<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/NCT04438902</url>
  </required_header>
  <id_info>
    <org_study_id>TRAIN</org_study_id>
    <nct_id>NCT04438902</nct_id>
  </id_info>
  <brief_title>Osimertinib Combined With Anlotinib in EGFR T790M Mutated NSCLC Patients With Progression on Osimertinib Treatment</brief_title>
  <official_title>A Prospective, Multi-center, Interventional Study of Osimertinib Combined With Anlotinib in Acquired EGFR T790M Mutated NSCLC Patients With Gradual Progression on Osimertinib Treatment</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>First Affiliated Hospital of Zhejiang University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>First Affiliated Hospital of Zhejiang University</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>
      EGFR T790M gatekeeper mutation accounts for approximately 60% of acquired resistance to the&#xD;
      first- or second-generation EGFR-TKI treatment. Osimertinib, a third-generation EGFR TKI, has&#xD;
      become the standard therapy for NSCLC patients with acquired EGFR T790M mutation. However,&#xD;
      acquired resistance to osimertinib is still inevitable and there is no established targetable&#xD;
      agent currently. Thus, treatment strategy for patients with acquire resistance to osimertinib&#xD;
      remains an urgent issue. In this study, we aimed to evaluate the efficacy of osimertinib&#xD;
      combined with anlotinib in acquired EGFR T790M mutated NSCLC patients with gradual&#xD;
      progression on osimertinib treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In current clinical practice, acquired resistance to osimertinib can be divided into three&#xD;
      clinical modes: dramatic progression, gradual progression and local progression. For patients&#xD;
      with gradual progression,there are various clinical explorations，including the continuation&#xD;
      of osimertinib with chemotherapy or radiotherapy, osimertinib combined with antiangiogenic&#xD;
      agents. In preclinical studies, an overactive vascular endothelial growth factor/vascular&#xD;
      endothelial growth factor receptor (VEGF/VEGFR) pathway and tumour angiogenesis plays a&#xD;
      crucial role in the resistance to EGFR-TKIs, and the dual targeting of both the VEGF and EGFR&#xD;
      pathways may prevent resistance.&#xD;
&#xD;
      Anlotinib (AL3818) is an inhibitor targeting multiple receptor tyrosine kinases involved in&#xD;
      tumour progression, especially VEGFR 2/3, PDGFRα/β and c-Kit. We suppose that the combination&#xD;
      treatment of osimertinib and anlotinib may ameliorate acquired resistance to osimertinib.This&#xD;
      is a multi-center, open, single-arm, exploratory phase 2 trial evaluating osimertinib&#xD;
      combined with anlotinib in acquired EGFR T790M mutated NSCLC patients with gradual&#xD;
      progression on osimertinib treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Many patients can't tolerate the combination treatment due to adverse events.&#xD;
  </why_stopped>
  <start_date type="Actual">December 12, 2020</start_date>
  <completion_date type="Actual">February 16, 2023</completion_date>
  <primary_completion_date type="Actual">December 8, 2022</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>This is a multi-center, open, single-arm, exploratory phase 2 trial.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>progression-free survival (PFS)</measure>
    <time_frame>from the date of first dose of osimertinib until the date of disease progression，assessed up to 12 months.</time_frame>
    <description>PFS is defined as the time from beginning of osimertinib to disease progression on combination treatment of osimertinib and anlotinib.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>from the date of combination of osimertinib and anlotinib, assessed up to 6 weeks.</time_frame>
    <description>Objective Response Rate (ORR), is defined as the percentage of patients with complete response or partial response by investigator assessment as recorded in the CRF, which usually refer to Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 in clinical practice.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>from the date of combination of osimertinib and anlotinib, assessed up to 6 weeks.</time_frame>
    <description>Disease Control Rate (DCR), is defined as the percentage of patients with complete response or partial response or stable disease by investigator assessment as recorded in the CRF, which usually refer to RECIST v1.1 in clinical practice.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events/Serious adverse events</measure>
    <time_frame>From signing ICF to 30 days after the end of treatment.</time_frame>
    <description>Incidence of Adverse Events (AEs): Incidence, severity and seriousness of adverse events, incidence of serious adverse events (SAEs), which usually be graded by CTCAE v5.0 based on current clinical practice.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Non Small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>osimertinib combined with anlotinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>osimertinib mesylate tablets and anlotinib hydrochloride capsules</intervention_name>
    <description>osimertinib mesylate tablets 80mg qd and anlotinib hydrochloride capsules 10mg qd day 1-14 of a 21-day cycle</description>
    <arm_group_label>osimertinib combined with anlotinib</arm_group_label>
    <other_name>TAGRISSO and FOCUS V</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Ability to provide informed consent, complete all study assessments and have complete&#xD;
             medical record.&#xD;
&#xD;
          2. Age:18-75 years.&#xD;
&#xD;
          3. Histologically or cytologically confirmed diagnosis of local advanced or metastatic&#xD;
             NSCLC.&#xD;
&#xD;
          4. Patients should be confirmed acquired EGFR T790M mutation and received osimertinib as&#xD;
             the second line treatment, and they should have the following: (1) benefit from&#xD;
             treatment with osimertinib initially ;(2) gradual progression on osimertinib treatment&#xD;
             as defined by minor increment of tumor burden (≥10% but &lt;20% in the sum of target&#xD;
             lesions).&#xD;
&#xD;
          5. At least one measurable lesion as defined by lesions ≥10mm in long axis according to&#xD;
             RECIST 1.1.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients who will be or were involved in any other interventional antitumour clinical&#xD;
             studies for locally advanced/metastatic NSCLC currently or previously.&#xD;
&#xD;
          2. Small cell lung cancer (including small lung cancer mixed with non-small cell lung&#xD;
             cancer).&#xD;
&#xD;
          3. Patients at risk of bleeding.&#xD;
&#xD;
          4. Patients with renal dysfunction.&#xD;
&#xD;
          5. Uncontrolled severe hypertension.&#xD;
&#xD;
          6. Any concomitant condition evaluated by physicians which is not suitable for&#xD;
             osimertinib or anlotinib treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Yuehong Wang</last_name>
    <role>Principal Investigator</role>
    <affiliation>First Affiliated Hospital of Zhejiang University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The First Affiliated Hospital, College of Medicine, Zhejiang University</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <zip>310003</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital of Jiaxing College</name>
      <address>
        <city>Jiaxing</city>
        <state>Zhejiang</state>
        <zip>314001</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>June 15, 2020</study_first_submitted>
  <study_first_submitted_qc>June 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 19, 2020</study_first_posted>
  <last_update_submitted>February 17, 2023</last_update_submitted>
  <last_update_submitted_qc>February 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>non-small-cell lung cancer</keyword>
  <keyword>EGFR T790M</keyword>
  <keyword>osimertinib</keyword>
  <keyword>anlotinib</keyword>
  <keyword>acquired resistance</keyword>
  <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>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>No plan to share participant data of the trial.</ipd_description>
  </patient_data>
  <!-- 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/NCT04438902
org study id: TRAIN
nct id: NCT04438902
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
EGFR T790M gatekeeper mutation accounts for approximately 60% of acquired resistance to the
      first- or second-generation EGFR-TKI treatment. Osimertinib, a third-generation EGFR TKI, has
      become the standard therapy for NSCLC patients with acquired EGFR T790M mutation. However,
      acquired resistance to osimertinib is still inevitable and there is no established targetable
      agent currently. Thus, treatment strategy for patients with acquire resistance to osimertinib
      remains an urgent issue. In this study, we aimed to evaluate the efficacy of osimertinib
      combined with anlotinib in acquired EGFR T790M mutated NSCLC patients with gradual
      progression on osimertinib treatment.
In current clinical practice, acquired resistance to osimertinib can be divided into three
      clinical modes: dramatic progression, gradual progression and local progression. For patients
      with gradual progression,there are various clinical explorations，including the continuation
      of osimertinib with chemotherapy or radiotherapy, osimertinib combined with antiangiogenic
      agents. In preclinical studies, an overactive vascular endothelial growth factor/vascular
      endothelial growth factor receptor (VEGF/VEGFR) pathway and tumour angiogenesis plays a
      crucial role in the resistance to EGFR-TKIs, and the dual targeting of both the VEGF and EGFR
      pathways may prevent resistance.

      Anlotinib (AL3818) is an inhibitor targeting multiple receptor tyrosine kinases involved in
      tumour progression, especially VEGFR 2/3, PDGFRα/β and c-Kit. We suppose that the combination
      treatment of osimertinib and anlotinib may ameliorate acquired resistance to osimertinib.This
      is a multi-center, open, single-arm, exploratory phase 2 trial evaluating osimertinib
      combined with anlotinib in acquired EGFR T790M mutated NSCLC patients with gradual
      progression on osimertinib treatment.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is a multi-center, open, single-arm, exploratory phase 2 trial.
primary purpose: Treatment
masking: None (Open Label)
measure: progression-free survival (PFS)
time frame: from the date of first dose of osimertinib until the date of disease progression，assessed up to 12 months.
description: PFS is defined as the time from beginning of osimertinib to disease progression on combination treatment of osimertinib and anlotinib.
measure: Objective Response Rate (ORR)
time frame: from the date of combination of osimertinib and anlotinib, assessed up to 6 weeks.
description: Objective Response Rate (ORR), is defined as the percentage of patients with complete response or partial response by investigator assessment as recorded in the CRF, which usually refer to Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 in clinical practice.
measure: Disease Control Rate (DCR)
time frame: from the date of combination of osimertinib and anlotinib, assessed up to 6 weeks.
description: Disease Control Rate (DCR), is defined as the percentage of patients with complete response or partial response or stable disease by investigator assessment as recorded in the CRF, which usually refer to RECIST v1.1 in clinical practice.
measure: Adverse events/Serious adverse events
time frame: From signing ICF to 30 days after the end of treatment.
description: Incidence of Adverse Events (AEs): Incidence, severity and seriousness of adverse events, incidence of serious adverse events (SAEs), which usually be graded by CTCAE v5.0 based on current clinical practice.
arm group label: osimertinib combined with anlotinib
arm group type: Experimental
intervention type: Drug
intervention name: osimertinib mesylate tablets and anlotinib hydrochloride capsules
description: osimertinib mesylate tablets 80mg qd and anlotinib hydrochloride capsules 10mg qd day 1-14 of a 21-day cycle
arm group label: osimertinib combined with anlotinib
other name: TAGRISSO and FOCUS V
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Yuehong Wang
role: Principal Investigator
affiliation: First Affiliated Hospital of Zhejiang University
facility: 
facility: 
country: China
responsible party type: Sponsor
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Osimertinib
sharing ipd: No
ipd description: No plan to share participant data of the trial.