<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/NCT02228369</url>
  </required_header>
  <id_info>
    <org_study_id>D6030C00001</org_study_id>
    <nct_id>NCT02228369</nct_id>
  </id_info>
  <brief_title>Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, AZD3759 or AZD9291, in Patients Who Have Advanced Non-Small Cell Lung Cancer</brief_title>
  <acronym>BLOOM</acronym>
  <official_title>A Phase I, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumour Activity of AZD3759 or AZD9291 in Patients With EGFR Mutation Positive Advanced Stage Non Small Cell Lung Cancer (NSCLC)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AstraZeneca</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is the first time in patient study to assess the safety, tolerability and preliminary&#xD;
      efficacy of AZD3759 in patients with advanced Non Small Cell Lung Cancer (NSCLC) In this&#xD;
      study, patients with Leptomeningeal Metastasis and Brain Metastasis may also be enrolled to&#xD;
      assess the anti-tumour efficacy, safety, pharmacokinetics and potential biological activity&#xD;
      of AZD9291&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics&#xD;
      and Preliminary Anti-Tumour Activity of AZD3759 or AZD9291 in Patients with EGFR Mutation&#xD;
      Positive Advanced Stage Non Small Cell Lung Cancer (NSCLC) who failed standard treatment and&#xD;
      developed brain or leptomeningeal diseases&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 5, 2014</start_date>
  <completion_date type="Actual">October 28, 2020</completion_date>
  <primary_completion_date type="Actual">August 19, 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and Tolerability (The number of patients with each AE by system organ class, preferred term and CTCAE grade)</measure>
    <time_frame>From Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.</time_frame>
    <description>Adverse events will be collected from Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.Physical exam (screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation). ECG and vital signs (screening, Day 1 and 2 of Cycle 0 for AZD3759 cohorts, Day 8 of Cycle 1 for AZD3759 cohorts, Day 1 of every 3-week cycle, treatment discontinuation, and if occurrence of any cardiac adverse event). Lab variables (screening, first dosing day, Day 1, 8 and 15 of multiple dosing, Day 1 of every 3-week cycle and treatment discontinuation). Eye exam (at screening and study drug discontinuation and upon occurrence of any visual AE). Echocardiogram or multigated radionuclide angiography (at screening,whenever necessary as clinically indicated throughout the study for AZD3759 cohorts.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma concentration of AZD3759 and metabolite and pharmacokinetics parameters after single dose of AZD3759(Cmax, tmax, terminal rate constant, half life, AUC, clearance, volume of distribution, mean residence time)</measure>
    <time_frame>Cycle 0 Day 1 to 3 in Part A patients.</time_frame>
    <description>The parent drug and N-demethylated metabolite in plasma samples will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, hour in Day 1; 24hour in Day 2 and 48hour in Day 3.&#xD;
AUC: Area Under Curve</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma,urine,cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).</measure>
    <time_frame>Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A. CSF samples: pre-dose of Cycle 1 Day 8 in BM; Pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in LM</time_frame>
    <description>The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1 . The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients. AUCss: Area Under Curve Steady State CLss: Clearance Steady State</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma,urine, cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)</measure>
    <time_frame>Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A patients. CSF samples: pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in Part B patients .</time_frame>
    <description>The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1. The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma, cerebrospinal fluid concentration of AZD9291 and metabolite and pharmacokinetics parameters after multiple dose of AZD9291(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).</measure>
    <time_frame>Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.</time_frame>
    <description>The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma, cerebrospinal fluid concentration of AZD9291 and metabolites and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)</measure>
    <time_frame>Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.</time_frame>
    <description>The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival follow up for all expansion patients</measure>
    <time_frame>Every 6 weeks after the 28- day safety follow-up visit</time_frame>
    <description>After 28-day follow-up visit, patients will be followed for overall survival via telephone every 6 weeks until death, lost to follow-up or consent withdrawal</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>4b-hydroxy cholesterol in Part B patients with BM</measure>
    <time_frame>pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15</time_frame>
    <description>Blood collection at pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15 to evaluate if AZD3759 affects 4b-hydroxy cholesterol which is an endogenous marker of CYP enzyme induction</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The effect of food on the pharmacokinetics of a single dose of AZD3759 in plasma</measure>
    <time_frame>Cycle 0 Day 1 to Day 4 in Part B patients with BM</time_frame>
    <description>Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hour of Cycle 0 Day 1and Day 4; 24 hour of Cycle 0 Day 2 and Day 4.A Mixed Effects model with treatment (fed/fasted) and period as fixed effects and patient as a random effect will be used to compare AUC/Cmax in the fed state with AUC/Cmax in the fasted state.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebrospinal fluid response rate for patients with LM and/or BM</measure>
    <time_frame>Screening and every 6 weeks (relative to first dose of multiple dosing) until progression, expected average 6 months</time_frame>
    <description>Cerebrospinal fluid collection at screening and every 6 weeks until progression to evaluate the cerebrospinal fluid response rate which is defined as the percentage of leptomeningeal metastasis patients who have at least one cerebrospinal fluid response (100% clearance of tumour cells from cerebrospinal</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline in central nervous system symptoms (analyzed from QLQ-BN20) in patients with LM treated with AZD3759 /AZD9291</measure>
    <time_frame>Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.</time_frame>
    <description>Quality of life questionnaire-Brain Cancer 20 questionnaire completed by patients at screening, Day 1 of every 3-week cycle and treatment discontinuation. Use relevant symptom questions to evaluate improvement of central nervous system symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline in neurological exam in patients with LM treated with AZD3759 /AZD9291</measure>
    <time_frame>Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.</time_frame>
    <description>Neurological exam will be performed: screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of Objective Response Rate (ORR)</measure>
    <time_frame>Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.</time_frame>
    <description>ORR assessed through the number of patients who achieve a disease response (i.e. complete response or partial response) assessed according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease and overall disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of Disease Control Rate (DCR)</measure>
    <time_frame>Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.</time_frame>
    <description>DCR assessed through the number of patients who achieve a best response of confirmed CR, confirmed PR or responding, or stable disease according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease, leptomeningeal disease and overall disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of Response Rate (RR)</measure>
    <time_frame>Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.</time_frame>
    <description>RR assessed through the number of patients who have at least one confirmed response of Complete Response or Responding prior to any evidence of progression according to modified RECIST 1.1 criteria for leptomeningeal disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of Progression Free Survival (PFS)</measure>
    <time_frame>Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.</time_frame>
    <description>PFS assessed through change in tumour size (as well as assessment of non-target lesions and appearance of any new lesions) according to modified RECIST 1.1 criteria for Part B patients with brain metastasis and patients with leptomeningeal metastasis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best Leptomeningeal Metastasis (LM) assessment for AZD9291 LM patients</measure>
    <time_frame>Screening within 28days</time_frame>
    <description>Best LM assessment via LANO criteria through the number of patients with LM present at baseline, without a requirement for confirmation. LANO assessments will be mapped to RECIST-like scores and performed via central imaging reading.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">108</enrollment>
  <condition>EGFR Mutation Positive Advanced Non Small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>Daily dose of AZD3759</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Daily oral dose of AZD3759</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Daily Dose of AZD9291</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Daily oral dose of AZD9291</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD3759</intervention_name>
    <description>Starting dose 50 mg, administered twice daily. If tolerated subsequent cohorts will test increasing doses of AZD3759, until a maximum tolerated dose or an effective dose is defined</description>
    <arm_group_label>Daily dose of AZD3759</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD9291</intervention_name>
    <description>AZD9291 160mg once daily</description>
    <arm_group_label>Daily Dose of AZD9291</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Obtained written informed consent&#xD;
&#xD;
          2. Male or female aged at least 18 years. Aged at least 20 if Japanese.&#xD;
&#xD;
          3. Histologically or cytologically confirmed diagnosis of NSCLC with single activating&#xD;
             EGFR mutations (L858R or Exon19Del).&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group performance status of 0 to1. For LM patients, 0 to&#xD;
             2 is acceptable.&#xD;
&#xD;
          5. In Part A, prior treatment with at least one line of a single agent EGFR TKI and at&#xD;
             least 1 line of chemotherapy.&#xD;
&#xD;
          6. In Part B-BM expansion, patients must have not received any EGFR TKI and have&#xD;
             asymptomatic brain metastasis, either found during screening process which does not&#xD;
             require local treatment in the opinion of the investigator or local treatment has been&#xD;
             given (surgery or radiation), patient must be stable without corticosteroid and/or&#xD;
             anti-convulsants treatment for at least 2 weeks before study enrollment. For Part B-LM&#xD;
             expansion, patients who received previous EGFR TKI treatment must have stable&#xD;
             extracranial disease;EGFR TKI treatment naïve patients can also be enrolled into&#xD;
             AZD9291 cohorts, or AZD3759 cohorts if efficacy signal seen in Part A and agreed by&#xD;
             Safety Review Committee.&#xD;
&#xD;
          7. For patients with neither LM nor measurable BM: At least one measurable extracranial&#xD;
             lesion. For patients with measurable BM but without LM: at least one measurable&#xD;
             intracranial lesion&#xD;
&#xD;
          8. For patients with LM: Confirmed diagnosis of LM by positive CSF cytology.&#xD;
&#xD;
          9. Male patients should be willing to use barrier contraception, i.e., condoms, until 3&#xD;
             months after last study drug is taken.&#xD;
&#xD;
         10. Females should agree to use adequate contraceptive measures, should not be breast&#xD;
             feeding and must have a negative pregnancy test prior to start of dosing if of&#xD;
             child-bearing potential or must have evidence of non-child-bearing potential&#xD;
&#xD;
         11. In Part B-AZD9291 LM expansion (sub-cohort of T790M+ LM patients), patients must have&#xD;
             central confirmation of T790M+ mutation status from a sample taken after documented&#xD;
             progression on the last treatment administered prior to enrolling in the study.&#xD;
             Patients must have received prior therapy with an EGFR TKI and may also have received&#xD;
             additional lines of treatment. Stable extracranial disease is not required.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. For patients with LM and/or BM, CNS complications that require urgent neurosurgical&#xD;
             intervention&#xD;
&#xD;
          2. For patient with LM, inability to undergo collection of CSF&#xD;
&#xD;
          3. Treatment with an EGFR TKI (e.g., erlotinib or gefitinib) within 8 days or&#xD;
             approximately 5 x half-life, whichever is the longer, of the first dose of study&#xD;
             treatment.&#xD;
&#xD;
          4. Any cytotoxic chemotherapy,or other anticancer drugs for the treatment of advanced&#xD;
             NSCLC from a previous treatment regimen within 14 days of the first dose of study&#xD;
             treatment&#xD;
&#xD;
          5. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a&#xD;
             limited field of radiation for palliation within 1 week of the first dose of study&#xD;
             treatment with the exception of patients receiving radiation to more than 30% of the&#xD;
             bone marrow which must be completed within 4 weeks of the first dose of study&#xD;
             treatment.&#xD;
&#xD;
          6. Patients currently receiving (or unable to stop use at least 1 week prior to receiving&#xD;
             the first dose of AZD3759/AZD9291) medications or herbal supplements known to be&#xD;
             potent inhibitors or inducers of cytochrome P450 3A4/5 and potential inhibitors of&#xD;
             cytochrome P450 2C8 (for patients to be enrolled into AZD9291 cohorts only).&#xD;
&#xD;
          7. Past medical history of interstitial lung disease, drug-induced interstitial lung&#xD;
             disease, radiation pneumonitis which required steroid treatment, or any evidence of&#xD;
             clinically active interstitial lung disease.&#xD;
&#xD;
          8. Known intracranial haemorrhage which is unrelated to tumour&#xD;
&#xD;
          9. Refractory nausea and vomiting if not controlled by supportive therapy, chronic&#xD;
             gastrointestinal diseases, inability to swallow the formulated product or previous&#xD;
             significant bowel resection that would preclude adequate absorption of AZD3759/AZD9291&#xD;
&#xD;
         10. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled&#xD;
             hypertension and active bleeding diatheses&#xD;
&#xD;
         11. Inadequate bone marrow reserve or organ function&#xD;
&#xD;
         12. Clinically significant ECG abnormalities or any factors that increase the risk of&#xD;
             corrected QT interval prolongation or risk of arrhythmic events&#xD;
&#xD;
         13. Prior history of whole brain radiotherapy (only applicable for AZD3759 BM expansion)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>130 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pamela Yang, M.D. PhD</last_name>
    <role>Study Director</role>
    <affiliation>Building 2, 199 Liangjing Road, Zhangjiang Hi-tech Park, Shanghai 201203, China</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Santa Monica</city>
        <state>California</state>
        <zip>90404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Camperdown</city>
        <zip>2050</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Heidelberg</city>
        <zip>3084</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seongnam-si</city>
        <zip>13620</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seoul</city>
        <zip>03080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seoul</city>
        <zip>03722</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seoul</city>
        <zip>05505</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seoul</city>
        <zip>135-710</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Taipei</city>
        <zip>10002</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Korea, Republic of</country>
    <country>Taiwan</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&amp;studyid=2978&amp;filename=BLOOM%20CSP_Redacted%20new.pdf</url>
    <description>BLOOM CSP_Redacted</description>
  </link>
  <link>
    <url>https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Search</url>
    <description>Results of this clinical trial are available on www.astrazenecaclinicaltrials.com</description>
  </link>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>August 20, 2014</study_first_submitted>
  <study_first_submitted_qc>August 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 29, 2014</study_first_posted>
  <last_update_submitted>January 4, 2021</last_update_submitted>
  <last_update_submitted_qc>January 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Non Small Cell Lung Cancer, EGFR, Tyrosine kinase inhibitor,EGFR mutation positive, Brain Metastasis, Leptomeningeal Metastasis</keyword>
  <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>
  </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>Yes</sharing_ipd>
    <ipd_description>Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.&#xD;
Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.</ipd_description>
    <ipd_time_frame>AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.</ipd_time_frame>
    <ipd_access_criteria>When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.</ipd_access_criteria>
    <ipd_url>https://astrazenecagroup-dt.pharmacm.com/DT/Home</ipd_url>
  </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/NCT02228369
org study id: D6030C00001
nct id: NCT02228369
lead sponsor: 
has dmc: No
This is the first time in patient study to assess the safety, tolerability and preliminary
      efficacy of AZD3759 in patients with advanced Non Small Cell Lung Cancer (NSCLC) In this
      study, patients with Leptomeningeal Metastasis and Brain Metastasis may also be enrolled to
      assess the anti-tumour efficacy, safety, pharmacokinetics and potential biological activity
      of AZD9291
A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics
      and Preliminary Anti-Tumour Activity of AZD3759 or AZD9291 in Patients with EGFR Mutation
      Positive Advanced Stage Non Small Cell Lung Cancer (NSCLC) who failed standard treatment and
      developed brain or leptomeningeal diseases
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety and Tolerability (The number of patients with each AE by system organ class, preferred term and CTCAE grade)
time frame: From Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.
description: Adverse events will be collected from Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.Physical exam (screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation). ECG and vital signs (screening, Day 1 and 2 of Cycle 0 for AZD3759 cohorts, Day 8 of Cycle 1 for AZD3759 cohorts, Day 1 of every 3-week cycle, treatment discontinuation, and if occurrence of any cardiac adverse event). Lab variables (screening, first dosing day, Day 1, 8 and 15 of multiple dosing, Day 1 of every 3-week cycle and treatment discontinuation). Eye exam (at screening and study drug discontinuation and upon occurrence of any visual AE). Echocardiogram or multigated radionuclide angiography (at screening,whenever necessary as clinically indicated throughout the study for AZD3759 cohorts.
measure: Plasma concentration of AZD3759 and metabolite and pharmacokinetics parameters after single dose of AZD3759(Cmax, tmax, terminal rate constant, half life, AUC, clearance, volume of distribution, mean residence time)
time frame: Cycle 0 Day 1 to 3 in Part A patients.
description: The parent drug and N-demethylated metabolite in plasma samples will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, hour in Day 1; 24hour in Day 2 and 48hour in Day 3.
AUC: Area Under Curve
measure: Plasma,urine,cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).
time frame: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A. CSF samples: pre-dose of Cycle 1 Day 8 in BM; Pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in LM
description: The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1 . The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients. AUCss: Area Under Curve Steady State CLss: Clearance Steady State
measure: Plasma,urine, cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)
time frame: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A patients. CSF samples: pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in Part B patients .
description: The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1. The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients.
measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolite and pharmacokinetics parameters after multiple dose of AZD9291(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).
time frame: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.
description: The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State
measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolites and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)
time frame: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.
description: The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State
measure: Overall survival follow up for all expansion patients
time frame: Every 6 weeks after the 28- day safety follow-up visit
description: After 28-day follow-up visit, patients will be followed for overall survival via telephone every 6 weeks until death, lost to follow-up or consent withdrawal
measure: 4b-hydroxy cholesterol in Part B patients with BM
time frame: pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15
description: Blood collection at pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15 to evaluate if AZD3759 affects 4b-hydroxy cholesterol which is an endogenous marker of CYP enzyme induction
measure: The effect of food on the pharmacokinetics of a single dose of AZD3759 in plasma
time frame: Cycle 0 Day 1 to Day 4 in Part B patients with BM
description: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hour of Cycle 0 Day 1and Day 4; 24 hour of Cycle 0 Day 2 and Day 4.A Mixed Effects model with treatment (fed/fasted) and period as fixed effects and patient as a random effect will be used to compare AUC/Cmax in the fed state with AUC/Cmax in the fasted state.
measure: Cerebrospinal fluid response rate for patients with LM and/or BM
time frame: Screening and every 6 weeks (relative to first dose of multiple dosing) until progression, expected average 6 months
description: Cerebrospinal fluid collection at screening and every 6 weeks until progression to evaluate the cerebrospinal fluid response rate which is defined as the percentage of leptomeningeal metastasis patients who have at least one cerebrospinal fluid response (100% clearance of tumour cells from cerebrospinal
measure: Changes from baseline in central nervous system symptoms (analyzed from QLQ-BN20) in patients with LM treated with AZD3759 /AZD9291
time frame: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.
description: Quality of life questionnaire-Brain Cancer 20 questionnaire completed by patients at screening, Day 1 of every 3-week cycle and treatment discontinuation. Use relevant symptom questions to evaluate improvement of central nervous system symptoms.
measure: Changes from baseline in neurological exam in patients with LM treated with AZD3759 /AZD9291
time frame: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.
description: Neurological exam will be performed: screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation
measure: Measurement of Objective Response Rate (ORR)
time frame: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.
description: ORR assessed through the number of patients who achieve a disease response (i.e. complete response or partial response) assessed according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease and overall disease
measure: Measurement of Disease Control Rate (DCR)
time frame: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.
description: DCR assessed through the number of patients who achieve a best response of confirmed CR, confirmed PR or responding, or stable disease according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease, leptomeningeal disease and overall disease
measure: Measurement of Response Rate (RR)
time frame: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.
description: RR assessed through the number of patients who have at least one confirmed response of Complete Response or Responding prior to any evidence of progression according to modified RECIST 1.1 criteria for leptomeningeal disease
measure: Measurement of Progression Free Survival (PFS)
time frame: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.
description: PFS assessed through change in tumour size (as well as assessment of non-target lesions and appearance of any new lesions) according to modified RECIST 1.1 criteria for Part B patients with brain metastasis and patients with leptomeningeal metastasis
measure: Best Leptomeningeal Metastasis (LM) assessment for AZD9291 LM patients
time frame: Screening within 28days
description: Best LM assessment via LANO criteria through the number of patients with LM present at baseline, without a requirement for confirmation. LANO assessments will be mapped to RECIST-like scores and performed via central imaging reading.
arm group label: Daily dose of AZD3759
arm group type: Experimental
description: Daily oral dose of AZD3759
arm group label: Daily Dose of AZD9291
arm group type: Experimental
description: Daily oral dose of AZD9291
intervention type: Drug
intervention name: AZD3759
description: Starting dose 50 mg, administered twice daily. If tolerated subsequent cohorts will test increasing doses of AZD3759, until a maximum tolerated dose or an effective dose is defined
arm group label: Daily dose of AZD3759
intervention type: Drug
intervention name: AZD9291
description: AZD9291 160mg once daily
arm group label: Daily Dose of AZD9291
criteria: 
gender: All
minimum age: 18 Years
maximum age: 130 Years
healthy volunteers: No
last name: Pamela Yang, M.D. PhD
role: Study Director
affiliation: Building 2, 199 Liangjing Road, Zhangjiang Hi-tech Park, Shanghai 201203, China
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country: Australia
country: Korea, Republic of
country: Taiwan
country: United States
url: http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&studyid=2978&filename=BLOOM%20CSP_Redacted%20new.pdf
description: BLOOM CSP_Redacted
url: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Search
description: Results of this clinical trial are available on www.astrazenecaclinicaltrials.com
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Osimertinib
sharing ipd: Yes
ipd description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
ipd time frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
ipd access criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
ipd url: https://astrazenecagroup-dt.pharmacm.com/DT/Home