<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/NCT03810066</url>
  </required_header>
  <id_info>
    <org_study_id>THEROS</org_study_id>
    <nct_id>NCT03810066</nct_id>
  </id_info>
  <brief_title>Exploring the Theragnostic Value of Osimertinib in EGFR-mutated Lung Cancer (THEROS)</brief_title>
  <official_title>Exploring the Theragnostic Value of Osimertinib in EGFR-mutated Lung Cancer (THEROS) - A Multicentric Phase II Study in Patients With TKI-resistant EGFR-mutated Lung Cancer Exhibiting Early Metabolic Response to Osimertinib</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Essen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Essen</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single arm, open label, multicentric proof-of-concept, phase II study in patients&#xD;
      with EGFR-mutated non-small-cell lung cancer (NSCLC) with acquired TKI resistance who are&#xD;
      &quot;unknown&quot; for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a&#xD;
      negative finding for EGFR T790M in a standard plasma genotyping assay. All patients will&#xD;
      receive osimertinib as continuous oral treatment for one cycle (28 days). Patients who&#xD;
      demonstrate a metabolic response by FDG-PET scanning (to be conducted between day 15 and day&#xD;
      28 of cycle 1) will continue treatment until clinical or radiological progression.&#xD;
      Osimertinib treatment will be terminated in patients not experiencing a metabolic response.&#xD;
&#xD;
      Primary objective:&#xD;
&#xD;
      To study the rate of early metabolic responses to osimertinib in patients with EGFR-mutated&#xD;
      NSCLC and acquired TKI resistance who are &quot;unknown&quot; for EGFR T790M status due to&#xD;
      non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a&#xD;
      standard plasma genotyping assay.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 3, 2019</start_date>
  <completion_date type="Actual">September 30, 2022</completion_date>
  <primary_completion_date type="Actual">December 31, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Simon 2 step design</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of metabolic responses</measure>
    <time_frame>28 days</time_frame>
    <description>Rate of metabolic responses as detected by FDG-PET before end of cycle 1. One cycle is defined as 28 days continuous treatment.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>NSCLC</condition>
  <condition>EGFR T790M</condition>
  <condition>FDG-PET</condition>
  <arm_group>
    <arm_group_label>Osimertinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Osimertinib</intervention_name>
    <description>All patients will be treated with osimertinib 80 mg/d for one cycle (28 days).</description>
    <arm_group_label>Osimertinib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of informed consent prior to any study specific procedures&#xD;
&#xD;
          2. Patients (male/female) must be &gt; 18 years of age.&#xD;
&#xD;
          3. EGFR-mutated NSCLC not amenable to curative treatment (surgery, curative&#xD;
             radiochemotherapy).&#xD;
&#xD;
          4. Acquired resistance to a first- or second-generation EGFR-TKI (e.g. afatinib,&#xD;
             erlotinib, gefitinib) following initial benefit (defined as objective response, or&#xD;
             stable disease for at least 3 months)&#xD;
&#xD;
          5. No tumor rebiopsy available or negative result for EGFR T790M mutation status by a SoC&#xD;
             molecular pathology test (e.g. Sanger sequencing, PCRbased genotyping, deep&#xD;
             sequencing) of a rebiopsy of a progressive tumor lesion&#xD;
&#xD;
          6. Negative finding from EGFR T790M mutation testing in plasma-derived DNA using a SoC&#xD;
             assay (e.g. Roche Cobas)&#xD;
&#xD;
          7. At least one tumor lesion with significant FDG uptake as determined by PET/CT scanning&#xD;
             prior to study treatment&#xD;
&#xD;
          8. Consent to the research use of donated biological samples.&#xD;
&#xD;
          9. World Health Organization (WHO) performance status 0-2.&#xD;
&#xD;
         10. Patients must have a life expectancy ≥ 12 weeks.&#xD;
&#xD;
         11. Females should be using adequate contraceptive measures, should not be breast feeding&#xD;
             and must have a negative pregnancy test prior to start of dosing if of childbearing&#xD;
             potential, which will be repeated on a monthly basis, or must have evidence of&#xD;
             non-child-bearing potential by fulfilling one of the following criteria at screening:&#xD;
&#xD;
               -  Post-menopausal defined as aged more than 50 years and amenorrheic for at least&#xD;
                  12 months following cessation of all exogenous hormonal treatments&#xD;
&#xD;
               -  Women under 50 years old would be consider postmenopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of exogenous hormonal&#xD;
                  treatments and with LH and FSH levels in the post-menopausal range for the&#xD;
                  institution&#xD;
&#xD;
               -  Documentation of irreversible surgical sterilisation by hysterectomy, bilateral&#xD;
                  oophorectomy or bilateral salpingectomy but not tubal ligation&#xD;
&#xD;
         12. Male patients should be willing to use barrier contraception (see Restrictions,&#xD;
             Section 3.6).&#xD;
&#xD;
         13. Patient is willing and able to comply with the protocol for the duration of the study&#xD;
             including undergoing treatment and scheduled visits and examinations including follow&#xD;
             up.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. EGFR-mutated NSCLC and demonstration of the T790M resistance mutation by standard&#xD;
             assay technology in tumor-derived or plasma-derived DNA&#xD;
&#xD;
          2. Absence of a tumor lesion with significant FDG uptake at PET/CT scanning prior to&#xD;
             study treatment&#xD;
&#xD;
          3. Involvement in the planning and/or conduct of the study (applies to both sponsor staff&#xD;
             and/or staff at the study site)&#xD;
&#xD;
          4. Previous treatment with osimertinib or any experimental or approved mutationspecific&#xD;
             EGFR-TKI with clinical activity against the EGFR T790M resistance mutation&#xD;
&#xD;
          5. Treatment with an investigational drug within one week or five drug half-lives&#xD;
             (whichever is longer) of the compound (3 weeks for antibodies)&#xD;
&#xD;
          6. Patients currently receiving (or unable to stop use prior to receiving the first dose&#xD;
             of study treatment) medications or herbal supplements known to be potent inducers of&#xD;
             CYP3A4 (at least 3 week prior) (Appendix A - Guidance regarding Potential Interactions&#xD;
             With Concomitant Medications). All patients must try to avoid concomitant use of any&#xD;
             medications, herbal supplements and/or ingestion of foods with known inducer effects&#xD;
             on CYP3A4. A list for drug interaction potential is found in section 5.1.6.4 of the&#xD;
             osimertinib IB.&#xD;
&#xD;
          7. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria&#xD;
             for Adverse Events (CTCAE) grade 1 at the time of starting study Treatment with the&#xD;
             exception of alopecia and grade 2, prior chemotherapy related neuropathy.&#xD;
&#xD;
          8. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled&#xD;
             hypertension and active bleeding diatheses, which in the investigator's opinion makes&#xD;
             it undesirable for the patient to participate in the trial or which would jeopardise&#xD;
             compliance with the protocol, or active infection including hepatitis B, hepatitis C&#xD;
             and human immunodeficiency virus (HIV). Screening for chronic conditions is not&#xD;
             required.&#xD;
&#xD;
          9. Patients with symptomatic CNS metastases who are neurologically unstable&#xD;
&#xD;
         10. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid&#xD;
             treatment, or any evidence of clinically active ILD&#xD;
&#xD;
         11. Fasting blood glucose levels above 150 mg/dl (precluding informative FDGPET/ CT&#xD;
             scanning)&#xD;
&#xD;
         12. Inadequate bone marrow reserve or organ function as demonstrated by any of the&#xD;
             following laboratory values:&#xD;
&#xD;
             Absolute neutrophil count &lt;1.5 x 109/L Platelet count &lt;100 x 109/L Haemoglobin &lt;90 g/L&#xD;
             Alanine aminotransferase &gt;2.5 times the upper limit of normal (ULN) if no demonstrable&#xD;
             liver metastases or &gt;5 times ULN in the presence of liver metastases Aspartate&#xD;
             aminotransferase &gt;2.5 times ULN if no demonstrable liver metastases or &gt;5 times ULN in&#xD;
             the presence of liver metastases Total bilirubin &gt;1.5 times ULN if no liver metastases&#xD;
             or &gt;3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated&#xD;
             hyperbilirubinaemia) or liver metastases Creatinine &gt;1.5 times ULN concurrent with&#xD;
             creatinine clearance &lt;50 ml/min (measured or calculated by Cockcroft and Gault&#xD;
             equation); confirmation of creatinine clearance is only required when creatinine is&#xD;
             &gt;1.5 times ULN.&#xD;
&#xD;
         13. Any of the following cardiac criteria:&#xD;
&#xD;
               1. Mean resting corrected QT interval (QTc using Fredericia's formula) &gt; 470 msec&#xD;
                  obtained from the screening clinic ECG machine-derived QTc value&#xD;
&#xD;
               2. Any clinically important abnormalities in rhythm, conduction or morphology of&#xD;
                  resting ECG (e.g., complete left bundle branch block, third degree heart block,&#xD;
                  second degree heart block)&#xD;
&#xD;
               3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic&#xD;
                  events such as heart failure, electrolyte abnormalities (including serum/plasma&#xD;
                  potassium level below lower level of normal), congenital long QT syndrome, family&#xD;
                  history of long QT syndrome or unexplained sudden death under 40 years of age in&#xD;
                  first degree relatives or any concomitant medication known to prolong the QT&#xD;
                  interval&#xD;
&#xD;
         14. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to&#xD;
             swallow the formulated product or previous significant bowel resection that would&#xD;
             preclude adequate absorption of osimertinib&#xD;
&#xD;
         15. History of hypersensitivity to osimertinib (or drugs with a similar chemical structure&#xD;
             or class to osimertinib) or any excipients of these agents&#xD;
&#xD;
         16. Males and females of reproductive potential who are not using an effective method of&#xD;
             birth control and females who are pregnant or breastfeeding or have a positive (urine&#xD;
             or serum) pregnancy test prior to study entry&#xD;
&#xD;
         17. Judgment by the Investigator that the patient should not participate in the study if&#xD;
             the patient is unlikely to comply with study procedures, restrictions and requirements&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Prof. Dr. med. Martin Schuler</name>
      <address>
        <city>Essen</city>
        <state>NRW</state>
        <zip>45147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>January 10, 2019</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>September 30, 2022</last_update_submitted>
  <last_update_submitted_qc>September 30, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 3, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osimertinib</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/NCT03810066
org study id: THEROS
nct id: NCT03810066
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
This is a single arm, open label, multicentric proof-of-concept, phase II study in patients
      with EGFR-mutated non-small-cell lung cancer (NSCLC) with acquired TKI resistance who are
      "unknown" for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a
      negative finding for EGFR T790M in a standard plasma genotyping assay. All patients will
      receive osimertinib as continuous oral treatment for one cycle (28 days). Patients who
      demonstrate a metabolic response by FDG-PET scanning (to be conducted between day 15 and day
      28 of cycle 1) will continue treatment until clinical or radiological progression.
      Osimertinib treatment will be terminated in patients not experiencing a metabolic response.

      Primary objective:

      To study the rate of early metabolic responses to osimertinib in patients with EGFR-mutated
      NSCLC and acquired TKI resistance who are "unknown" for EGFR T790M status due to
      non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a
      standard plasma genotyping assay.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Simon 2 step design
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of metabolic responses
time frame: 28 days
description: Rate of metabolic responses as detected by FDG-PET before end of cycle 1. One cycle is defined as 28 days continuous treatment.
arm group label: Osimertinib
arm group type: Experimental
intervention type: Drug
intervention name: Osimertinib
description: All patients will be treated with osimertinib 80 mg/d for one cycle (28 days).
arm group label: Osimertinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Osimertinib