<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/NCT03801200</url>
  </required_header>
  <id_info>
    <org_study_id>HBCH RT-2019-01</org_study_id>
    <nct_id>NCT03801200</nct_id>
  </id_info>
  <brief_title>Apatinib Combined With Radiotherapy in Patient With BM From Drive Gene Negative NSCLC</brief_title>
  <official_title>A Prospective, Multicenter, Randomized Controlled Trial of Apatinib Combined With Radiotherapy in Patient With Brain Metastases From Drive Gene Negative NSCLC</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hubei Cancer Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hubei Cancer Hospital</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>
      The purpose of this study is to evaluate the efficacy and safety of concurrent radiotherapy&#xD;
      with Apatinib in patients with Brain Metastases from drive gene wide-type Non-small-cell Lung&#xD;
      Cancer (NSCLC).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Brain metastases (BM) develop in 22-54% of NSCLC patients during the disease course. NSCLC&#xD;
      patients with BM with a median overall survival (OS) of 2-3 months when treated with systemic&#xD;
      corticosteroid alone, and a median OS of 3-6 months when treated with whole brain radiation&#xD;
      therapy (WBRT). Recently, several studies have reported the benefits of epidermal growth&#xD;
      factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for EGFR mutation NSCLC patients&#xD;
      with BM. The median OS of EGFR mutation patients with BM significantly improved with TKIs&#xD;
      treatment, which ranged from 11.8 to 18.8 months. However, for the EGFR wide-type NSCLC&#xD;
      patients with BM, the prognosis remains poor.&#xD;
&#xD;
      It was found that the combination of anti-VEGF drugs and brain radiotherapy can not only&#xD;
      reduce the volume of peritumoral brain edema (PTBE), reduce the intracranial pressure,&#xD;
      relieve the symptoms of nerve compression, reduce the risk of brain hernia during brain&#xD;
      radiotherapy, and but also inhibit the hypoxia of tumor cells, increase the radiosensitivity&#xD;
      of tumor cells, and ultimately improve the efficacy of radiotherapy.&#xD;
&#xD;
      Apatinib, a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial&#xD;
      growth factor receptor (VEGFR) and mildly inhibits c-Kit and c-SRC, has been reported to show&#xD;
      efficacy among some patients with malignant supratentorial gliomas.&#xD;
&#xD;
      Therefore, the investigators initiated this study to evaluate the efficacy and safety of&#xD;
      concurrent radiotherapy with Apatinib in patients with Brain Metastases from drive gene&#xD;
      wide-type Non-small-cell Lung Cancer (NSCLC).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">September 10, 2020</start_date>
  <completion_date type="Anticipated">September 10, 2023</completion_date>
  <primary_completion_date type="Actual">September 10, 2021</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>Intracranial progression-free survival (iPFS)</measure>
    <time_frame>Evaluated in 24 months since the treatment began</time_frame>
    <description>Defined as the time from randomisation to progression of intracranial disease or death from any cause.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Disease control rate (DCR)</measure>
    <time_frame>4 weeks after Radiotherapy.</time_frame>
    <description>Proportion of patients with reduction or keeping in stable in tumor burden of a predefined amount</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>4 weeks after Radiotherapy.</time_frame>
    <description>Proportion of patients with reduction in tumor burden of a predefined amount</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>intracranial time to progress (ITTP)</measure>
    <time_frame>Tumor assesment at 4 weeks and 12 weeks after radiotherapy, and then every 12 weeks, up to 24 months</time_frame>
    <description>Defined as the time from randomisation to progression of intracranial disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Tumor assesment at 4 weeks and 12 weeks after radiotherapy, and then every 12 weeks, up to 24 months</time_frame>
    <description>Defined as the time from randomisation to death from any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Peritumoalbrainedema (PTBE)</measure>
    <time_frame>4 weeks after Radiotherapy.</time_frame>
    <description>PTBE volume was measured in a similar manner by measuring the high SI region in T2WI that was clearly distinguished from normal tissues, including the tumor. Edema index was calculated by dividing the PTBE volume by tumor volume. The Edema index represents the degree of the PTBE, compared to tumor volume, with an index of 1.0 indicating no PTBE development.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">90</enrollment>
  <condition>NSCLC</condition>
  <arm_group>
    <arm_group_label>Apatinib combined with Radiotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Drugs: Apatinib Apatinib (500 mg/d) was given orally for one week before the brain radiotherapy, and then, continued to be administered at the same way during the brain radiotherapy period (3 weeks). It was given for another one week after the end of the brain radiotherapy.&#xD;
Radiotherapy: Intensity-modulated radiotherapy (IMRT).&#xD;
According to the patients KPS score, GPA score, the number and size of metastatic lesions can be selected:&#xD;
37.5Gy/15 fractions of whole brain irradiation for multiple brain metastases were more than 5;&#xD;
The whole brain was irradiated with 37.5Gy/15 and simultaneous integrated boost dose of 52.5Gy/15 to patients with 1-5 metastatic lesions.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Radiotherapy alone</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Radiotherapy: Intensity-modulated radiotherapy (IMRT).&#xD;
According to the patients KPS score, GPA score, the number and size of metastatic lesions can be selected:&#xD;
37.5Gy/15 fractions of whole brain irradiation for multiple brain metastases were more than 5;&#xD;
The whole brain was irradiated with 37.5Gy/15 and simultaneous integrated boost dose of 52.5Gy /15 to patients with 1-5 metastatic lesions.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Apatinib</intervention_name>
    <description>radiotherapy with Apatinib</description>
    <arm_group_label>Apatinib combined with Radiotherapy</arm_group_label>
    <other_name>Apatinib Mesylate</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 18-75 years old, male or female, signed informed consent;&#xD;
&#xD;
          2. The primary lesion is confirmed by histopathology. The patient with brain metastases&#xD;
             confirmed by histopathology or imaging confirmed the brain metastases. All patients&#xD;
             with non-small cell lung cancer brain metastases should be recommended for EGFR&#xD;
             mutation and ALK gene rearrangement assay，exclusion of patients with NSCLC brain&#xD;
             metastases with positive EGFR-sensitive mutations and ALK gene rearrangement detection&#xD;
             for TKI treatment; After multidisciplinary consultation and evaluation, patients with&#xD;
             single or local multiple metastatic tumors with well-controlled primary lesions, who&#xD;
             have the economic ability and are willing to undergo surgery for brain metastatic&#xD;
             tumors were excluded.&#xD;
&#xD;
          3. Observable imaging data such as CT, MRI, etc., have measurable lesions as defined by&#xD;
             RECIST 1.1 (R09-0262);&#xD;
&#xD;
          4. ECOG PS score: 0-2;&#xD;
&#xD;
          5. Hemogram index: RBC≥3.0×1012/L, WBC≥3.5×109/L, ANC≥1.5×109/L, PLT≥100×109/L, Hb≥90g/L&#xD;
&#xD;
          6. the expected survival time ≥ 3 months&#xD;
&#xD;
          7. Renal function: Cr≤1.2×UNL (upper limit of normal value);&#xD;
&#xD;
          8. Liver function: total bilirubin ≤ 1.5 × UNL; ALT, AST ≤ 1.5 × UNL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. . Allergies, known to be hypersensitive to any excipients in the study drug. ;&#xD;
&#xD;
          2. . Patients with recurrent brain metastases have previously received brain radiation&#xD;
             therapy&#xD;
&#xD;
          3. . Patients with high fever and acute infection;&#xD;
&#xD;
          4. . Patients with active, progressive bleeding or a significant bleeding tendency in the&#xD;
             primary lesion;&#xD;
&#xD;
          5. . Participated in any clinical trial of research drugs within 4 weeks prior to&#xD;
             enrollment&#xD;
&#xD;
          6. . Diarrhea is the main symptom of the important or newly diagnosed acute&#xD;
             gastrointestinal diseases, such as Crohn's disease, malabsorption or any cause of CTC&#xD;
             ≥ 2 grade diarrhea.&#xD;
&#xD;
          7. . Current clinically relevant cardiovascular disease or medical history, such as&#xD;
             refractory hypertension, NYHA grade 3 congestive heart failure, unstable angina or&#xD;
             poorly controlled arrhythmias. Myocardial infarction occurred 6 months before&#xD;
             randomization.&#xD;
&#xD;
          8. . Absolute neutrophil count &lt;1000/mm3;&#xD;
&#xD;
          9. . Platelet count &lt;50000/mm3;&#xD;
&#xD;
         10. . According to the investigator's point of view, any other serious disease or organ&#xD;
             system dysfunction that may affect patient safety or interfere with the safety&#xD;
             assessment of the test drug, such as proteinuria (CTCAE4.0-≥3), severe liver and&#xD;
             kidney dysfunction (CTCAE4.0-≥3), hand-foot syndrome (CTCAE4.0-≥3) and so on.&#xD;
&#xD;
         11. . There are ulcers, intestinal perforations, and intestinal obstruction.&#xD;
&#xD;
         12. . Pregnant and lactating women&#xD;
&#xD;
         13. . Suspected or indeed have a history of alcohol and drug abuse&#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>Desheng Hu</last_name>
    <role>Study Director</role>
    <affiliation>Associate dean</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hubei Cancer hospital</name>
      <address>
        <city>Wuhan</city>
        <state>Hubei</state>
        <zip>430079</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>December 30, 2018</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>February 4, 2022</last_update_submitted>
  <last_update_submitted_qc>February 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hubei Cancer Hospital</investigator_affiliation>
    <investigator_full_name>HAN GUANG</investigator_full_name>
    <investigator_title>Radiation Oncologist</investigator_title>
  </responsible_party>
  <keyword>Brain metastasis</keyword>
  <keyword>Apatinib</keyword>
  <keyword>Radiotherapy</keyword>
  <keyword>NSCLC</keyword>
  <keyword>Drive gene negative</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>Apatinib</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/NCT03801200
org study id: HBCH RT-2019-01
nct id: NCT03801200
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to evaluate the efficacy and safety of concurrent radiotherapy
      with Apatinib in patients with Brain Metastases from drive gene wide-type Non-small-cell Lung
      Cancer (NSCLC).
Brain metastases (BM) develop in 22-54% of NSCLC patients during the disease course. NSCLC
      patients with BM with a median overall survival (OS) of 2-3 months when treated with systemic
      corticosteroid alone, and a median OS of 3-6 months when treated with whole brain radiation
      therapy (WBRT). Recently, several studies have reported the benefits of epidermal growth
      factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for EGFR mutation NSCLC patients
      with BM. The median OS of EGFR mutation patients with BM significantly improved with TKIs
      treatment, which ranged from 11.8 to 18.8 months. However, for the EGFR wide-type NSCLC
      patients with BM, the prognosis remains poor.

      It was found that the combination of anti-VEGF drugs and brain radiotherapy can not only
      reduce the volume of peritumoral brain edema (PTBE), reduce the intracranial pressure,
      relieve the symptoms of nerve compression, reduce the risk of brain hernia during brain
      radiotherapy, and but also inhibit the hypoxia of tumor cells, increase the radiosensitivity
      of tumor cells, and ultimately improve the efficacy of radiotherapy.

      Apatinib, a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial
      growth factor receptor (VEGFR) and mildly inhibits c-Kit and c-SRC, has been reported to show
      efficacy among some patients with malignant supratentorial gliomas.

      Therefore, the investigators initiated this study to evaluate the efficacy and safety of
      concurrent radiotherapy with Apatinib in patients with Brain Metastases from drive gene
      wide-type Non-small-cell Lung Cancer (NSCLC).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Intracranial progression-free survival (iPFS)
time frame: Evaluated in 24 months since the treatment began
description: Defined as the time from randomisation to progression of intracranial disease or death from any cause.
measure: Disease control rate (DCR)
time frame: 4 weeks after Radiotherapy.
description: Proportion of patients with reduction or keeping in stable in tumor burden of a predefined amount
measure: Objective response rate (ORR)
time frame: 4 weeks after Radiotherapy.
description: Proportion of patients with reduction in tumor burden of a predefined amount
measure: intracranial time to progress (ITTP)
time frame: Tumor assesment at 4 weeks and 12 weeks after radiotherapy, and then every 12 weeks, up to 24 months
description: Defined as the time from randomisation to progression of intracranial disease
measure: Overall survival (OS)
time frame: Tumor assesment at 4 weeks and 12 weeks after radiotherapy, and then every 12 weeks, up to 24 months
description: Defined as the time from randomisation to death from any cause
measure: Rate of Peritumoalbrainedema (PTBE)
time frame: 4 weeks after Radiotherapy.
description: PTBE volume was measured in a similar manner by measuring the high SI region in T2WI that was clearly distinguished from normal tissues, including the tumor. Edema index was calculated by dividing the PTBE volume by tumor volume. The Edema index represents the degree of the PTBE, compared to tumor volume, with an index of 1.0 indicating no PTBE development.
arm group label: Apatinib combined with Radiotherapy
arm group type: Experimental
description: Drugs: Apatinib Apatinib (500 mg/d) was given orally for one week before the brain radiotherapy, and then, continued to be administered at the same way during the brain radiotherapy period (3 weeks). It was given for another one week after the end of the brain radiotherapy.
Radiotherapy: Intensity-modulated radiotherapy (IMRT).
According to the patients KPS score, GPA score, the number and size of metastatic lesions can be selected:
37.5Gy/15 fractions of whole brain irradiation for multiple brain metastases were more than 5;
The whole brain was irradiated with 37.5Gy/15 and simultaneous integrated boost dose of 52.5Gy/15 to patients with 1-5 metastatic lesions.
arm group label: Radiotherapy alone
arm group type: No Intervention
description: Radiotherapy: Intensity-modulated radiotherapy (IMRT).
According to the patients KPS score, GPA score, the number and size of metastatic lesions can be selected:
37.5Gy/15 fractions of whole brain irradiation for multiple brain metastases were more than 5;
The whole brain was irradiated with 37.5Gy/15 and simultaneous integrated boost dose of 52.5Gy /15 to patients with 1-5 metastatic lesions.
intervention type: Drug
intervention name: Apatinib
description: radiotherapy with Apatinib
arm group label: Apatinib combined with Radiotherapy
other name: Apatinib Mesylate
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Desheng Hu
role: Study Director
affiliation: Associate dean
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Hubei Cancer Hospital
investigator full name: HAN GUANG
investigator title: Radiation Oncologist
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Apatinib