<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/NCT02197234</url>
  </required_header>
  <id_info>
    <org_study_id>D5160C00014</org_study_id>
    <secondary_id>2014-002070-36</secondary_id>
    <nct_id>NCT02197234</nct_id>
  </id_info>
  <brief_title>Study to Assess the Effect of AZD9291 on the Blood Levels of Simvastatin in Patients With EGFRm+ NSCLC</brief_title>
  <official_title>A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Simvastatin (a Sensitive CYP3A4 Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI</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 a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of&#xD;
      epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer&#xD;
      (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase&#xD;
      inhibitor (TKI) agent.&#xD;
&#xD;
      Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of&#xD;
      simvastatin and simvastatin acid, following multiple oral dosing of AZD9291 in a fasted&#xD;
      state.&#xD;
&#xD;
      Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will&#xD;
      provide for additional safety data collection. All patients from Part A who completed&#xD;
      treatment may continue to receive AZD9291 80 mg once daily until: disease progression; they&#xD;
      are no longer deriving clinical benefit; or any other reason.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 22, 2014</start_date>
  <completion_date type="Anticipated">December 29, 2023</completion_date>
  <primary_completion_date type="Actual">April 30, 2015</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cmax of Simvastatin</measure>
    <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
    <description>Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC of Simvastatin</measure>
    <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
    <description>Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tmax of Simvastatin and Simvastatin Acid</measure>
    <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
    <description>Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CL/F of Simvastatin</measure>
    <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
    <description>Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of Simvastatin Acid</measure>
    <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
    <description>Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC of Simvastatin Acid</measure>
    <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
    <description>Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(0-t) of Simvastatin and Simvastatin Acid</measure>
    <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
    <description>Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">52</enrollment>
  <condition>Non Small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>AZD9291 and simvastatin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Pharmacokinetic sampling - AZD9291</intervention_name>
    <description>Blood sampling to measure AZD9291</description>
    <arm_group_label>AZD9291 and simvastatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Simvastatin</intervention_name>
    <description>Simvastatin (CYP substrate) 40mg taken once daily on Days 1 and 31 (Part A)</description>
    <arm_group_label>AZD9291 and simvastatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD9291 tablet dosing</intervention_name>
    <description>AZD9291 80mg tablet taken from Days 3 to 32. (Part B) AZD9291 80mg tablet taken daily for 12 months.</description>
    <arm_group_label>AZD9291 and simvastatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Pharmacokinetic sampling - simvastatin</intervention_name>
    <description>Blood sampling to measure simvastatin levels</description>
    <arm_group_label>AZD9291 and simvastatin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Pharmacokinetic sampling - AZ5140 and AZ7550</intervention_name>
    <description>Blood samples to measure levels of AZ5140 and AZ7550</description>
    <arm_group_label>AZD9291 and simvastatin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        For inclusion in the study patient should fulfil the following criteria:&#xD;
&#xD;
          1. Male or female, aged at least 18 years.&#xD;
&#xD;
          2. Histological or cytological confirmation diagnosis of NSCLC.&#xD;
&#xD;
          3. Radiological documentation of disease progression while on a previous continuous&#xD;
             treatment with an EGFR TKI, eg gefitinib, afatinib or erlotinib. In addition, other&#xD;
             lines of therapy may have been given. All patients must have documented radiological&#xD;
             progression on the last treatment administered prior to enrolling in the study.&#xD;
&#xD;
          4. Confirmation that the tumour harbours an EGFR mutation known to be associated with&#xD;
             EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).&#xD;
&#xD;
          5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration&#xD;
             over the previous 2 weeks (Appendix G).&#xD;
&#xD;
          6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of&#xD;
             screening.&#xD;
&#xD;
          7. Females should be using adequate contraceptive measures and must have a negative&#xD;
             pregnancy test prior to start of dosing if of child-bearing potential, or must have&#xD;
             evidence of non-child-bearing potential by fulfilling one of the following criteria at&#xD;
             screening: Post-menopausal defined as aged more than 50 years and amenorrhoeic for at&#xD;
             least 12 months following cessation of all exogenous hormonal treatments; women under&#xD;
             50 years old would be considered post-menopausal if they have been amenorrhoeic for 12&#xD;
             months or more following cessation of exogenous hormonal treatments and with LH and&#xD;
             FSH levels in the post-menopausal range for the institution; documentation of&#xD;
             irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or&#xD;
             bilateral salpingectomy, but not tubal ligation.&#xD;
&#xD;
          8. Male patients should be willing to use barrier contraception, ie, condoms, until 6&#xD;
             months after last study drug is taken.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Participation in another study with an IP during the last 14 days (or a longer period&#xD;
             depending on the defined characteristics of the agents used).&#xD;
&#xD;
          2. Treatment with any of the following: Treatment with an EGFR TKI (eg, erlotinib or&#xD;
             gefitinib) within 8 days or approx. 5 x half-life, whichever is the longer, of the&#xD;
             first dose of study treatment; any cytotoxic chemotherapy, investigational agents or&#xD;
             other anticancer drugs from a previous treatment regimen or clinical study within 14&#xD;
             days of the first dose; major surgery (excluding placement of vascular access) within&#xD;
             4 weeks of the first dose of study treatment; radiotherapy with a limited field of&#xD;
             radiation for palliation within 1 week of the first dose of study treatment, with the&#xD;
             exception of patients receiving radiation to more than 30% of the bone marrow or with&#xD;
             a wide field of radiation which must be completed within 4 weeks of the first dose;&#xD;
             patients currently receiving (or unable to stop use prior to receiving the first dose&#xD;
             of study treatment) medications or herbal supplements known to be potent inhibitors of&#xD;
             CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior).&#xD;
             All patients must avoid concomitant use of any medications, herbal supplements and/or&#xD;
             ingestion of foods with known inducer/inhibitory effects on CYP3A4.&#xD;
&#xD;
          3. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of&#xD;
             starting study treatment with the exception of alopecia and Grade 2, prior&#xD;
             platinum-therapy related neuropathy.&#xD;
&#xD;
          4. Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade,&#xD;
             or other products containing grapefruit or Seville oranges within 7 days of the first&#xD;
             administration of the IP until the final PK sample collection on Day 32 of Part A.&#xD;
&#xD;
          5. Spinal cord compression or brain metastases unless asymptomatic, stable and not&#xD;
             requiring steroids for at least 4 weeks prior to start of study treatment.&#xD;
&#xD;
          6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled&#xD;
             hypertension and active bleeding diatheses, which in the PI's opinion makes it&#xD;
             undesirable for the patient to participate in the study or which would jeopardise&#xD;
             compliance with the protocol, or active infection including hepatitis B, hepatitis C,&#xD;
             and HIV. Screening for chronic conditions not required.&#xD;
&#xD;
          7. Inadequate bone marrow reserve or organ function as demonstrated by any of the&#xD;
             following laboratory values: ANC &lt;1.5 x 10^9/L; platelet count &lt;100 x 10^9/L;&#xD;
             haemoglobin &lt;90 g/L; ALT &gt;2.5 times ULN if no demonstrable liver metastases or &gt;5&#xD;
             times ULN in the presence of liver metastases; Aspartate aminotransferase (AST) &gt;2.5&#xD;
             times ULN if no demonstrable liver metastases or &gt;5 times ULN in the presence of liver&#xD;
             metastases; total bilirubin &gt;1.5 times ULN if no liver metastases or &gt;3 times ULN in&#xD;
             the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or&#xD;
             liver metastases; creatinine &gt;1.5 times ULN concurrent with creatinine clearance &lt;50&#xD;
             ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of&#xD;
             creatinine clearance is only required when creatinine is &gt;1.5 times ULN.&#xD;
&#xD;
          8. Any of the following cardiac criteria: mean resting corrected QT interval corrected&#xD;
             for heart rate using Fridericia's correction factor (QTcF) &gt;470 msec obtained from 3&#xD;
             ECGs; any clinically important abnormalities in rhythm, conduction or morphology of&#xD;
             resting ECG eg, complete left bundle branch block, third degree heart block, second&#xD;
             degree heart block, PR interval &gt;250 msec; any factors that increase the risk of QTc&#xD;
             prolongation or risk of arrhythmic events such as heart failure, hypokalaemia,&#xD;
             congenital long QT syndrome, family history of long QT syndrome or unexplained sudden&#xD;
             death under age of 40 or any concomitant medication known to prolong the QT interval.&#xD;
&#xD;
          9. Patients unable to swallow oral medication or patients with GI disorders or&#xD;
             significant GI resection likely to interfere with the absorption of AZD9291.&#xD;
&#xD;
         10. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required&#xD;
             steroid treatment, or any evidence of clinically active ILD.&#xD;
&#xD;
         11. Women who are breastfeeding.&#xD;
&#xD;
         12. Patients with a known hypersensitivity to AZD9291, simvastatin, or any of the&#xD;
             excipients of the products.&#xD;
&#xD;
         13. Concomitant medication contraindicated for use with simvastatin due to drug&#xD;
             interaction associated with increased risk of rhabdomyolysis (including, but not&#xD;
             limited to): itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin,&#xD;
             telithromycin, HIV protease inhibitors (eg, nelfinavir), nefazodone, cyclosporine,&#xD;
             danazol, gemfibrozil, amiodarone, amlodipine.&#xD;
&#xD;
         14. 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitors, such as&#xD;
             lovastatin and simvastatin.&#xD;
&#xD;
         15. For optional genetic research: Previous allogenic bone marrow transplant or&#xD;
             non-leukocyte depleted whole blood transfusion within 120 days of the date of the&#xD;
             genetic sample collection.&#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>Serban Ghiorghiu, MSD</last_name>
    <role>Study Director</role>
    <affiliation>AstraZeneca</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Angers Cedex 9</city>
        <zip>49055</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Dijon cedex</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Marseille</city>
        <zip>13385</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Rennes</city>
        <zip>35033</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Saint Herblain</city>
        <zip>44805</zip>
        <country>France</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>06351</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Badalona</city>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Barcelona</city>
        <zip>08041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Madrid</city>
        <zip>28046</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Sevilla</city>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>France</country>
    <country>Korea, Republic of</country>
    <country>Spain</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Canada</country>
    <country>Taiwan</country>
  </removed_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>July 21, 2014</study_first_submitted>
  <study_first_submitted_qc>July 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <results_first_submitted>April 8, 2016</results_first_submitted>
  <results_first_submitted_qc>May 16, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">June 22, 2016</results_first_posted>
  <last_update_submitted>July 10, 2023</last_update_submitted>
  <last_update_submitted_qc>July 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 11, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>oncology, cancer, non small cell lung cancer, anticancer drug, pharmacokinetics, AZD9291, simvastatin, EGFR genes</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>
    <mesh_term>Simvastatin</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.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <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>

  <clinical_results>

    <participant_flow>
      <recruitment_details>First patient enrolled: 22 December 2014; Last Subject Last Visit Part A: 30 April 2015 and Part B: 13 May 2016. Study performed at 17 sites across Asia, North America and Western Europe. Part A assessed effect of multiple doses of AZD9291 on PK of simvastatin; Part B allowed subjects further access to AZD9291 and provided additional safety data.</recruitment_details>
      <pre_assignment_details>57 patients were enrolled (signed informed consent). Patients were assigned to treatment if they met all the inclusion and none of the exclusion criteria. 5 patients were enrolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment. The remaining 52 patients started Period 1 and received treatment.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Simvastatin and AZD9291 (Part A); AZD9291 Alone (Part B)</title>
          <description>In Part A of the study, sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 30 days (Days 3 to 32) and single 40 mg oral doses of simvastatin on Day 1 and Day 31.&#xD;
In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Part A: Day 1-2 (Simvastatin Alone)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="52"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="52"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Part A: Day 3-30 (AZD9291 Alone)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="52"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Condition under investigation worsened</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Part A: Day 31-32 (Simvastatin+AZD9291)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Part B: Day 33 to End Part B (AZD9291)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="50">49 completed Part A + 1 entered Part B without completing Part A (due to AE) = 50 started Part B</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Condition under investigation worsened</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Simvastatin and AZD9291 (Part A); AZD9291 Alone (Part B)</title>
          <description>In Part A of the study, sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 30 days (Days 3 to 32) and single 40 mg oral doses of simvastatin on Day 1 and Day 31.&#xD;
In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="52"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="63.5" spread="11.28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="37"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Cmax of Simvastatin</title>
        <description>Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration</description>
        <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
        <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
        <group_list>
          <group group_id="O1">
            <title>Simvastatin Alone</title>
            <description>Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Simvastatin</title>
            <description>AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of Simvastatin</title>
          <description>Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration</description>
          <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="46"/>
                <count group_id="O2" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.54" lower_limit="2.69" upper_limit="75.5"/>
                    <measurement group_id="O2" value="18.65" lower_limit="3.87" upper_limit="141"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Study sized so experiment-wise power for the 90% CIs of geometric mean ratios for both AUC and Cmax of AUC9291 being within 70-143% was 90% (95% for each parameter). Within patient CV assumed to be 45%. No change in exposure was also assumed.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence (legacy)</non_inferiority_type>
            <non_inferiority_desc>90% CIs being within 70% to 143%.</non_inferiority_desc>
            <param_type>Geometric mean ratio</param_type>
            <param_value>77.08</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>63.41</ci_lower_limit>
            <ci_upper_limit>93.70</ci_upper_limit>
            <estimate_desc>Simvastatin + AZD9291 / Simvastatin alone. Based on linear mixed-effects model with treatment as fixed effect and patient as a random effect.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC of Simvastatin</title>
        <description>Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity</description>
        <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
        <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
        <group_list>
          <group group_id="O1">
            <title>Simvastatin Alone</title>
            <description>Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Simvastatin</title>
            <description>AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC of Simvastatin</title>
          <description>Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity</description>
          <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
          <units>ng.h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="46"/>
                <count group_id="O2" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="80.25" lower_limit="23.9" upper_limit="289"/>
                    <measurement group_id="O2" value="73.54" lower_limit="25.2" upper_limit="488"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Study sized so experiment-wise power for the 90% CIs of geometric mean ratios for both AUC and Cmax of AUC9291 being within 70-143% was 90% (95% for each parameter). Within patient CV assumed to be 45%. No change in exposure was also assumed.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence (legacy)</non_inferiority_type>
            <non_inferiority_desc>90% CIs being within 70% to 143%.</non_inferiority_desc>
            <param_type>Geometric mean ratio</param_type>
            <param_value>91.46</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>77.16</ci_lower_limit>
            <ci_upper_limit>108.41</ci_upper_limit>
            <estimate_desc>Simvastatin + AZD9291 / Simvastatin alone. Based on linear mixed-effects model with treatment as fixed effect and patient as a random effect.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tmax of Simvastatin and Simvastatin Acid</title>
        <description>Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax</description>
        <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
        <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
        <group_list>
          <group group_id="O1">
            <title>Simvastatin Alone</title>
            <description>Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Simvastatin</title>
            <description>AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax of Simvastatin and Simvastatin Acid</title>
          <description>Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax</description>
          <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
          <units>hours</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="46"/>
                <count group_id="O2" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Simvastatin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.50" lower_limit="0.45" upper_limit="4.00"/>
                    <measurement group_id="O2" value="1.50" lower_limit="0.50" upper_limit="10.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Simvastatin acid</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.08" lower_limit="0.50" upper_limit="10.00"/>
                    <measurement group_id="O2" value="3.08" lower_limit="1.50" upper_limit="12.45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>CL/F of Simvastatin</title>
        <description>Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration</description>
        <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
        <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
        <group_list>
          <group group_id="O1">
            <title>Simvastatin Alone</title>
            <description>Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Simvastatin</title>
            <description>AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.</description>
          </group>
        </group_list>
        <measure>
          <title>CL/F of Simvastatin</title>
          <description>Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration</description>
          <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
          <units>L/h</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="46"/>
                <count group_id="O2" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="498.3" lower_limit="138" upper_limit="1670"/>
                    <measurement group_id="O2" value="543.9" lower_limit="82.0" upper_limit="1590"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cmax of Simvastatin Acid</title>
        <description>Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration</description>
        <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
        <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
        <group_list>
          <group group_id="O1">
            <title>Simvastatin Alone</title>
            <description>Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Simvastatin</title>
            <description>AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax of Simvastatin Acid</title>
          <description>Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration</description>
          <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="46"/>
                <count group_id="O2" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.187" lower_limit="0.482" upper_limit="68.5"/>
                    <measurement group_id="O2" value="4.161" lower_limit="0.849" upper_limit="66.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC of Simvastatin Acid</title>
        <description>Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity</description>
        <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
        <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
        <group_list>
          <group group_id="O1">
            <title>Simvastatin Alone</title>
            <description>Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Simvastatin</title>
            <description>AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC of Simvastatin Acid</title>
          <description>Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity</description>
          <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
          <units>ng.h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="42"/>
                <count group_id="O2" value="37"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.18" lower_limit="6.19" upper_limit="436"/>
                    <measurement group_id="O2" value="30.16" lower_limit="6.69" upper_limit="443"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(0-t) of Simvastatin and Simvastatin Acid</title>
        <description>Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose</description>
        <time_frame>Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A</time_frame>
        <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
        <group_list>
          <group group_id="O1">
            <title>Simvastatin Alone</title>
            <description>Simvastatin (CYP substrate) 40mg taken as single dose on Day 1.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Simvastatin</title>
            <description>AZD9291 80 mg once daily on Days 3 to 32; Simvastatin 40 mg on Day 31.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-t) of Simvastatin and Simvastatin Acid</title>
          <description>Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose</description>
          <population>Pharmacokinetic population - all patients who received at least 1 dose of simvastatin or AZD9291 and had at least 1 postdose PK measurement without important protocol deviations/violations.</population>
          <units>ng.h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="46"/>
                <count group_id="O2" value="43"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Simvastatin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="77.97" lower_limit="21.6" upper_limit="279"/>
                    <measurement group_id="O2" value="70.17" lower_limit="24.9" upper_limit="470"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Simvastatin acid</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.25" lower_limit="5.71" upper_limit="435"/>
                    <measurement group_id="O2" value="29.60" lower_limit="6.34" upper_limit="442"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Approximately 1 month for Part A; up to approximately 14 months for Part B and approximately 15 months for Overall (Parts A and B combined).</time_frame>
      <desc>Part A: Adverse events (AEs) collected from day of first dose until day prior to first dose in Part B (Day 33), or until 30 days after last dose if discontinued in Part A.&#xD;
Part B: AEs collected from day of first dose in Part B until 30 days after last dose, or until last dose in Part B for those entering continued access phase (CAP).</desc>
      <group_list>
        <group group_id="E1">
          <title>Overall Safety Population</title>
          <description>Parts A and B of the study combined.</description>
        </group>
        <group group_id="E2">
          <title>Part A Safety Population</title>
          <description>In Part A of the study, each patient received 80 mg oral doses of AZD9291 tablets once daily for 30 days (Days 3 to 32) and single 40 mg oral doses of simvastatin on Day 1 and Day 31.</description>
        </group>
        <group group_id="E3">
          <title>Part B Safety Population</title>
          <description>In Part B of the study, each patient received 80 mg oral AZD9291 tablet formulation once daily, for the duration of their participation.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 19.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="52"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Bundle branch block left</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Left ventricular dysfunction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pancreatitis acute</sub_title>
                <description>Death</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infectious pleural effusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Pneumonitis chemical</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Spinal compression fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>General physical condition abnormal</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Myelodysplastic syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Thrombotic stroke</sub_title>
                <description>Death</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Acute pulmonary oedema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pneumonia aspiration</sub_title>
                <description>Death (same subject as Respiratory failure fatal outcome SAE)</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <description>Death (same subject as Pneumonia aspiration fatal outcome SAE)</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thrombophlebitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vasculitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 19.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="50" subjects_at_risk="52"/>
                <counts group_id="E2" subjects_affected="41" subjects_at_risk="52"/>
                <counts group_id="E3" subjects_affected="45" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="6" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="6" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Lymphopenia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="5" subjects_affected="3" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="12" subjects_affected="9" subjects_at_risk="52"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E3" events="8" subjects_affected="6" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="22" subjects_affected="21" subjects_at_risk="52"/>
                <counts group_id="E2" events="9" subjects_affected="8" subjects_at_risk="52"/>
                <counts group_id="E3" events="13" subjects_affected="13" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Haemorrhoids</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="14" subjects_affected="11" subjects_at_risk="52"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="52"/>
                <counts group_id="E3" events="8" subjects_affected="8" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" events="22" subjects_affected="11" subjects_at_risk="52"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E3" events="18" subjects_affected="9" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="11" subjects_affected="10" subjects_at_risk="52"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E3" events="7" subjects_affected="7" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="52"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E3" events="6" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Xerosis</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" events="16" subjects_affected="11" subjects_at_risk="52"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E3" events="13" subjects_affected="8" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="5" subjects_affected="2" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Blood creatine phosphokinase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="15" subjects_affected="12" subjects_at_risk="52"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E3" events="10" subjects_affected="7" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="4" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypoalbuminaemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="4" subjects_affected="2" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="7" subjects_affected="6" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" events="10" subjects_affected="10" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="9" subjects_affected="9" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="6" subjects_affected="6" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Dysuria</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="21" subjects_affected="17" subjects_at_risk="52"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E3" events="17" subjects_affected="14" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="52"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nasal inflammation</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="52"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="52"/>
                <counts group_id="E3" events="6" subjects_affected="6" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dermatitis acneiform</sub_title>
                <counts group_id="E1" events="12" subjects_affected="7" subjects_at_risk="52"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E3" events="8" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="19" subjects_affected="11" subjects_at_risk="52"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="52"/>
                <counts group_id="E3" events="13" subjects_affected="9" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="52"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Rash macular</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="52"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Rash papular</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="52"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="52"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="52"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The Principal Investigator (PI) agrees to collaborate on the contents and formation of any publication and to pay due consideration to comments and opinions offered. AstraZeneca have 30 days for final manuscript review and may require that submission for publication be delayed in order to file patent application.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>At end of Part B, the CAP allowed patients to continue receiving AZD9291 if still deriving clinical benefit. No clinical data was databased during the CAP; thus AE data is presented to end of Part B only.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr Karen So</name_or_title>
      <organization>AstraZeneca</organization>
      <email>ClinicalTrialTransparency@astrazeneca.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02197234
org study id: D5160C00014
secondary id: 2014-002070-36
nct id: NCT02197234
lead sponsor: 
has dmc: No
This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of
      epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer
      (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase
      inhibitor (TKI) agent.

      Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of
      simvastatin and simvastatin acid, following multiple oral dosing of AZD9291 in a fasted
      state.

      Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will
      provide for additional safety data collection. All patients from Part A who completed
      treatment may continue to receive AZD9291 80 mg once daily until: disease progression; they
      are no longer deriving clinical benefit; or any other reason.
allocation: N/A
primary purpose: Treatment
masking: None (Open Label)
measure: Cmax of Simvastatin
time frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A
description: Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration
measure: AUC of Simvastatin
time frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A
description: Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity
measure: Tmax of Simvastatin and Simvastatin Acid
time frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A
description: Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax
measure: CL/F of Simvastatin
time frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A
description: Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration
measure: Cmax of Simvastatin Acid
time frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A
description: Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration
measure: AUC of Simvastatin Acid
time frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A
description: Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity
measure: AUC(0-t) of Simvastatin and Simvastatin Acid
time frame: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A
description: Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose
arm group label: AZD9291 and simvastatin
arm group type: Experimental
description: Sequential treatments of simvastatin alone followed by AZD9291 alone, followed by simvastatin + AZD9291.
intervention type: Procedure
intervention name: Pharmacokinetic sampling - AZD9291
description: Blood sampling to measure AZD9291
arm group label: AZD9291 and simvastatin
intervention type: Drug
intervention name: Simvastatin
description: Simvastatin (CYP substrate) 40mg taken once daily on Days 1 and 31 (Part A)
arm group label: AZD9291 and simvastatin
intervention type: Drug
intervention name: AZD9291 tablet dosing
description: AZD9291 80mg tablet taken from Days 3 to 32. (Part B) AZD9291 80mg tablet taken daily for 12 months.
arm group label: AZD9291 and simvastatin
intervention type: Procedure
intervention name: Pharmacokinetic sampling - simvastatin
description: Blood sampling to measure simvastatin levels
arm group label: AZD9291 and simvastatin
intervention type: Procedure
intervention name: Pharmacokinetic sampling - AZ5140 and AZ7550
description: Blood samples to measure levels of AZ5140 and AZ7550
arm group label: AZD9291 and simvastatin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 130 Years
healthy volunteers: No
last name: Serban Ghiorghiu, MSD
role: Study Director
affiliation: AstraZeneca
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Belgium
country: France
country: Korea, Republic of
country: Spain
country: United States
country: Canada
country: Taiwan
responsible party type: Sponsor
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Osimertinib
mesh term: Simvastatin
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.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
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
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: At end of Part B, the CAP allowed patients to continue receiving AZD9291 if still deriving clinical benefit. No clinical data was databased during the CAP; thus AE data is presented to end of Part B only.
point of contact: 