<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/NCT04413201</url>
  </required_header>
  <id_info>
    <org_study_id>AFAMOSI</org_study_id>
    <secondary_id>2019-002197-31</secondary_id>
    <nct_id>NCT04413201</nct_id>
  </id_info>
  <brief_title>AFAMOSI: Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Nonsquamous NSCLC</brief_title>
  <official_title>AFAMOSI: Prospective, Randomized, Multicenter Phase IV Study to Evaluate the Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Non-squamous NSCLC in the First-line Setting</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Michael Hopp</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Johannes Gutenberg University Mainz</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This randomized, open label Phase IV trial will be performed in patients with a diagnosis of&#xD;
      advanced NSCLC (non-squamous cell histology), harboring EGFR mutation positive but T790M&#xD;
      Mutation negative, who have no previous chemotherapy for metastatic NSCLC. Neoadjuvant or&#xD;
      adjuvant systemic treatments had to be finished at least (≥) 6 months before study inclusion.&#xD;
      In conclusion, this study is investigating the important clinical question whether tumor&#xD;
      growth and long term overall survival for a patient is better controlled in a specific&#xD;
      treatment sequence of different EGFR-inhibitors. Patients will be treated with registered&#xD;
      compounds according to their label in both treatment arms. Thus, all patients will get an&#xD;
      effective treatment regimen and patients who progressed on afatinib, and who developed a&#xD;
      T790M mutation will be treated subsequently with osimertinib. Those who progressed under&#xD;
      osimertinib or under afatinib without T790M mutation will be treated according to the current&#xD;
      treatment guidelines with Investigator´s choice of active therapy (ICT) including but not&#xD;
      limited to platin doublet chemotherapy.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 11, 2020</start_date>
  <completion_date type="Anticipated">June 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
  <phase>Phase 4</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>Time to EGFR-TKI failure within 24 months for afatinib followed by osimertinib in T790Mpositive group vs osimertinib</measure>
    <time_frame>24 months</time_frame>
    <description>The main objective is to investigate whether the time to EGFR-TKI failure at 24 months is better for the treatment sequence of afatinib followed by osimertinib in the T790M positive group compared to osimertinib.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to EGFR-TKI failure (afatinib versus osimertinib)</measure>
    <time_frame>24 months</time_frame>
    <description>Time from randomization until ICT is indicated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS: afatinib followed by osimertinib or ICT vs osimertinib followed by ICT)</measure>
    <time_frame>24 months</time_frame>
    <description>Time from randomization until disease progression according to RECIST or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>24 months</time_frame>
    <description>Survival Status</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response Rate (RR)</measure>
    <time_frame>12 months</time_frame>
    <description>CR+PR according to RECIST</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response Rate (RR)</measure>
    <time_frame>24 months</time_frame>
    <description>CR+PR according to RECIST</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>12 months</time_frame>
    <description>CR+PR+SD according to RECIST</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>24 months</time_frame>
    <description>CR+PR+SD according to RECIST</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>24 months</time_frame>
    <description>Adverse Events as assessed by intensity of the of the adverse events and the causal relation to trial medication Intensity/Severity: investigator will use the following definitions of severity in accordance with National Cancer Institute common terminology criteria for adverse events, CTCAE, version 5.0; assessment of the relationship of an adverse event to the administration of study drug is a clinical decision by the investigator Institute common terminology criteria for adverse events, CTCAE, version 5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Symptom control assessed by patient-reported quality of life (QoL): EQ-5D</measure>
    <time_frame>24 months</time_frame>
    <description>patient-reported quality of life assessed by European Quality of Life 5 Dimensions Questionnaire (EQ-5D)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-C30</measure>
    <time_frame>24 months</time_frame>
    <description>patient-reported quality of life assessed by Questionnaire of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-LC29</measure>
    <time_frame>24 months</time_frame>
    <description>EORTC QLQ-LC29</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Non-squamous NSCLC</condition>
  <arm_group>
    <arm_group_label>Afatinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Afatinib followed by osimertinib or ICT depending on T790M status</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Osimertinib</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Osimertinib followed by ICT</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Afatinib</intervention_name>
    <description>Afatinib followed by osimertinib or ICT</description>
    <arm_group_label>Afatinib</arm_group_label>
    <other_name>Osimertinib</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Osimertinib</intervention_name>
    <description>Osimertinib followed by ICT</description>
    <arm_group_label>Afatinib</arm_group_label>
    <arm_group_label>Osimertinib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed non-squamous NSCLC harboring EGFR mutation positive but T790M&#xD;
             mutation negative by local testing&#xD;
&#xD;
          -  Unresectable stage UICC ≥ IIIb or metastatic stage UICC IV disease&#xD;
&#xD;
          -  TKI naïve for metastatic NSCLC, neoadjuvant or adjuvant chemotherapy allowed&#xD;
&#xD;
          -  At least one evaluable lesion according to RECIST v1.1&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  ECOG performance status 0 - 2&#xD;
&#xD;
          -  Adequate organ function, defined as all of the following:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) ≥ 1500/mm3. (ANC &gt; 1000/mm3 may be considered in&#xD;
                  special circumstances such as benign cyclical neutropenia as judged by the&#xD;
                  investigator and in discussion with the coordinating investigator)&#xD;
&#xD;
               2. Platelet count ≥ 75,000/mm3&#xD;
&#xD;
               3. Estimated glomerular filtration rate (eGFR) &gt; 45 ml/min/1.73 m2 according to the&#xD;
                  Cockcroft-Gault formula d. If history of cardiac comorbidity: Left ventricular&#xD;
                  function with resting ejection fraction ≥ 50% or above the institutional lower&#xD;
                  limit of normal (LLN)&#xD;
&#xD;
             e. Total Bilirubin ≤ 1.5 times upper limit of normal (ULN), (if related to liver&#xD;
             metastases ≤ 3 times ULN). (Patients with Gilbert's syndrome total Bilirubin must be ≤&#xD;
             4 times institutional upper limit of normal) f. Aspartate amino transferase (AST) or&#xD;
             alanine amino transferase (ALT) ≤ 3 times the upper limit of normal (ULN) (if related&#xD;
             to liver metastases ≤ 5 times ULN)&#xD;
&#xD;
          -  Recovered from any previous therapy related toxicity to ≤ Grade 1 at before&#xD;
             randomization (except for stable sensory neuropathy ≤ Grade 2 and alopecia)&#xD;
&#xD;
          -  Written informed consen&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any investigational drug within 30 days or hormonal anticancer treatment within 2&#xD;
             weeks prior to randomization (continued use of anti-androgens and/or gonadorelin&#xD;
             analogues for treatment of prostate cancer permitted)&#xD;
&#xD;
          -  T790M mutation positive tumors (by local testing)&#xD;
&#xD;
          -  Radiotherapy within 2 weeks prior to randomization, except as follows:&#xD;
&#xD;
               1. Palliative radiation to target organs other than chest may be allowed up to 1&#xD;
                  week prior to randomization&#xD;
&#xD;
               2. Single dose palliative treatment for symptomatic metastasis outside above&#xD;
                  allowance to be discussed with coordinating investigator prior to enrolling&#xD;
&#xD;
          -  Major surgery within 2 weeks before starting study treatment or scheduled for surgery&#xD;
             during the projected course of the study&#xD;
&#xD;
          -  Known hypersensitivity to afatinib or osimertinib or the excipients of any of the&#xD;
             trial drugs&#xD;
&#xD;
          -  History or presence of clinically relevant cardiovascular abnormalities such as&#xD;
&#xD;
               1. uncontrolled hypertension&#xD;
&#xD;
               2. congestive heart failure NYHA classification of ≥ 3&#xD;
&#xD;
               3. unstable angina or poorly controlled arrhythmia as determined by the investigator&#xD;
&#xD;
               4. Myocardial infarction within 6 months prior to randomization&#xD;
&#xD;
               5. Clinically important abnormalities in rhythm and conduction as measured by&#xD;
                  resting electrocardiogram (ECG) (e.g. QTc interval greater than 470 ms) or QTc&#xD;
                  interval prolongation with signs/symptoms of serious arrhythmia&#xD;
&#xD;
               6. Congenital long QT syndrome, congestive heart failure, electrolyte abnormalities,&#xD;
                  or intake of medicinal products that are known to prolong the QTc interval&#xD;
&#xD;
          -  Patients with a past or present medical history of&#xD;
&#xD;
               1. Interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis that&#xD;
                  required steroid treatment, or any evidence of clinically active ILD&#xD;
&#xD;
               2. Any history of or concomitant condition that, in the opinion of the Investigator,&#xD;
                  would compromise the patient's ability to comply with the study or interfere with&#xD;
                  the evaluation of the efficacy and safety of the test drug&#xD;
&#xD;
               3. Any history or presence of poorly controlled gastrointestinal disorders that&#xD;
                  could affect the absorption of the study drug (e.g. Crohn's disease, ulcerative&#xD;
                  colitis, chronic diarrhoea, malabsorption)&#xD;
&#xD;
               4. Known active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B&#xD;
                  DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or&#xD;
                  known HIV carrier&#xD;
&#xD;
               5. Previous or concomitant malignancies at other sites, except effectively treated&#xD;
                  non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in&#xD;
                  situ or effectively treated malignancy that has been in remission for more than 5&#xD;
                  years and is considered to be cured&#xD;
&#xD;
          -  Pregnancy and contraception:&#xD;
&#xD;
               1. Women who are pregnant, nursing, or who plan to become pregnant while in the&#xD;
                  trial&#xD;
&#xD;
               2. Women of child-bearing potential (WOCBP) and men who are able to father a child,&#xD;
                  unwilling to be abstinent or use highly effective methods of birth control that&#xD;
                  result in a low failure rate of less than 1% per year when used consistently and&#xD;
                  correctly beginning at informed consent, for the duration of study participation&#xD;
                  and for at least 2 months for females and 4 months for males after last dose&#xD;
&#xD;
          -  Requiring treatment with any of the prohibited concomitant medications protein&#xD;
             Inhibitors/Inductors CYP3A4/5 Inhibitors/Inductors that cannot be stopped for the&#xD;
             duration of trial participation or concomitant St. John's Wort&#xD;
&#xD;
          -  Uncontrolled brain metastases (Patients with brain or subdural metastases are not&#xD;
             eligible, unless they have completed local therapy (≤ 2 weeks apart from last&#xD;
             radiotherapy or radiosurgery) and have discontinued the use of corticosteroids,&#xD;
             anticonvulsants or have been on stable dose of corticosteroids (i.e. Dexamethasone ≤ 8&#xD;
             mg) for at least 4 weeks before starting study treatment. Any symptoms attributed to&#xD;
             brain metastases must be stable for at least 4 weeks before starting study treatment)&#xD;
             or Leptomeningeal carcinomatosis 11. Other contraindications to study treatment&#xD;
             (Investigators opinion) or legal incapacity or limited legal capacity&#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>Thomas Wehler, Prof Dr med</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universitätsklinikum Gießen Marburg</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Klinikum der Ludwig-Maximilians-Universität München</name>
      <address>
        <city>München</city>
        <state>Bayern</state>
        <zip>80336</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Gießen Marburg</name>
      <address>
        <city>Gießen</city>
        <state>Hessen</state>
        <zip>35392</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sana-Klinikum Offenbach</name>
      <address>
        <city>Offenbach</city>
        <state>Hessen</state>
        <zip>63069</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Evangelische Lungenklinik Berlin</name>
      <address>
        <city>Berlin</city>
        <zip>13125</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikum Bremen-Ost</name>
      <address>
        <city>Bremen</city>
        <zip>28325</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Studiengesellschaft Hämato-Onkologie Hamburg</name>
      <address>
        <city>Hamburg</city>
        <zip>20251</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Evangelisches Krankenhaus Hamm</name>
      <address>
        <city>Hamm</city>
        <zip>59063</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinikverbund Allgäug gGmbH, Klinik für Pneumologie, c/o Klinik</name>
      <address>
        <city>Immenstadt</city>
        <zip>87509</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gemeinnützige Krankenhausbetriebsgesellschaft Konstanz Mbh</name>
      <address>
        <city>Konstanz</city>
        <zip>78464</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik Löwenstein gGmbH</name>
      <address>
        <city>Löwenstein</city>
        <zip>74245</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Regensburg</name>
      <address>
        <city>Regensburg</city>
        <zip>93053</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 1, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 2, 2020</study_first_posted>
  <last_update_submitted>June 1, 2023</last_update_submitted>
  <last_update_submitted_qc>June 1, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 2, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Johannes Gutenberg University Mainz</investigator_affiliation>
    <investigator_full_name>Michael Hopp</investigator_full_name>
    <investigator_title>Head of Interdisciplinary Center for Clinical Studies (IZKS)</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osimertinib</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/NCT04413201
org study id: AFAMOSI
secondary id: 2019-002197-31
nct id: NCT04413201
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This randomized, open label Phase IV trial will be performed in patients with a diagnosis of
      advanced NSCLC (non-squamous cell histology), harboring EGFR mutation positive but T790M
      Mutation negative, who have no previous chemotherapy for metastatic NSCLC. Neoadjuvant or
      adjuvant systemic treatments had to be finished at least (≥) 6 months before study inclusion.
      In conclusion, this study is investigating the important clinical question whether tumor
      growth and long term overall survival for a patient is better controlled in a specific
      treatment sequence of different EGFR-inhibitors. Patients will be treated with registered
      compounds according to their label in both treatment arms. Thus, all patients will get an
      effective treatment regimen and patients who progressed on afatinib, and who developed a
      T790M mutation will be treated subsequently with osimertinib. Those who progressed under
      osimertinib or under afatinib without T790M mutation will be treated according to the current
      treatment guidelines with Investigator´s choice of active therapy (ICT) including but not
      limited to platin doublet chemotherapy.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Time to EGFR-TKI failure within 24 months for afatinib followed by osimertinib in T790Mpositive group vs osimertinib
time frame: 24 months
description: The main objective is to investigate whether the time to EGFR-TKI failure at 24 months is better for the treatment sequence of afatinib followed by osimertinib in the T790M positive group compared to osimertinib.
measure: Time to EGFR-TKI failure (afatinib versus osimertinib)
time frame: 24 months
description: Time from randomization until ICT is indicated
measure: Progression-free survival (PFS: afatinib followed by osimertinib or ICT vs osimertinib followed by ICT)
time frame: 24 months
description: Time from randomization until disease progression according to RECIST or death
measure: Overall Survival (OS)
time frame: 24 months
description: Survival Status
measure: Response Rate (RR)
time frame: 12 months
description: CR+PR according to RECIST
measure: Response Rate (RR)
time frame: 24 months
description: CR+PR according to RECIST
measure: Disease Control Rate (DCR)
time frame: 12 months
description: CR+PR+SD according to RECIST
measure: Disease Control Rate (DCR)
time frame: 24 months
description: CR+PR+SD according to RECIST
measure: Adverse Events
time frame: 24 months
description: Adverse Events as assessed by intensity of the of the adverse events and the causal relation to trial medication Intensity/Severity: investigator will use the following definitions of severity in accordance with National Cancer Institute common terminology criteria for adverse events, CTCAE, version 5.0; assessment of the relationship of an adverse event to the administration of study drug is a clinical decision by the investigator Institute common terminology criteria for adverse events, CTCAE, version 5.0
measure: Symptom control assessed by patient-reported quality of life (QoL): EQ-5D
time frame: 24 months
description: patient-reported quality of life assessed by European Quality of Life 5 Dimensions Questionnaire (EQ-5D)
measure: Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-C30
time frame: 24 months
description: patient-reported quality of life assessed by Questionnaire of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
measure: Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-LC29
time frame: 24 months
description: EORTC QLQ-LC29
arm group label: Afatinib
arm group type: Experimental
description: Afatinib followed by osimertinib or ICT depending on T790M status
arm group label: Osimertinib
arm group type: Active Comparator
description: Osimertinib followed by ICT
intervention type: Drug
intervention name: Afatinib
description: Afatinib followed by osimertinib or ICT
arm group label: Afatinib
other name: Osimertinib
intervention type: Drug
intervention name: Osimertinib
description: Osimertinib followed by ICT
arm group label: Afatinib
arm group label: Osimertinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Thomas Wehler, Prof Dr med
role: Principal Investigator
affiliation: Universitätsklinikum Gießen Marburg
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Germany
responsible party type: Sponsor-Investigator
investigator affiliation: Johannes Gutenberg University Mainz
investigator full name: Michael Hopp
investigator title: Head of Interdisciplinary Center for Clinical Studies (IZKS)
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Osimertinib
mesh term: Afatinib