<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/NCT02197247</url>
  </required_header>
  <id_info>
    <org_study_id>D5160C00013</org_study_id>
    <secondary_id>2014-001525-32</secondary_id>
    <nct_id>NCT02197247</nct_id>
  </id_info>
  <brief_title>Study to Assess the Effect of Rifampicin on Blood Levels and Safety of AZD9291, in Patients With EGFRm+ NSCLC</brief_title>
  <official_title>A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of Rifampicin (a CYP3A4 Inducer) on the Pharmacokinetics of AZD9291 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 rifampicin on the pharmacokinetic (PK) parameters of AZD9291&#xD;
      and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and&#xD;
      AZD9291 in a fasted 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 who complete Part A will be able&#xD;
      to enter part B, and continue to receive AZD9291 80 mg once daily until: disease progression;&#xD;
      they are no longer deriving clinical benefit; or any other reason.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 4, 2014</start_date>
  <completion_date type="Actual">May 26, 2021</completion_date>
  <primary_completion_date type="Actual">July 9, 2015</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)</measure>
    <time_frame>Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)</measure>
    <time_frame>Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assessment of Css,Max for AZD9291 Before and After Rifampicin</measure>
    <time_frame>Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Css,Max for AZ5104 (Metabolite)</measure>
    <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Css,Max for AZ7550 (Metabolite)</measure>
    <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Css,Max for Rifampicin</measure>
    <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of AUCtau for AZD9291 Before and After Rifampicin</measure>
    <time_frame>Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of AUCtau for AZ5104 (Metabolite)</measure>
    <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of AUCtau for AZ7550 (Metabolite)</measure>
    <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of AUCtau for Rifampicin</measure>
    <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)</measure>
    <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Tss,Max for Rifampicin</measure>
    <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)</measure>
    <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Css,Min for Rifampicin</measure>
    <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of CLss/F for AZD9291</measure>
    <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of CLss/F for Rifampicin</measure>
    <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)</measure>
    <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)</measure>
    <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
    <description>Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Non Small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>Rifampicin and AZD9291</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Sequential treatments of AZD9291 alone followed by AZD9291 +rifampicin, followed by AZD9291 alone.</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>Rifampicin and AZD9291</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifampicin</intervention_name>
    <description>Rifampicin (CYP inducer) 600mg taken once daily from Day 29 to Day 49 (Part A)</description>
    <arm_group_label>Rifampicin and AZD9291</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD9291 tablet dosing</intervention_name>
    <description>Part A: AZD9291 80mg tablet taken daily from Days 1 to 77. Part B: AZD9291 80mg tablet taken daily for 12 months.</description>
    <arm_group_label>Rifampicin and AZD9291</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Pharmacokinetic sampling - rifampicin</intervention_name>
    <description>Blood sampling to measure rifampicin levels</description>
    <arm_group_label>Rifampicin and AZD9291</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>Rifampicin and AZD9291</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. 2. Histological or cytological confirmation&#xD;
        diagnosis of NSCLC. 3. Radiological documentation of disease progression while on a&#xD;
        previous continuous treatment with an EGFR TKI, eg gefitinib, erlotinib or afatinib. In&#xD;
        addition, other lines of therapy may have been given. All patients must have documented&#xD;
        radiological progression on the last treatment administered prior to enrolling in the&#xD;
        study.&#xD;
&#xD;
        4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR&#xD;
        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 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 least&#xD;
        12 months following cessation of all exogenous hormonal treatments. Women under 50 years&#xD;
        old would be considered post-menopausal if they have been amenorrhoeic for 12 months or&#xD;
        more following cessation of exogenous hormonal treatments and with LH and FSH levels in the&#xD;
        post-menopausal range for the institution. Documentation of irreversible surgical&#xD;
        sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not&#xD;
        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;
        9. Contact lens wearers must be prepared to not wear contact lenses and wear glasses for&#xD;
        the duration of the rifampicin dosing.&#xD;
&#xD;
          1. Participation in another clinical study with an IP during the last 14 days (or a&#xD;
             longer period 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) w/in 8 days or approx. 5 x half-life, whichever is the longer, of the first&#xD;
             dose of study treatment; any cytotoxic chemo, investigational agents or other&#xD;
             anticancer drugs from a previous treatment regimen w/in 14 days of the first dose of&#xD;
             study treatment; major surgery (excluding placement of vascular access) w/in 4 weeks&#xD;
             of the first dose of study treatment; radiotherapy with a limited field of radiation&#xD;
             for palliation w/in 1 week of the first dose of study treatment, with the exception of&#xD;
             patients receiving radiation to more than 30% of bone marrow or with a wide field of&#xD;
             radiation which must be completed w/in 4 weeks of the first; patients currently&#xD;
             receiving (or unable to stop use prior to receiving the first dose) medications or&#xD;
             herbal supplements known to be potent inhibitors of CYP3A4 (at least 1 week prior) and&#xD;
             potent inducers of CYP3A4 (at least 3 week prior). All patients must avoid concomitant&#xD;
             use of any medications, herbal supplements and/or ingestion of foods with known&#xD;
             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 78 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 Investigator's opinion makes&#xD;
             it 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 is 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 the ULN if no demonstrable liver metastases or &gt;5&#xD;
             times ULN in the presence of liver metastases; AST &gt;2.5 times ULN if no demonstrable&#xD;
             liver metastases or &gt;5 times ULN in the presence of liver metastases; Total bilirubin&#xD;
             &gt;1.5 times ULN if no liver metastases or &gt;3 times ULN in the presence of documented&#xD;
             Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases; creatinine&#xD;
             &gt;1.5 times ULN concurrent with creatinine clearance &lt;50 ml/min (measured or calculated&#xD;
             by Cockcroft and Gault equation); confirmation of creatinine clearance is only&#xD;
             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;
             electrocardiograms (ECGs); any clinically important abnormalities in rhythm,&#xD;
             conduction or morphology of resting ECG eg, complete left bundle branch block, third&#xD;
             degree heart block, second degree heart block, PR interval &gt;250 msec; any factors that&#xD;
             increase the risk of QTc prolongation or risk of arrhythmic events such as heart&#xD;
             failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome&#xD;
             or unexplained sudden death under 40 years of age or any concomitant medication known&#xD;
             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 or rifampicin or any of the&#xD;
             excipients of the products.&#xD;
&#xD;
         13. Concomitant medication contraindicated for use with rifampicin (including, but not&#xD;
             limited to): cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide,&#xD;
             triazolam, levacetylmethadol (levomethadyl), 3-hydroxy-3-methyl-glutaryl coenzyme A&#xD;
             (HMG-CoA)-reductase inhibitors metabolised by CYP3A4, such as lovastatin and&#xD;
             simvastatin, ergot alkaloids metabolised by CYP3A4, such as dihydroergotamine,&#xD;
             ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).&#xD;
&#xD;
         14. 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>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</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>03722</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>Amsterdam</city>
        <zip>1066 CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Maastricht</city>
        <zip>6229 HX</zip>
        <country>Netherlands</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>L'Hospitalet de Llobregat</city>
        <zip>08908</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Madrid</city>
        <zip>28041</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>Málaga</city>
        <zip>29010</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>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Taipei</city>
        <zip>10002</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Taipei</city>
        <zip>112</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Cardiff</city>
        <zip>CF14 2TL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Manchester</city>
        <zip>M20 4BX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
    <country>Netherlands</country>
    <country>Spain</country>
    <country>Taiwan</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&amp;studyid=2990&amp;filename=StudyD5160C00013_redacted.pdf</url>
    <description>StudyD5160C00013_redacted</description>
  </link>
  <verification_date>June 2021</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>May 24, 2016</results_first_submitted>
  <results_first_submitted_qc>August 5, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">September 28, 2016</results_first_posted>
  <last_update_submitted>June 18, 2021</last_update_submitted>
  <last_update_submitted_qc>June 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">July 12, 2021</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, rifampicin, CYP P450 inducer, 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>Rifampin</mesh_term>
    <mesh_term>Osimertinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.</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: 04 December 2014; Last Subject Last Visit Part A: 09 July 2015 and Part B: 29 June 2016. Study performed at 18 sites across Asia, North America and Western Europe. Part A assessed effect of multiple doses of rifampicin on PK of AZD9291; Part B allowed subjects further access to AZD9291 and provided additional safety data.</recruitment_details>
      <pre_assignment_details>51 patients were enrolled (signed informed consent). Patients were assigned to treatment if they met all the inclusion and none of the exclusion criteria. 10 subjects were enrolled but failed inclusion/exclusion criteria and so were not eligible to be assigned treatment. The remaining 41 patients started Period 1 and received treatment.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>AZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)</title>
          <description>In Part A of the study, sequential treatments of AZD9291 alone, followed by AZD9291 + rifampicin, followed by AZD9291 alone. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 77 days (Days 1 to 77) and additionally received 600 mg oral doses of rifampicin once daily on Days 29 to 49.&#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 1-28 (AZD9291 Alone)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
              </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 29-49 (AZD9291+Rifampicin)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Condition under investigation worsened</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Part A: Day 50-77 (AZD9291 Alone)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="32"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </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="5"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Part B: Day 78 to End Part B (AZD9291)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="34">32 completed Part A + 2 entered Part B without completing Part A (both due to AE) =34 started Part B</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Newly discovered brain metastases</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="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Condition under investigation worsened</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>All patients in the safety analysis set who received at least one dose of AZD9291 (n = 41) were included in the baseline analysis.</population>
      <group_list>
        <group group_id="B1">
          <title>AZD9291 and Rifampicin (Part A); AZD9291 Alone (Part B)</title>
          <description>In Part A of the study, sequential treatments of AZD9291 alone, followed by AZD9291 + rifampicin, followed by AZD9291 alone. Each patient received 80 mg oral doses of AZD9291 tablets once daily for 77 days (Days 1 to 77) and additionally received 600 mg oral doses of rifampicin once daily on Days 29 to 49.&#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="41"/>
          </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="62.5" spread="11.74"/>
                  </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="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </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="15"/>
                  </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="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                  </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>Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)</title>
        <description>Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).</description>
        <time_frame>Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)</title>
          <description>Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nanomolar (nM)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="577.4" spread="44.7"/>
                    <measurement group_id="O2" value="147.5" spread="48.2"/>
                  </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>Natural log-transformed Css,max values were compared between periods using a mixed effects analysis of variance (ANOVA) with period as fixed effect and patient as random effect. It was assumed the within-patient coefficient of variation for AZD9291 in both area under the plasma concentration-time curve during the dosing interval (AUCtau) and Cmax was 34%. A 33% decrease in exposure for AZD9291 when given with rifampicin was also assumed.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence (legacy)</non_inferiority_type>
            <non_inferiority_desc>No effect on the PK of AZD9291 after co-administration of rifampicin was concluded if the lower bound of the 90% confidence intervals (CIs) for the ratios (Period 2 versus Period 1) of AZD9291 AUCtau and Css,max were both above 50%. The experiment-wide power for the ratios being above 50% was 90% (95% power for each parameter).</non_inferiority_desc>
            <param_type>Geometric least-squares (LS) mean ratio</param_type>
            <param_value>27.16</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>24.36</ci_lower_limit>
            <ci_upper_limit>30.29</ci_upper_limit>
            <estimate_desc>AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)</title>
        <description>Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).</description>
        <time_frame>Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)</title>
          <description>Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nM * hour (nM*h)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10870" spread="44.3"/>
                    <measurement group_id="O2" value="2192" spread="43.8"/>
                  </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>Natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as fixed effect and patient as random effect. It was assumed the within-patient coefficient of variation for AZD9291 in both AUCtau and Cmax was 34%. A 33% decrease in exposure for AZD9291 when given with rifampicin was also assumed.</groups_desc>
            <non_inferiority_type>Non-Inferiority or Equivalence (legacy)</non_inferiority_type>
            <non_inferiority_desc>No effect on the PK of AZD9291 after co-administration of rifampicin was concluded if the lower bound of the 90% CIs for the ratios (Period 2 versus Period 1) of AZD9291 AUCtau and Css,max were both above 50%. The experiment-wide power for the ratios being above 50% was 90% (95% power for each parameter).</non_inferiority_desc>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>21.55</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>19.50</ci_lower_limit>
            <ci_upper_limit>23.83</ci_upper_limit>
            <estimate_desc>AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Css,Max for AZD9291 Before and After Rifampicin</title>
        <description>Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).</description>
        <time_frame>Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Css,Max for AZD9291 Before and After Rifampicin</title>
          <description>Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nM</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="577.4" spread="44.7"/>
                    <measurement group_id="O2" value="531.4" spread="37.9"/>
                  </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>Natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>95.53</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>85.27</ci_lower_limit>
            <ci_upper_limit>107.03</ci_upper_limit>
            <estimate_desc>AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for AZD9291 alone in separate periods, but analysed for consistency with AZD9291+rifampicin / AZD9291 alone analysis (primary outcome measure).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Css,Max for AZ5104 (Metabolite)</title>
        <description>Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
        <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
          <group group_id="O3">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Css,Max for AZ5104 (Metabolite)</title>
          <description>Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nM</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
                <count group_id="O3" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60.40" spread="57.2"/>
                    <measurement group_id="O2" value="12.28" spread="52.6"/>
                    <measurement group_id="O3" value="50.73" spread="49.8"/>
                  </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>For AZ5104 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>21.72</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>19.08</ci_lower_limit>
            <ci_upper_limit>24.72</ci_upper_limit>
            <estimate_desc>AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>For AZ5104 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>88.31</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>77.17</ci_lower_limit>
            <ci_upper_limit>101.07</ci_upper_limit>
            <estimate_desc>AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Css,Max for AZ7550 (Metabolite)</title>
        <description>Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
        <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
          <group group_id="O3">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Css,Max for AZ7550 (Metabolite)</title>
          <description>Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nM</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
                <count group_id="O3" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53.54" spread="43.7"/>
                    <measurement group_id="O2" value="73.14" spread="25.0"/>
                    <measurement group_id="O3" value="53.24" spread="34.4"/>
                  </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>For AZ7550 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>139.32</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>127.74</ci_lower_limit>
            <ci_upper_limit>151.96</ci_upper_limit>
            <estimate_desc>AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>For AZ7550 (metabolite), natural log-transformed Css,max values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>100.75</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>92.04</ci_lower_limit>
            <ci_upper_limit>110.29</ci_upper_limit>
            <estimate_desc>AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Css,Max for Rifampicin</title>
        <description>Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).</description>
        <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Css,Max for Rifampicin</title>
          <description>Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nanogram per millilitre (ng/mL)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13810" spread="40.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of AUCtau for AZD9291 Before and After Rifampicin</title>
        <description>Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).</description>
        <time_frame>Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of AUCtau for AZD9291 Before and After Rifampicin</title>
          <description>Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nM*h</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10870" spread="44.3"/>
                    <measurement group_id="O2" value="10060" spread="36.8"/>
                  </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>Natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>95.89</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>86.37</ci_lower_limit>
            <ci_upper_limit>106.45</ci_upper_limit>
            <estimate_desc>AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for AZD9291 alone in separate periods, but analysed for consistency with AZD9291+rifampicin / AZD9291 alone analysis (primary outcome measure).</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of AUCtau for AZ5104 (Metabolite)</title>
        <description>Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
        <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
          <group group_id="O3">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of AUCtau for AZ5104 (Metabolite)</title>
          <description>Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nM*h</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
                <count group_id="O3" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1206" spread="55.8"/>
                    <measurement group_id="O2" value="210.3" spread="48.0"/>
                    <measurement group_id="O3" value="1029" spread="49.7"/>
                  </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>For AZ5104 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>18.76</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>16.61</ci_lower_limit>
            <ci_upper_limit>21.19</ci_upper_limit>
            <estimate_desc>AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>For AZ5104 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>90.08</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>79.34</ci_lower_limit>
            <ci_upper_limit>102.27</ci_upper_limit>
            <estimate_desc>AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of AUCtau for AZ7550 (Metabolite)</title>
        <description>Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
        <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
          <group group_id="O3">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of AUCtau for AZ7550 (Metabolite)</title>
          <description>Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nM*h</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
                <count group_id="O3" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1107" spread="41.7"/>
                    <measurement group_id="O2" value="1416" spread="25.6"/>
                    <measurement group_id="O3" value="1111" spread="31.7"/>
                  </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>For AZ7550 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>129.81</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>119.14</ci_lower_limit>
            <ci_upper_limit>141.44</ci_upper_limit>
            <estimate_desc>AZD9291+rifampicin / AZD9291 alone (Period 2 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <groups_desc>For AZ7550 (metabolite), natural log-transformed AUCtau values were compared between periods using a mixed effects ANOVA with period as a fixed effect and patient as a random effect.</groups_desc>
            <non_inferiority_type>Superiority or Other (legacy)</non_inferiority_type>
            <param_type>Geometric LS Mean Ratio</param_type>
            <param_value>100.76</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>92.15</ci_lower_limit>
            <ci_upper_limit>110.19</ci_upper_limit>
            <estimate_desc>AZD9291 alone / AZD9291 alone (Period 3 versus Period 1). No pre-specified margins for equivalence test for metabolites, but analysed for consistency with AZD9291 analysis.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of AUCtau for Rifampicin</title>
        <description>Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).</description>
        <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of AUCtau for Rifampicin</title>
          <description>Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="58610" spread="36.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)</title>
        <description>Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
        <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
          <group group_id="O3">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)</title>
          <description>Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>h</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
                <count group_id="O3" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AZD9291 tss,max</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.97" lower_limit="2.88" upper_limit="9.88"/>
                    <measurement group_id="O2" value="5.88" lower_limit="3.00" upper_limit="10.00"/>
                    <measurement group_id="O3" value="6.00" lower_limit="3.17" upper_limit="23.92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AZ5104 tss,max</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.00" lower_limit="0.00" upper_limit="24.00"/>
                    <measurement group_id="O2" value="6.03" lower_limit="3.00" upper_limit="11.43"/>
                    <measurement group_id="O3" value="6.00" lower_limit="0.00" upper_limit="24.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AZ7550 tss,max</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.14" lower_limit="2.88" upper_limit="24.92"/>
                    <measurement group_id="O2" value="7.95" lower_limit="4.00" upper_limit="12.00"/>
                    <measurement group_id="O3" value="7.03" lower_limit="1.10" upper_limit="24.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Tss,Max for Rifampicin</title>
        <description>Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).</description>
        <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Tss,Max for Rifampicin</title>
          <description>Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>h</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.00" lower_limit="0.83" upper_limit="6.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)</title>
        <description>Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
        <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
          <group group_id="O3">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)</title>
          <description>Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>nM</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="31"/>
                <count group_id="O3" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AZD9291 Css,min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="354.7" spread="52.4"/>
                    <measurement group_id="O2" value="50.56" spread="47.9"/>
                    <measurement group_id="O3" value="326.9" spread="41.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AZ5104 Css,min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.80" spread="62.1"/>
                    <measurement group_id="O2" value="5.816" spread="51.6"/>
                    <measurement group_id="O3" value="35.37" spread="51.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AZ7550 Css,min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.99" spread="44.0"/>
                    <measurement group_id="O2" value="44.89" spread="26.9"/>
                    <measurement group_id="O3" value="37.68" spread="35.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of Css,Min for Rifampicin</title>
        <description>Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).</description>
        <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of Css,Min for Rifampicin</title>
          <description>Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" spread="NA">Geometric mean and percent geometric coefficient of variation were not determined for Css,min for rifampicin since a number of patients had concentration values below the limits of quantitation at the end of the 24 hour dosing interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of CLss/F for AZD9291</title>
        <description>Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
        <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
          <group group_id="O3">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of CLss/F for AZD9291</title>
          <description>Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
          <units>Litre per hour (L/h)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
                <count group_id="O3" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.74" spread="44.2"/>
                    <measurement group_id="O2" value="73.07" spread="43.8"/>
                    <measurement group_id="O3" value="15.92" spread="36.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of CLss/F for Rifampicin</title>
        <description>Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).</description>
        <time_frame>Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of CLss/F for Rifampicin</title>
          <description>Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).</description>
          <units>L/h</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.23" spread="36.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)</title>
        <description>Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
        <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
          <group group_id="O3">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)</title>
          <description>Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>Ratio</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
                <count group_id="O3" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AZ5104 Css,max / AZD9291 Css,max</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.1046" spread="31.0"/>
                    <measurement group_id="O2" value="0.08327" spread="27.4"/>
                    <measurement group_id="O3" value="0.09544" spread="27.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AZ7550 Css,max / AZD9291 Css,max</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.09276" spread="49.3"/>
                    <measurement group_id="O2" value="0.4960" spread="33.1"/>
                    <measurement group_id="O3" value="0.1002" spread="38.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)</title>
        <description>Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
        <time_frame>Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.</time_frame>
        <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
        <group_list>
          <group group_id="O1">
            <title>AZD9291 Alone (Period 1)</title>
            <description>AZD9291 80 mg once daily on Days 1 to 28 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 28.</description>
          </group>
          <group group_id="O2">
            <title>AZD9291 + Rifampicin (Period 2)</title>
            <description>Concomitant treatment with AZD9291 80 mg once daily and rifampicin 600 mg once daily on Days 29 to 49 (Part A). All treatments (AZD9291 and rifampicin) were administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 49.</description>
          </group>
          <group group_id="O3">
            <title>AZD9291 Alone (Period 3)</title>
            <description>AZD9291 80 mg once daily on Days 50 to 77 (Part A). AZD9291 was administered fasted from at least 2 hours before dosing to at least 2 hours after dosing. Water was allowed as desired except for 1 hour before and after AZD9291 administration on Day 77.</description>
          </group>
        </group_list>
        <measure>
          <title>Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)</title>
          <description>Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).</description>
          <population>The PK analysis set included all dosed patients who had at least 1 quantifiable plasma concentration collected post-dose without any important deviations or events that would exclude the patient.</population>
          <units>Ratio</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="32"/>
                <count group_id="O3" value="28"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AZ5104 AUCtau / AZD9291 AUCtau</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.1109" spread="29.0"/>
                    <measurement group_id="O2" value="0.09595" spread="23.6"/>
                    <measurement group_id="O3" value="0.1023" spread="28.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>AZ7550 AUCtau / AZD9291 AUCtau</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.1019" spread="52.3"/>
                    <measurement group_id="O2" value="0.6459" spread="28.2"/>
                    <measurement group_id="O3" value="0.1104" spread="38.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Approximately 3 months for Part A; up to approximately 14 months for Part B and approximately 17 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 77), 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</title>
          <description>Parts A and B of the study combined.</description>
        </group>
        <group group_id="E2">
          <title>Part A</title>
          <description>In Part A of the study, each patient received 80 mg oral doses of AZD9291 tablets once daily for 77 days (Days 1 to 77) and additionally received 600 mg oral doses of rifampicin once daily on Days 29 to 49.</description>
        </group>
        <group group_id="E3">
          <title>Part B</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="41"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Cardiac failure congestive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Ileus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Hepatitis B</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Pulmonary sepsis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Femur fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Thrombotic stroke</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </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="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="34"/>
              </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="40" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="39" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="34" subjects_at_risk="34"/>
              </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="6" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Neutropenia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye pruritus</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E3" events="6" subjects_affected="5" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="39" subjects_affected="22" subjects_at_risk="41"/>
                <counts group_id="E2" events="18" subjects_affected="14" subjects_at_risk="41"/>
                <counts group_id="E3" events="21" subjects_affected="14" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="24" subjects_affected="13" subjects_at_risk="41"/>
                <counts group_id="E2" events="14" subjects_affected="8" subjects_at_risk="41"/>
                <counts group_id="E3" events="10" subjects_affected="9" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" events="14" subjects_affected="10" subjects_at_risk="41"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E3" events="8" subjects_affected="6" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="16" subjects_affected="11" subjects_at_risk="41"/>
                <counts group_id="E2" events="7" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E3" events="9" subjects_affected="7" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Face oedema</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="14" subjects_affected="13" subjects_at_risk="41"/>
                <counts group_id="E2" events="9" subjects_affected="8" subjects_at_risk="41"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Folliculitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" events="13" subjects_affected="8" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="11" subjects_affected="6" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="12" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E3" events="6" subjects_affected="2" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Electrocardiogram QT prolonged</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="34"/>
              </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="22" subjects_affected="19" subjects_at_risk="41"/>
                <counts group_id="E2" events="8" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E3" events="14" subjects_affected="13" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Iron deficiency</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Hyperkalaemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </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="6" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="17" subjects_affected="11" subjects_at_risk="41"/>
                <counts group_id="E2" events="8" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E3" events="9" subjects_affected="5" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="41"/>
                <counts group_id="E2" events="6" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="13" subjects_affected="8" subjects_at_risk="41"/>
                <counts group_id="E2" events="10" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Pollakiuria</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="34"/>
              </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="12" subjects_affected="10" subjects_at_risk="41"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="41"/>
                <counts group_id="E3" events="5" subjects_affected="4" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Dermatitis acneiform</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="27" subjects_affected="17" subjects_at_risk="41"/>
                <counts group_id="E2" events="12" subjects_affected="10" subjects_at_risk="41"/>
                <counts group_id="E3" events="15" subjects_affected="12" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Nail discolouration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="8" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="34"/>
              </event>
              <event>
                <sub_title>Skin fissures</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="1" subjects_at_risk="34"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="34"/>
              </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/NCT02197247
org study id: D5160C00013
secondary id: 2014-001525-32
nct id: NCT02197247
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 rifampicin on the pharmacokinetic (PK) parameters of AZD9291
      and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and
      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 who complete Part A will be able
      to enter part B, and continue to receive AZD9291 80 mg once daily until: disease progression;
      they are no longer deriving clinical benefit; or any other reason.
primary purpose: Other
masking: None (Open Label)
measure: Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)
time frame: Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).
measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)
time frame: Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).
measure: Assessment of Css,Max for AZD9291 Before and After Rifampicin
time frame: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).
measure: Assessment of Css,Max for AZ5104 (Metabolite)
time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).
measure: Assessment of Css,Max for AZ7550 (Metabolite)
time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).
measure: Assessment of Css,Max for Rifampicin
time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).
measure: Assessment of AUCtau for AZD9291 Before and After Rifampicin
time frame: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).
measure: Assessment of AUCtau for AZ5104 (Metabolite)
time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).
measure: Assessment of AUCtau for AZ7550 (Metabolite)
time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).
measure: Assessment of AUCtau for Rifampicin
time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).
measure: Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)
time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).
measure: Assessment of Tss,Max for Rifampicin
time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).
measure: Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)
time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).
measure: Assessment of Css,Min for Rifampicin
time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).
measure: Assessment of CLss/F for AZD9291
time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).
measure: Assessment of CLss/F for Rifampicin
time frame: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).
measure: Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)
time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).
measure: Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)
time frame: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.
description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).
arm group label: Rifampicin and AZD9291
arm group type: Experimental
description: Sequential treatments of AZD9291 alone followed by AZD9291 +rifampicin, followed by AZD9291 alone.
intervention type: Procedure
intervention name: Pharmacokinetic sampling - AZD9291
description: Blood sampling to measure AZD9291
arm group label: Rifampicin and AZD9291
intervention type: Drug
intervention name: Rifampicin
description: Rifampicin (CYP inducer) 600mg taken once daily from Day 29 to Day 49 (Part A)
arm group label: Rifampicin and AZD9291
intervention type: Drug
intervention name: AZD9291 tablet dosing
description: Part A: AZD9291 80mg tablet taken daily from Days 1 to 77. Part B: AZD9291 80mg tablet taken daily for 12 months.
arm group label: Rifampicin and AZD9291
intervention type: Procedure
intervention name: Pharmacokinetic sampling - rifampicin
description: Blood sampling to measure rifampicin levels
arm group label: Rifampicin and AZD9291
intervention type: Procedure
intervention name: Pharmacokinetic sampling - AZ5140 and AZ7550
description: Blood samples to measure levels of AZ5140 and AZ7550
arm group label: Rifampicin and AZD9291
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: 
facility: 
facility: 
country: Korea, Republic of
country: Netherlands
country: Spain
country: Taiwan
country: United Kingdom
country: United States
url: http://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_7111&studyid=2990&filename=StudyD5160C00013_redacted.pdf
description: StudyD5160C00013_redacted
responsible party type: Sponsor
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Rifampin
mesh term: Osimertinib
sharing ipd: Yes
ipd description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
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: 