xD;
      antitumour activity in human pancreatic carcinoma xenografts compared to gemcitabine alone&#xD;
      (see also Larbouret 2007 [15]). Furthermore, synergistic antitumour activity was observed&#xD;
      when monoclonal antibodies directed against the EGFR1 and erbB2 were combined (Ben-Kasus 2009&#xD;
      [3]). Based on these data, there is a good rationale to further investigate the combined&#xD;
      inhibition of the erbB family in pancreatic cancer patients.&#xD;
&#xD;
      Afatinib (BIBW 2992) is a novel irreversible EGFR1- and HER2 and HER4 inhibitor that is&#xD;
      applied orally. The purpose of the present trial is to investigate the erbB family inhibition&#xD;
      by afatinib in patients with metastatic pancreatic cancer.&#xD;
&#xD;
      In the planned trial, afatinib will be applied at the dose (40 mg/day) that was chosen for&#xD;
      the randomised phase III trial (LUX 5 study) that investigates afatinib plus weekly&#xD;
      paclitaxel (80mg/m2).&#xD;
&#xD;
      Presently there is also a phase I study ongoing that investigates the combination of afatinib&#xD;
      with gemcitabine (ClinicalTrials.gov Identifier: NCT01251653 U10-2249-02 ). Possibly the data&#xD;
      will be available once the study is ready to start. Otherwise a modification of the regimen&#xD;
      will be planned once the respective data will be available.&#xD;
&#xD;
      In this trial, we integrate a translational project which may allow the identification of&#xD;
      patients that primarily benefit from this novel treatment approach. The availability of&#xD;
      tumour tissue- and blood samples from each patient is therefore an important inclusion&#xD;
      criterion.&#xD;
&#xD;
      A 2:1 randomisation is chosen favouring the experimental arm since a large body of data is&#xD;
      available on gemcitabine alone and since sufficient efficacy and toxicity data shall be&#xD;
      gained in the experimental arm. In addition, the patients' motivation to take part in the&#xD;
      trial will be greatly enhanced by a greater chance to receive the experimental agent.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>April 2013</start_date>
  <completion_date type="Anticipated">January 2018</completion_date>
  <primary_completion_date type="Actual">January 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Survial</measure>
    <time_frame>approximately 36 months</time_frame>
    <description>Overall Survival</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>PFS</measure>
    <time_frame>Approximately 36 months</time_frame>
    <description>Progression-free survival (PFS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>approximately 36 months</time_frame>
    <description>Duration of response</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>1 Year Survial</measure>
    <time_frame>approximately 36 months</time_frame>
    <description>One Year Survial</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CA19-9</measure>
    <time_frame>approximately 36 months</time_frame>
    <description>Biochemical tumour marker response (serum CA 19- 9)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>approximately 36 months</time_frame>
    <description>Evaluation of Quality of life with EORTC QLQ C-30 Questionaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity</measure>
    <time_frame>approximately 36 months</time_frame>
    <description>Toxicity (NCI CTC-AE v4.0)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Staging</measure>
    <time_frame>approximately 36 months</time_frame>
    <description>All tumour assessments will be done by CT or MRI at 2-months intervals. One method of imaging will be kept consistent for each individual patient. All comparisons will be refrenced to baseline imaging (performed within 4 weeks prior to randomisation).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">119</enrollment>
  <condition>Focus of Study Instead</condition>
  <arm_group>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>1000 mg/m² d1,8,15 q4weeks</description>
    <arm_group_label>Arm A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Afatinib</intervention_name>
    <description>40mg flat dose, po, once daily</description>
    <arm_group_label>Arm A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>1000 mg/m², d1,8,15 q4weeks</description>
    <arm_group_label>Arm B</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent in advance of any study-specific procedure&#xD;
&#xD;
          -  Histologically (not cytologically) confirmed diagnosis of metastatic pancreatic&#xD;
             adenocarcinoma (stage IV according to UICC 2009 classification: each T, each N, M1)&#xD;
&#xD;
          -  Availability of tumour samples&#xD;
&#xD;
          -  Informed consent that tumour- and blood samples are centrally collected and will serve&#xD;
             for translational analyses according to the study protocol.&#xD;
&#xD;
          -  Age &gt;= 18 years&#xD;
&#xD;
          -  ECOG 0-1&#xD;
&#xD;
          -  Life expectancy at least 3 months&#xD;
&#xD;
          -  No option for surgical resection or radiation in curative intent&#xD;
&#xD;
          -  At least one measurable tumour lesion (CT-scan or MRI) according to RECIST Version 1.1&#xD;
&#xD;
          -  Possibility of long-term follow-up&#xD;
&#xD;
          -  Negative pregnancy test in fertile females&#xD;
&#xD;
          -  Given legal capacity of the patient&#xD;
&#xD;
          -  Adequate hepatic, renal and bone marrow function&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Evidence of weight loss &gt; 15% within one month&#xD;
&#xD;
          -  Active brain metastases (stable for &lt;28 days, symptomatic, or requiring concurrent&#xD;
             steroids) or leptomeningeal disease. Patients who have received prior whole brain&#xD;
             irradiation and whose brain metastases are stable according to the criteria above will&#xD;
             not be excluded&#xD;
&#xD;
          -  Previous gemcitabine treatment is allowed only if applied as monotherapy in the&#xD;
             adjuvant setting and if the adjuvant single-agent gemcitabine chemotherapy was&#xD;
             terminated at least 6 months before study entry&#xD;
&#xD;
          -  Previous systemic treatment with chemotherapy or radiotherapy for locally advanced,&#xD;
             non resectable or metastatic pancreatic cancer&#xD;
&#xD;
          -  Radiotherapy within four weeks prior to randomization or radiation of target lesions&#xD;
&#xD;
          -  Prior treatment with EGFR targeting therapies or treatment with EGFR- or HER2&#xD;
             inhibiting drugs within the past 4 weeks before start of therapy or concomitantly with&#xD;
             this trial&#xD;
&#xD;
          -  Hypersensitivity to afatinib or to gemcitabine or to any of the excipients or to&#xD;
             compounds with similar chemical or biologic composition&#xD;
&#xD;
          -  Contraindications against the use of gemcitabine&#xD;
&#xD;
          -  Severe renal insufficiency (baseline creatinine clearance &lt; 30 ml/mi)&#xD;
&#xD;
          -  LDH elevated by &gt; 2.5 ULN&#xD;
&#xD;
          -  Severe hepatic dysfunction&#xD;
&#xD;
          -  Any disease e. g. active infection, uncontrolled hypertension, clinically significant&#xD;
             cardiovascular disease for example CVA (&lt;= 6 months before study start), myocardial&#xD;
             infarction (&lt;= 6 months before study start), unstable angina, NYHA &gt;= grade 2 CHF,&#xD;
             arrhythmia requiring medication, metabolic dysfunction giving reasonable suspicion of&#xD;
             a disease or condition that contra-indicates the use of the study drugs or puts the&#xD;
             patient at high risk for treatment-related complications&#xD;
&#xD;
          -  Significant or recent acute gastrointestinal disorders with diarrhoea as a major&#xD;
             symptom e.g. Crohn's disease, malabsorption or CTC grade &gt; 2 diarrhoea of any&#xD;
             aetiology&#xD;
&#xD;
          -  Pregnant or lactating females, non-effective contraception in men and women of&#xD;
             childbearing potential (an effective contraceptive measure has a Pearl Index &lt; 1)&#xD;
&#xD;
          -  Any major surgery within the last 2 weeks before study entry&#xD;
&#xD;
          -  Chemo- or immunotherapy within the past 4 weeks&#xD;
&#xD;
          -  Treatment with an investigational drug in another clinical study within the past 28&#xD;
             days prior to the start of therapy or concomitantly with this study&#xD;
&#xD;
          -  Any persisting toxicities which are deemed to be clinically significant from the&#xD;
             previous therapy&#xD;
&#xD;
          -  Patients with pre-existing interstitital lung disease&#xD;
&#xD;
          -  Psychological, familial, social or geographic conditions that may prevent an adequate&#xD;
             compliance with the study protocol&#xD;
&#xD;
          -  Known or suspected alcohol- or drug abuse&#xD;
&#xD;
          -  Patients unable to comply with the protocol&#xD;
&#xD;
          -  Known hepatitis B infection, known hepatitis C infection or HIV carrier&#xD;
&#xD;
          -  Requirement for treatment with any of the prohibited concomitant medications&#xD;
&#xD;
          -  Any other malignancies within the last 5 years before study start, except for&#xD;
             adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer&#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>Volker Heinemann, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical Department III and Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Munich</name>
      <address>
        <city>Munich</city>
        <zip>81377</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <link>
    <url>http://www.klinikum.uni-muenchen.de/Pankreaszentrum-Muenchen/de/startseitenmeldungen/index.html</url>
    <description>Homepage of the PancreasCenter at LMU Munich</description>
  </link>
  <verification_date>July 2017</verification_date>
  <study_first_submitted>July 5, 2012</study_first_submitted>
  <study_first_submitted_qc>November 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 20, 2012</study_first_posted>
  <last_update_submitted>July 16, 2017</last_update_submitted>
  <last_update_submitted_qc>July 16, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">July 19, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Ludwig-Maximilians - University of Munich</investigator_affiliation>
    <investigator_full_name>PD Dr. med. Volker Heinemann</investigator_full_name>
    <investigator_title>Sponsor Delegated Person</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gemcitabine</mesh_term>
    <mesh_term>Afatinib</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01728818
org study id: 2011-004063-77
nct id: NCT01728818
lead sponsor: 
collaborator: 
has dmc: Yes
Single-agent gemcitabine is currently still regarded as one international standard of care
      for patients with advanced pancreatic cancer (Burris 1997 [4]). The oral EGFR tyrosine kinase
      inhibitor erlotinib received EMEA-approval for the treatment of patients with metastatic
      pancreatic cancer in January 2007.

      In the pivotal phase III trial, the combination of gemcitabine plus erlotinib was associated
      with a statistically significant prolongation of OS (compared to single-agent gemcitabine),
      however, the absolute survival benefit was - for the overall study population - clinically
      moderate (median OS: 6.24 vs 5.91 months, 1-year OS rate: 23% vs 17%; HR = 0.82, p=0.038)
      (Moore 2007 [19]).

      The recently presented FOLFIRINOX regimen shows enhanced activity in metastatic pancreatic
      cancer patients. This regimen is, however, limited to patients with good performance status
      (ECOG 0-1), no major comorbidity, age <75 years, and bilirubin <1.5 ULN (Conroy 2011 [6]).
      The majority of pancreatic cancer patients will therefore not be treated with this regimen.

      Accordingly, novel treatment concepts are urgently needed in pancreatic cancer and
      pre-clinical data indicate an important role of the EGFR1/erbB2 receptor signalling in the
      pathogenesis of pancreatic adenocarcinoma (Yeh 2007 [24]). A recent publication (Larbouret
      2010 [16]) indicates that the combination of cetuximab and trastuzumab induced superior
      antitumour activity in human pancreatic carcinoma xenografts compared to gemcitabine alone
      (see also Larbouret 2007 [15]). Furthermore, synergistic antitumour activity was observed
      when monoclonal antibodies directed against the EGFR1 and erbB2 were combined (Ben-Kasus 2009
      [3]). Based on these data, there is a good rationale to further investigate the combined
      inhibition of the erbB family in pancreatic cancer patients.

      Afatinib (BIBW 2992) is a novel irreversible EGFR1- and HER2 and HER4 inhibitor that is
      applied orally. The purpose of the present trial is to investigate the erbB family inhibition
      by afatinib in patients with metastatic pancreatic cancer.

      In the planned trial, afatinib will be applied at the dose (40 mg/day) that was chosen for
      the randomised phase III trial (LUX 5 study) that investigates afatinib plus weekly
      paclitaxel (80mg/m2).

      Presently there is also a phase I study ongoing that investigates the combination of afatinib
      with gemcitabine (ClinicalTrials.gov Identifier: NCT01251653 U10-2249-02 ). Possibly the data
      will be available once the study is ready to start. Otherwise a modification of the regimen
      will be planned once the respective data will be available.

      In this trial, we integrate a translational project which may allow the identification of
      patients that primarily benefit from this novel treatment approach. The availability of
      tumour tissue- and blood samples from each patient is therefore an important inclusion
      criterion.

      A 2:1 randomisation is chosen favouring the experimental arm since a large body of data is
      available on gemcitabine alone and since sufficient efficacy and toxicity data shall be
      gained in the experimental arm. In addition, the patients' motivation to take part in the
      trial will be greatly enhanced by a greater chance to receive the experimental agent.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Survial
time frame: approximately 36 months
description: Overall Survival
measure: PFS
time frame: Approximately 36 months
description: Progression-free survival (PFS)
measure: Duration of response
time frame: approximately 36 months
description: Duration of response
measure: 1 Year Survial
time frame: approximately 36 months
description: One Year Survial
measure: CA19-9
time frame: approximately 36 months
description: Biochemical tumour marker response (serum CA 19- 9)
measure: Quality of life
time frame: approximately 36 months
description: Evaluation of Quality of life with EORTC QLQ C-30 Questionaire
measure: Toxicity
time frame: approximately 36 months
description: Toxicity (NCI CTC-AE v4.0)
measure: Staging
time frame: approximately 36 months
description: All tumour assessments will be done by CT or MRI at 2-months intervals. One method of imaging will be kept consistent for each individual patient. All comparisons will be refrenced to baseline imaging (performed within 4 weeks prior to randomisation).
arm group label: Arm A
arm group type: Experimental
arm group label: Arm B
arm group type: Active Comparator
intervention type: Drug
intervention name: Gemcitabine
description: 1000 mg/m² d1,8,15 q4weeks
arm group label: Arm A
intervention type: Drug
intervention name: Afatinib
description: 40mg flat dose, po, once daily
arm group label: Arm A
intervention type: Drug
intervention name: Gemcitabine
description: 1000 mg/m², d1,8,15 q4weeks
arm group label: Arm B
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Volker Heinemann, Professor
role: Principal Investigator
affiliation: Medical Department III and Comprehensive Cancer Center
facility: 
country: Germany
url: http://www.klinikum.uni-muenchen.de/Pankreaszentrum-Muenchen/de/startseitenmeldungen/index.html
description: Homepage of the PancreasCenter at LMU Munich
responsible party type: Sponsor-Investigator
investigator affiliation: Ludwig-Maximilians - University of Munich
investigator full name: PD Dr. med. Volker Heinemann
investigator title: Sponsor Delegated Person
mesh term: Gemcitabine
mesh term: Afatinib