<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/NCT03257124</url>
  </required_header>
  <id_info>
    <org_study_id>2016-09-058</org_study_id>
    <nct_id>NCT03257124</nct_id>
  </id_info>
  <brief_title>Study of AZD9291 in NSCLC Patients Harboring T790M Mutation Who Failed EGFR TKI and With Brain and/or LMS</brief_title>
  <official_title>An Open Label, Multicenter, Phase II Study of AZD9291 in Non-small Cell Lung Cancer (NSCLC) Patients Harboring T790M Mutation Who Failed EGFR TKIs and With Brain and/or Leptomeningeal Metastasis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Samsung Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Samsung Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and&#xD;
      T790M resistance mutation but sparing wild-type EGFR. Preclinical studies indicate that&#xD;
      AZD9291 has significant exposure in the brain and activity against EGFR mutant brain&#xD;
      metastasis. In addition, anti-tumor activities of AZD9291 in patients with advanced stage&#xD;
      EGFR mutant NSCLC including patients with brain metastasis have been reported in an ongoing&#xD;
      Phase I study. More recently, AZD9291 at a dose of 160mg also showed promising efficacy in&#xD;
      heavily pre-treated patients with leptomeningeal disease from EGFR mutant NSCLC. Among 11&#xD;
      evaluable for response, 6 patients had LM imaging improvement and 3 out of 7 patients with&#xD;
      abnormal neurological exam at baseline had symptomatic improvement. Compared to AZD9291,&#xD;
      other 3rd generation EGFR TKIs, rociletinib or HM61713 has not been reported to be effective&#xD;
      in most of CNS disease of NSCLC. Further, previous studies with AZD9291 showed anecdotal case&#xD;
      series or undetermined for T790M mutation status, indicating more systematic study is&#xD;
      warranted.&#xD;
&#xD;
      Based on these data, the investigators are going to conduct phase II study of AZD9291 in&#xD;
      NSCLC patients harboring T790M mutation who failed EGFR TKIs and brain and/or leptomeningeal&#xD;
      metastasis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. Primary end points&#xD;
&#xD;
             -  Overall response rate (ORR) in CNS -brain metastasis cohort&#xD;
&#xD;
             -  Overall survival - Leptomeningeal with or without brain metastasis cohort&#xD;
&#xD;
        2. Secondary end points&#xD;
&#xD;
             -  Whole body disease control rate (DCR)&#xD;
&#xD;
             -  Time to brain progression&#xD;
&#xD;
             -  Progression free survival (PFS) in BM cohort&#xD;
&#xD;
             -  Overall survival (OS)&#xD;
&#xD;
             -  Adverse events (AEs)&#xD;
&#xD;
             -  Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal&#xD;
                fluid (CSF)&#xD;
&#xD;
        3. Treatment AZD9291 160mg po daily (1 cycle of 28 days)&#xD;
&#xD;
        4. Total patient sample size Eligible patients will be divided into two cohorts, brain&#xD;
           metastasis (BM) cohort and leptomeningeal metastasis (LM) with or without BM cohort. The&#xD;
           two patient cohorts use different primary endpoints.&#xD;
&#xD;
        5. BM cohort For the BM cohort, the primary outcome is overall response (CR+PR). Let P&#xD;
           denote the overall response rate of AZD9291. From some preliminary data of response in&#xD;
           the brain or leptomeningeal seeding with AZD 9291 in phase II AURA and BLOOM study, we&#xD;
           hypothesized that H0:P= 10% and H1:P =30%. The BM cohort uses Simon's optimal two-stage&#xD;
           design as follows.&#xD;
&#xD;
           Stage 1: Treat n1 = 18 patients. If r1 = 2 or fewer patients respond, stop the BM cohort&#xD;
           concluding that the study therapy is inefficacious. Otherwise, proceed to Stage 2.&#xD;
&#xD;
           Stage 2: Treat additional n2 = 17 patients. If r = 6 or fewer patients respond among the&#xD;
           cumulative n1 + n2 = 35 patients, then conclude that the study therapy is inefficacious.&#xD;
           Otherwise, accept the study therapy for further investigation.&#xD;
&#xD;
           This design has 1-sided alpha = 5% for P0 = 10% and power = 90% for P1 = 30%.&#xD;
           Considering about 10%, of attrition due to ineligibility and dropout, a total of 40&#xD;
           patients will be enrolled into the BM cohort.&#xD;
&#xD;
        6. LM ± BM cohort&#xD;
&#xD;
           The primary outcome of the LM ± BM cohort is overall survival (OS). Let μ denote the&#xD;
           median OS of AZD9291 in this cohort. Based on some preliminary results (we need a&#xD;
           reference), we hypothesize that H0: μ=3 months vs. H1: μ=5 months. Assuming an&#xD;
           exponential OS distribution under H0, the investigators will conduct the 1-sample&#xD;
           log-rank test. In this cohort, the investigators expect an accrual rate of 30 patients&#xD;
           per year and about 10% of attrition, and will have an additional follow-up of 6 months&#xD;
           after completion of accrual. Under these assumptions, we need N=40 patients (D=29&#xD;
           deaths) for 90% of power by the 1-sample log-rank test with 1-sided alpha=5% (refer to&#xD;
           Kwak and Jung 2013). The trial of this cohort is expected to take about 22 months (=16&#xD;
           months for patient accrual + 6 months for additional follow-up).&#xD;
&#xD;
        7. Statistical analysis plan&#xD;
&#xD;
      The analysis is conducted separately for each cohort. OS, PFS, and time to brain progression&#xD;
      will be summarized by Kaplan-Meier method. DCR and AEs will be summarized using contingency&#xD;
      tables. Cohort specific analyses are conducted as follows.&#xD;
&#xD;
      BM cohort&#xD;
&#xD;
      Two-stage testing on ORR will be conducted as described in &quot;Target number&quot; section. If the&#xD;
      final sample size is different from n1=18 or n1 + n2=35, then a 1-sided p-value will be&#xD;
      calculated by Jung et al. (2006) and accept the experimental therapy if it is smaller than&#xD;
      alpha = 5%. The ORR will be unbiasedly estimated by Jung and Kim (2004), and its confidence&#xD;
      interval will be calculated by Jennison and Turnbull (1983).&#xD;
&#xD;
      LM ± BM cohort&#xD;
&#xD;
      The final analysis of this cohort will be conducted when D29 deaths are observed, which is&#xD;
      expected to be about 22 months from the study open. The investigators will conduct a 1-sample&#xD;
      log-rank test assuming the exponential OS distribution with a median of 3 months under H0.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">May 8, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Actual">August 31, 2019</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>Brain Metastasis cohort (BM cohort)&#xD;
Leptomeningeal Metastasis cohort (LM cohort)</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall response rate (ORR) in CNS -brain metastasis cohort</measure>
    <time_frame>December, 2019 (one-year follow-up from last patient -in)</time_frame>
    <description>At least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall survival - Leptomeningeal with or without brain metastasis cohort</measure>
    <time_frame>From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months</time_frame>
    <description>From the date of study start to the date of all cause death</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Whole body disease control rate (DCR)</measure>
    <time_frame>December, 2019 (one-year follow-up from last patient -in)</time_frame>
    <description>At least one visit response of CR (complete response), PR (partial response) or SD (stable disease) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to brain progression</measure>
    <time_frame>December, 2019 (one-year follow-up from last patient -in)</time_frame>
    <description>Time to brain progression is measured from the date of start of study to the date of progression of BM or LM.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS) in BM cohort</measure>
    <time_frame>December, 2019 (one-year follow-up from last patient -in)</time_frame>
    <description>measured from the date of start of study to the date of disease progression or death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>December, 2019 (one-year follow-up from last patient -in)</time_frame>
    <description>OS is measured from the date of start of study to the date of death from any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events (AEs)</measure>
    <time_frame>December, 2019 (one-year follow-up from last patient -in)</time_frame>
    <description>Adverse events will be measured by the CTCAE scale, version 4.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory analysis of EGFR mutation/T790M</measure>
    <time_frame>December, 2019 (one-year follow-up from last patient -in)</time_frame>
    <description>Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">80</enrollment>
  <condition>Non-Small Cell Lung Cancer With EGFR T790M Mutation</condition>
  <condition>With Brain and/or Leptomeningeal Metastasis</condition>
  <condition>Failed Tyrosine Kinase Inhibitors</condition>
  <arm_group>
    <arm_group_label>AZD9291 in BM or LM cohort in T790M positive</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Brain metastasis cohort (BM cohort)&#xD;
Leptomeningeal metastasis cohort (LM cohort)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD9291</intervention_name>
    <description>AZD9291 160mg per oral daily (1 cycle of 28 days)</description>
    <arm_group_label>AZD9291 in BM or LM cohort in T790M positive</arm_group_label>
    <other_name>Osimertinib</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  EGFR activating mutant NSCLC patients who failed EGFR TKIs (gefitinib, erlotinib, or&#xD;
             afatinib) and develop CNS disease (BM and/or LM) with T790M mutation either tissue or&#xD;
             plasma. For patients with intracranial progression, prior radiation therapy is not&#xD;
             mandatory. Extracranial progression is allowed.&#xD;
&#xD;
          -  Patients who failed to 3rd generation EGFR TKIs (AZD9291 (80mg), Rociletinib, HM61713)&#xD;
             and develop CNS progression but stable extracranial disease&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  ECOG performance status of 0 to 2&#xD;
&#xD;
          -  For BM, at least one measurable intracranial lesion as ≥ 10mm in the longest diameter&#xD;
             by magnetic resonance imaging (MRI)&#xD;
&#xD;
          -  For LM, at least one site of CNS leptomeningeal disease that can be assessed by MRI&#xD;
&#xD;
          -  Adequate organ function as evidenced by the following;&#xD;
&#xD;
               -  Absolute neutrophil count &gt; 1.5 x 109/L;&#xD;
&#xD;
               -  platelets &gt; 100 x 109/L;&#xD;
&#xD;
               -  total bilirubin ≤1.5 UNL;&#xD;
&#xD;
               -  AST and/or ALT &lt; 5 UNL;&#xD;
&#xD;
               -  CCr ≥ 50mL/min.&#xD;
&#xD;
          -  Female subjects must either be of non-reproductive potential&#xD;
&#xD;
          -  Subject is willing and able to comply with the protocol&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a&#xD;
             limited field of radiation for palliation within 1 week&#xD;
&#xD;
          -  Any unresolved toxicities from prior therapy, greater than CTCAE grade 1&#xD;
&#xD;
          -  Mean QT interval corrected for heart rate (QTc) ≥ 470 ms&#xD;
&#xD;
          -  Uncontrolled systemic illness including uncontrolled hypertension, active bleeding, or&#xD;
             active infection.&#xD;
&#xD;
          -  Past medical history of interstitial lung disease, drug induced interstitial lung&#xD;
             disease, radiation pneumonitis which required steroid treatment&#xD;
&#xD;
          -  History of hypersensitivity to AZD9291&#xD;
&#xD;
          -  Known intracranial haemorrahge which is unrelated to tumor Refractory nausea and&#xD;
             vomiting&#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>Myung-Ju Ahn, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Samsung Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine</name>
      <address>
        <city>Seoul</city>
        <zip>135-710</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <reference>
    <citation>Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57. doi: 10.1056/NEJMoa0810699. Epub 2009 Aug 19.</citation>
    <PMID>19692680</PMID>
  </reference>
  <reference>
    <citation>Bonomi PD. Implications of key trials in advanced nonsmall cell lung cancer. Cancer. 2010 Mar 1;116(5):1155-64. doi: 10.1002/cncr.24815.</citation>
    <PMID>20087963</PMID>
  </reference>
  <reference>
    <citation>Mok TS. Personalized medicine in lung cancer: what we need to know. Nat Rev Clin Oncol. 2011 Aug 23;8(11):661-8. doi: 10.1038/nrclinonc.2011.126.</citation>
    <PMID>21862980</PMID>
  </reference>
  <reference>
    <citation>Lee SJ, Lee JI, Nam DH, Ahn YC, Han JH, Sun JM, Ahn JS, Park K, Ahn MJ. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol. 2013 Feb;8(2):185-91. doi: 10.1097/JTO.0b013e3182773f21.</citation>
    <PMID>23328548</PMID>
  </reference>
  <reference>
    <citation>Lee E, Keam B, Kim DW, Kim TM, Lee SH, Chung DH, Heo DS. Erlotinib versus gefitinib for control of leptomeningeal carcinomatosis in non-small-cell lung cancer. J Thorac Oncol. 2013 Aug;8(8):1069-74. doi: 10.1097/JTO.0b013e318294c8e8.</citation>
    <PMID>23804027</PMID>
  </reference>
  <reference>
    <citation>Gow CH, Chien CR, Chang YL, Chiu YH, Kuo SH, Shih JY, Chang YC, Yu CJ, Yang CH, Yang PC. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008 Jan 1;14(1):162-8. doi: 10.1158/1078-0432.CCR-07-1468.</citation>
    <PMID>18172267</PMID>
  </reference>
  <reference>
    <citation>Wu YL, Zhou C, Cheng Y, Lu S, Chen GY, Huang C, Huang YS, Yan HH, Ren S, Liu Y, Yang JJ. Erlotinib as second-line treatment in patients with advanced non-small-cell lung cancer and asymptomatic brain metastases: a phase II study (CTONG-0803). Ann Oncol. 2013 Apr;24(4):993-9. doi: 10.1093/annonc/mds529. Epub 2012 Nov 4.</citation>
    <PMID>23129122</PMID>
  </reference>
  <reference>
    <citation>Umemura S, Tsubouchi K, Yoshioka H, Hotta K, Takigawa N, Fujiwara K, Horita N, Segawa Y, Hamada N, Takata I, Yamane H, Kamei H, Kiura K, Tanimoto M. Clinical outcome in patients with leptomeningeal metastasis from non-small cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer. 2012 Jul;77(1):134-9. doi: 10.1016/j.lungcan.2012.03.002. Epub 2012 Apr 7.</citation>
    <PMID>22487432</PMID>
  </reference>
  <reference>
    <citation>Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005 Mar;2(3):e73. doi: 10.1371/journal.pmed.0020073. Epub 2005 Feb 22.</citation>
    <PMID>15737014</PMID>
  </reference>
  <reference>
    <citation>Planchard D, Loriot Y, Andre F, Gobert A, Auger N, Lacroix L, Soria JC. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015 Oct;26(10):2073-8. doi: 10.1093/annonc/mdv319. Epub 2015 Aug 12.</citation>
    <PMID>26269204</PMID>
  </reference>
  <reference>
    <citation>Janne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. doi: 10.1056/NEJMoa1411817.</citation>
    <PMID>25923549</PMID>
  </reference>
  <reference>
    <citation>Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61. doi: 10.1158/2159-8290.CD-14-0337. Epub 2014 Jun 3.</citation>
    <PMID>24893891</PMID>
  </reference>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>May 7, 2017</study_first_submitted>
  <study_first_submitted_qc>August 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 22, 2017</study_first_posted>
  <last_update_submitted>August 8, 2021</last_update_submitted>
  <last_update_submitted_qc>August 8, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 16, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Samsung Medical Center</investigator_affiliation>
    <investigator_full_name>Myung-Ju Ahn</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Meningeal Carcinomatosis</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>
  </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/NCT03257124
org study id: 2016-09-058
nct id: NCT03257124
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and
      T790M resistance mutation but sparing wild-type EGFR. Preclinical studies indicate that
      AZD9291 has significant exposure in the brain and activity against EGFR mutant brain
      metastasis. In addition, anti-tumor activities of AZD9291 in patients with advanced stage
      EGFR mutant NSCLC including patients with brain metastasis have been reported in an ongoing
      Phase I study. More recently, AZD9291 at a dose of 160mg also showed promising efficacy in
      heavily pre-treated patients with leptomeningeal disease from EGFR mutant NSCLC. Among 11
      evaluable for response, 6 patients had LM imaging improvement and 3 out of 7 patients with
      abnormal neurological exam at baseline had symptomatic improvement. Compared to AZD9291,
      other 3rd generation EGFR TKIs, rociletinib or HM61713 has not been reported to be effective
      in most of CNS disease of NSCLC. Further, previous studies with AZD9291 showed anecdotal case
      series or undetermined for T790M mutation status, indicating more systematic study is
      warranted.

      Based on these data, the investigators are going to conduct phase II study of AZD9291 in
      NSCLC patients harboring T790M mutation who failed EGFR TKIs and brain and/or leptomeningeal
      metastasis.
1. Primary end points

             -  Overall response rate (ORR) in CNS -brain metastasis cohort

             -  Overall survival - Leptomeningeal with or without brain metastasis cohort

        2. Secondary end points

             -  Whole body disease control rate (DCR)

             -  Time to brain progression

             -  Progression free survival (PFS) in BM cohort

             -  Overall survival (OS)

             -  Adverse events (AEs)

             -  Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal
                fluid (CSF)

        3. Treatment AZD9291 160mg po daily (1 cycle of 28 days)

        4. Total patient sample size Eligible patients will be divided into two cohorts, brain
           metastasis (BM) cohort and leptomeningeal metastasis (LM) with or without BM cohort. The
           two patient cohorts use different primary endpoints.

        5. BM cohort For the BM cohort, the primary outcome is overall response (CR+PR). Let P
           denote the overall response rate of AZD9291. From some preliminary data of response in
           the brain or leptomeningeal seeding with AZD 9291 in phase II AURA and BLOOM study, we
           hypothesized that H0:P= 10% and H1:P =30%. The BM cohort uses Simon's optimal two-stage
           design as follows.

           Stage 1: Treat n1 = 18 patients. If r1 = 2 or fewer patients respond, stop the BM cohort
           concluding that the study therapy is inefficacious. Otherwise, proceed to Stage 2.

           Stage 2: Treat additional n2 = 17 patients. If r = 6 or fewer patients respond among the
           cumulative n1 + n2 = 35 patients, then conclude that the study therapy is inefficacious.
           Otherwise, accept the study therapy for further investigation.

           This design has 1-sided alpha = 5% for P0 = 10% and power = 90% for P1 = 30%.
           Considering about 10%, of attrition due to ineligibility and dropout, a total of 40
           patients will be enrolled into the BM cohort.

        6. LM ± BM cohort

           The primary outcome of the LM ± BM cohort is overall survival (OS). Let μ denote the
           median OS of AZD9291 in this cohort. Based on some preliminary results (we need a
           reference), we hypothesize that H0: μ=3 months vs. H1: μ=5 months. Assuming an
           exponential OS distribution under H0, the investigators will conduct the 1-sample
           log-rank test. In this cohort, the investigators expect an accrual rate of 30 patients
           per year and about 10% of attrition, and will have an additional follow-up of 6 months
           after completion of accrual. Under these assumptions, we need N=40 patients (D=29
           deaths) for 90% of power by the 1-sample log-rank test with 1-sided alpha=5% (refer to
           Kwak and Jung 2013). The trial of this cohort is expected to take about 22 months (=16
           months for patient accrual + 6 months for additional follow-up).

        7. Statistical analysis plan

      The analysis is conducted separately for each cohort. OS, PFS, and time to brain progression
      will be summarized by Kaplan-Meier method. DCR and AEs will be summarized using contingency
      tables. Cohort specific analyses are conducted as follows.

      BM cohort

      Two-stage testing on ORR will be conducted as described in "Target number" section. If the
      final sample size is different from n1=18 or n1 + n2=35, then a 1-sided p-value will be
      calculated by Jung et al. (2006) and accept the experimental therapy if it is smaller than
      alpha = 5%. The ORR will be unbiasedly estimated by Jung and Kim (2004), and its confidence
      interval will be calculated by Jennison and Turnbull (1983).

      LM ± BM cohort

      The final analysis of this cohort will be conducted when D29 deaths are observed, which is
      expected to be about 22 months from the study open. The investigators will conduct a 1-sample
      log-rank test assuming the exponential OS distribution with a median of 3 months under H0.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Brain Metastasis cohort (BM cohort)
Leptomeningeal Metastasis cohort (LM cohort)
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate (ORR) in CNS -brain metastasis cohort
time frame: December, 2019 (one-year follow-up from last patient -in)
description: At least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria
measure: Overall survival - Leptomeningeal with or without brain metastasis cohort
time frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
description: From the date of study start to the date of all cause death
measure: Whole body disease control rate (DCR)
time frame: December, 2019 (one-year follow-up from last patient -in)
description: At least one visit response of CR (complete response), PR (partial response) or SD (stable disease) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria.
measure: Time to brain progression
time frame: December, 2019 (one-year follow-up from last patient -in)
description: Time to brain progression is measured from the date of start of study to the date of progression of BM or LM.
measure: Progression free survival (PFS) in BM cohort
time frame: December, 2019 (one-year follow-up from last patient -in)
description: measured from the date of start of study to the date of disease progression or death from any cause.
measure: Overall survival (OS)
time frame: December, 2019 (one-year follow-up from last patient -in)
description: OS is measured from the date of start of study to the date of death from any cause
measure: Adverse events (AEs)
time frame: December, 2019 (one-year follow-up from last patient -in)
description: Adverse events will be measured by the CTCAE scale, version 4.
measure: Exploratory analysis of EGFR mutation/T790M
time frame: December, 2019 (one-year follow-up from last patient -in)
description: Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF)
arm group label: AZD9291 in BM or LM cohort in T790M positive
arm group type: Experimental
description: Brain metastasis cohort (BM cohort)
Leptomeningeal metastasis cohort (LM cohort)
intervention type: Drug
intervention name: AZD9291
description: AZD9291 160mg per oral daily (1 cycle of 28 days)
arm group label: AZD9291 in BM or LM cohort in T790M positive
other name: Osimertinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Myung-Ju Ahn, Professor
role: Principal Investigator
affiliation: Samsung Medical Center
facility: 
country: Korea, Republic of
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PMID: 23804027
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citation: Planchard D, Loriot Y, Andre F, Gobert A, Auger N, Lacroix L, Soria JC. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol. 2015 Oct;26(10):2073-8. doi: 10.1093/annonc/mdv319. Epub 2015 Aug 12.
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PMID: 24893891
responsible party type: Principal Investigator
investigator affiliation: Samsung Medical Center
investigator full name: Myung-Ju Ahn
investigator title: Professor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Neoplasm Metastasis
mesh term: Meningeal Carcinomatosis
mesh term: Osimertinib
sharing ipd: No