<clinical_study>
  <!-- This xml conforms to an XML Schema at:
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  <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/NCT03778229</url>
  </required_header>
  <id_info>
    <org_study_id>D5084C00007</org_study_id>
    <secondary_id>2018-003012-51</secondary_id>
    <nct_id>NCT03778229</nct_id>
  </id_info>
  <brief_title>Osimertinib Plus Savolitinib in EGFRm+/MET+ NSCLC Following Prior Osimertinib</brief_title>
  <acronym>SAVANNAH</acronym>
  <official_title>A Phase II Study Assessing the Efficacy of Osimertinib in Combination With Savolitinib in Patients With EGFRm+ and MET+, Locally Advanced or Metastatic Non Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hutchison MediPharma</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>AstraZeneca</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study (the SAVANNAH study) will investigate the efficacy of osimertinib in combination&#xD;
      with savolitinib in patients with EGFRm+ and MET+, locally advanced or metastatic NSCLC who&#xD;
      have progressed following treatment with osimertinib&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The combination of osimertinib with savolitinib in this study (the SAVANNAH study) will&#xD;
      explore if the combination will overcome MET-amplification as a mechanism of resistance. The&#xD;
      SAVANNAH study will investigate the efficacy of osimertinib in combination with savolitinib&#xD;
      in patients with EGFRm+ and MET-amplified/overexpressed, locally advanced or metastatic NSCLC&#xD;
      who have progressed following treatment with osimertinib.&#xD;
&#xD;
      Eligible patients will be those with histologically or cytologically confirmed diagnosis of&#xD;
      EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+) NSCLC that is locally advanced or&#xD;
      metastatic and is not amenable to further surgery or radiotherapy with curative intent. The&#xD;
      disease must have progressed following treatment with first line osimertinib. Patients must&#xD;
      have confirmation of MET-amplified/overexpressed tumour by central FISH and IHC testing&#xD;
      (requirements summarised in the main body of the protocol and fully explained in the Central&#xD;
      Laboratory Manual). Patients must not have received prior or current treatment with&#xD;
      savolitinib or another MET inhibitor.&#xD;
&#xD;
      All patients confirmed as eligible will begin treatment on Day 1 with osimertinib +&#xD;
      savolitinib combination therapy or placebo to osimertinib + savolitinib. Treatment will&#xD;
      continue in 28 day cycles until either objective disease progression by investigator per&#xD;
      RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn or another&#xD;
      discontinuation criterion is met.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 9, 2019</start_date>
  <completion_date type="Anticipated">February 28, 2025</completion_date>
  <primary_completion_date type="Anticipated">May 27, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Under Protocol versions 1-6 the study model was single arm (open-label).&#xD;
Starting protocol version 7 patients will be randomised in a double blinded manner to receive savolitinib in combination with osimertinib or savolitinib with placebo to osimertinib with crossover option upon disease progression assessed by Investigator.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1</measure>
    <time_frame>The primary (ORR) analysis for the study will be performed at 6 months after the last patient under CSP version 7.0 has been randomised to treatment.</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1</measure>
    <time_frame>The primary (ORR) analysis for the study will be performed at 6 months after the last patient under CSP version 7.0 has been randomised to treatment.</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) by all cause mortality.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To describe the difference in the efficacy of savolitinib (300 mg bid) in combination with osimertinib and savolitinib (300 mg bid) in combination with placebo in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib therapy under CSP version 7.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) by all cause mortality.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) by all cause mortality.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) by all cause mortality.</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR) assessed by BICR in accordance with RECIST 1.1</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR) assessed by BICR in accordance with RECIST 1.1</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) assessed by BICR in accordance with RECIST 1.1</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality-of-life questionnaire (QLQ-C30).</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in this patient population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) complementary 13-item quality-of-life questionnaire - lung cancer symptoms questionnaire (QLQ-LC13).</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in this patient population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma concentrations of osimertinib, savolitinib and their metabolites.</measure>
    <time_frame>Blood sampling on Cycles 1 and 2 on Day 1 pre-dose, 1 hour and 3 hours post-dose; Day 1 of Cycles 3, 6, and 11; discontinuation visit (if discontinued due to liver toxicity) (One cycle = 28 days)</time_frame>
    <description>To evaluate the pharmacokinetics of osimertinib and savolitinib in this patient population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies).</measure>
    <time_frame>From date of first dose until the date of first documented progression, up to approximately 36 months.</time_frame>
    <description>To determine the prevalence of ctDNA clearance after osimertinib and savolitinib treatment in this patient population.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AEs, SAEs and discontinuation rate due to AEs, as characterized and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event [CTCAE] v5.</measure>
    <time_frame>Continuously from first dose to 28 (+/-7) days after discontinuation of study drug, or up to approximately 36 months.</time_frame>
    <description>To evaluate the safety and tolerability of savolitinib in combination with osimertinib and savolitinib in combination with placebo.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>CNS PFS by BICR assessments in accordance with RECIST 1.1</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To assess the efficacy of savolitinib plus osimertinib and savolitinib plus placebo, respectively, on CNS metastases in patients with CNS metastases at baseline.</description>
  </other_outcome>
  <other_outcome>
    <measure>The presence/absence of CNS lesions at progression by BICR assessments in accordance with RECIST 1.1</measure>
    <time_frame>Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment</time_frame>
    <description>To assess the efficacy of savolitinib plus osimertinib and savolitinib plus placebo, respectively, on the prevention of CNS metastases in patients without CNS metastases at baseline.</description>
  </other_outcome>
  <other_outcome>
    <measure>PRO CTCAE symptoms</measure>
    <time_frame>From date of consent until the date of first documented progression, up to approximately 36 months.</time_frame>
    <description>To assess the impact of savolitinib in combination with osimertinib on patient reported treatment-related symptoms.</description>
  </other_outcome>
  <other_outcome>
    <measure>Patient's Global Impression of Severity (PGIS)</measure>
    <time_frame>From date of consent until the date of first documented progression, up to approximately 36 months.</time_frame>
    <description>To assess patients' overall impression of severity of cancer symptoms. In patients centrally confirmed as MET positive in all patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>EQ-5D-5L</measure>
    <time_frame>From date of consent until the date of first documented progression, up to approximately 36 months.</time_frame>
    <description>To explore the impact of treatment and disease on health state utility. In patients centrally confirmed as MET positive in all patients.</description>
  </other_outcome>
  <other_outcome>
    <measure>Longitudinal changes in circulating DNA and/or RNA compared with PFS, OS and ORR.</measure>
    <time_frame>Blood samples collected at Screening within 28 days before the first dose of study treatment; on day of first dose of study treatment; at discontinuation 7 days after last dose of study treatment. (One cycle = 28 days)</time_frame>
    <description>To assess the predictive value of changes in circulating biomarkers on clinical efficacy endpoints.</description>
  </other_outcome>
  <other_outcome>
    <measure>Pharmacogenetic analyses on blood samples.</measure>
    <time_frame>Screening within 28 days before first dose; at first dose; 7 days after last dose. (One cycle = 28 days)</time_frame>
    <description>To collect and store DNA (according to each country's local and ethical procedures) for future exploratory research into genes/genetic variation that may influence response (ie, distribution, safety, tolerability and efficacy) to study treatments and or susceptibility to disease (optional).</description>
  </other_outcome>
  <other_outcome>
    <measure>Disease relevant or response markers in tumour tissue and circulating tumour DNA/RNA including but not limited to EGFR mutations and MET amplifications.</measure>
    <time_frame>Screening within 28 days before first dose; at first dose; 7 days after last dose. Tumour tissue collected during Pre-screening and at treatment discontinuation 7 days after last dose. (One cycle = 28 days)</time_frame>
    <description>To collect and store tissue, plasma and serum samples for diagnostic development and exploratory analyses.</description>
  </other_outcome>
  <other_outcome>
    <measure>HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity).</measure>
    <time_frame>On first day of study treatment at Cycle 1 Day 1. (One cycle = 28 days)</time_frame>
    <description>To collect and store germline DNA for exploration of the role of HLA alleles in developmental toxicity.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">360</enrollment>
  <condition>Carcinoma</condition>
  <arm_group>
    <arm_group_label>osimertinib + savolitinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>osimertinib + savolitinib</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo + savolitinib</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>placebo + savolitinib</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>osimertinib</intervention_name>
    <description>osimertinib (80 mg oral OD).</description>
    <arm_group_label>osimertinib + savolitinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>savolitinib</intervention_name>
    <description>savolitinib (300 mg oral OD or 300 mg oral BID or 600 mg oral OD)</description>
    <arm_group_label>osimertinib + savolitinib</arm_group_label>
    <arm_group_label>placebo + savolitinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>placebo to osimertinib (oral OD)</description>
    <arm_group_label>placebo + savolitinib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Patients must be ≥18 years of age (≥20 years of age in Japan). All genders are&#xD;
             permitted.&#xD;
&#xD;
          -  Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC&#xD;
             harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity and&#xD;
             permitted in the osimertinib national label (such as either exon 19 deletion and/or&#xD;
             L858R) which is not amenable to curative therapy.&#xD;
&#xD;
          -  Documented radiologic disease progression on 1L osimertinib.&#xD;
&#xD;
          -  MET amplification and/or overexpression (FISH10+ and/or IHC90+) as determined by FISH&#xD;
             (central) and IHC (central) testing on tumour sample collected following progression&#xD;
             on 1L osimertinib treatment.&#xD;
&#xD;
          -  Available tumour sample for central MET FISH and IHC analysis or willingness to&#xD;
             collect additional sample for central testing which fulfils the following&#xD;
             requirements:&#xD;
&#xD;
        Obtained following progression on previous osimertinib therapy;&#xD;
&#xD;
        obtained within 2 years of submission for MET analysis;&#xD;
&#xD;
        sufficient tissue to meet the minimum tissue requirement defined in the current Laboratory&#xD;
        Manual.&#xD;
&#xD;
          -  At least 1 lesion, not previously irradiated, not biopsied during the screening&#xD;
             period, that can be accurately measured at baseline as ≥10 mm in the longest diameter&#xD;
             (except lymph nodes which must have short axis ≥15 mm) with CT or MRI which is&#xD;
             suitable for accurate repeated measurements. If only 1 measurable lesion exists, it is&#xD;
             acceptable to be used as long as baseline tumour assessment scans are done at least 14&#xD;
             days after the screening tumour sample collection is performed.&#xD;
&#xD;
          -  Prior lines of therapy in locally advanced/metastatic setting: Only prior 1L&#xD;
             osimertinib treatment in metastatic setting is permitted.&#xD;
&#xD;
          -  Adequate haematological function defined as:&#xD;
&#xD;
          -  Absolute neutrophil count ≥1500/μL&#xD;
&#xD;
          -  Haemoglobin ≥9 g/dL (no transfusion in the past 2 weeks)&#xD;
&#xD;
          -  Platelets ≥100,000/μL (no transfusion in the past 10 days)&#xD;
&#xD;
          -  Adequate liver function&#xD;
&#xD;
          -  ALT, AST ≤2.5 x ULN with TBL ≤ ULN OR&#xD;
&#xD;
          -  TBL &gt;ULN to ≤1.5x ULN with ALT and AST ≤ ULN&#xD;
&#xD;
          -  Adequate renal function - defined as a serum creatinine &lt;1.5 times the institutional&#xD;
             ULN OR a glomerular filtration rate ≥50 mL/min. Confirmation of creatinine clearance&#xD;
             is only required when creatinine is only required when creatinine is &gt;1.5 times ULN.&#xD;
&#xD;
          -  Adequate coagulation parameters: INR &lt;1.5 and activated partial thromboplastin time&#xD;
             &lt;1.5 x ULN unless patients are receiving therapeutic anti coagulation which affects&#xD;
             these parameters.&#xD;
&#xD;
          -  Patients with known tumour thrombus or deep vein thrombosis are eligible if clinically&#xD;
             stable on low molecular weight heparin for ≥2 weeks. The use of direct oral&#xD;
             anticoagulants such as apixaban/rivaroxaban will be accepted as treatment for cancer&#xD;
             related thromboembolism treatment. The use of warfarin for oral anticoagulation is not&#xD;
             recommended.&#xD;
&#xD;
          -  ECOG/WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks&#xD;
             and a minimum life expectancy of 12 weeks.&#xD;
&#xD;
          -  Females must be using highly effective contraceptive measures, should not be breast&#xD;
             feeding and must have a negative pregnancy test if of childbearing potential, or must&#xD;
             have evidence of non-childbearing potential.&#xD;
&#xD;
          -  Males with a female partner of childbearing potential should be willing to use barrier&#xD;
             contraception during the study and for 6 months following discontinuation of study&#xD;
             drug.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 at the time of&#xD;
             starting study treatment with the exception of alopecia and Grade 2 prior platinum&#xD;
             therapy related neuropathy.&#xD;
&#xD;
          -  As judged by the investigator, active gastrointestinal disease or other condition that&#xD;
             will interfere significantly with the absorption, distribution, metabolism, or&#xD;
             excretion of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting,&#xD;
             diarrhoea Grade ≥2, malabsorption syndrome or previous significant bowel resection).&#xD;
&#xD;
          -  Any of the following cardiac diseases currently or within the last 6 months:&#xD;
&#xD;
        Unstable angina pectoris&#xD;
&#xD;
        Congestive heart failure (New York Heart Association [NYHA] ≥Grade 2)&#xD;
&#xD;
        Acute myocardial infarction&#xD;
&#xD;
        Stroke or transient ischemic attack&#xD;
&#xD;
        Uncontrolled hypertension (blood pressure [BP] ≥150/95 mmHg despite medical therapy).&#xD;
&#xD;
        Mean resting correct QT interval (QTcF) &gt;470 msec for women and &gt;450 msec for men at&#xD;
        Screening, obtained from 3 ECGs using the screening clinic ECG machine derived QTcF value.&#xD;
&#xD;
        Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events&#xD;
        such as heart failure, chronic hypokalaemia not correctable with supplements, congenital or&#xD;
        familial long QT syndrome, family history of unexplained sudden death under 40 years of age&#xD;
        in first-degree relatives or any concomitant medication known to prolong the QT interval&#xD;
        and cause Torsade de Pointes.&#xD;
&#xD;
        Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs,&#xD;
        eg, complete left bundle branch block, third degree heart block, second degree heart block,&#xD;
        P-R interval &gt;250 msec.&#xD;
&#xD;
        Acute coronary syndrome&#xD;
&#xD;
          -  Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89)&#xD;
             administered ≤28 days or limited field radiation for palliation ≤7 days prior to&#xD;
             starting study drug or has not recovered from side effects of such therapy.&#xD;
&#xD;
          -  Major surgical procedures ≤28 days of beginning study drug or minor surgical&#xD;
             procedures ≤7 days&#xD;
&#xD;
          -  Evidence of severe or uncontrolled systemic diseases, including renal transplant,&#xD;
             active bleeding diatheses or uncontrolled hypertension, which in the investigator's&#xD;
             opinion makes it undesirable for the patient to participate&#xD;
&#xD;
          -  Active hepatitis B or C or known serious active infection e.g. tuberculosis or human&#xD;
             immunodeficiency virus. Viral testing is not required for assessment of eligibility&#xD;
             for the study.&#xD;
&#xD;
          -  Known serious active infection including, but not limited to, tuberculosis, or human&#xD;
             immunodeficiency virus (positive human immunodeficiency virus 1/2 antibodies).&#xD;
&#xD;
          -  Presence of other active cancers, or history of treatment for invasive cancer, within&#xD;
             the last 5 years. Patients with Stage I cancer who have received definitive local&#xD;
             treatment at least 3 years previously, and are considered unlikely to recur are&#xD;
             eligible. All patients with previously treated in situ carcinoma (ie, non-invasive)&#xD;
             are eligible, as are patients with history of non-melanoma skin cancer.&#xD;
&#xD;
          -  Spinal cord compression or brain metastases unless asymptomatic, stable and not&#xD;
             requiring steroids for at least 2 weeks prior to start of study treatment.&#xD;
&#xD;
          -  Past medical history of interstitial lung disease(ILD), drug-induced ILD, radiation&#xD;
             pneumonitis which required steroid treatment, or any evidence of clinically active&#xD;
             ILD.&#xD;
&#xD;
          -  History of liver cirrhosis of any origin and clinical stage; or history of other&#xD;
             serious liver disease or chronic disease with relevant liver involvement, with or&#xD;
             without normal LFTs,&#xD;
&#xD;
          -  Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib&#xD;
&#xD;
          -  Prior or current treatment with savolitinib or another MET inhibitor (eg, foretinib,&#xD;
             crizotinib, cabozantinib, onartuzumab, capmatinib).&#xD;
&#xD;
          -  Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the&#xD;
             treatment of advanced NSCLC from a previous treatment regimen or clinical study within&#xD;
             14 days prior to the first dose of study treatment with the exception of monotherapy&#xD;
             osimertinib which may continue uninterrupted during screening.&#xD;
&#xD;
          -  Patients currently receiving (or unable to stop use prior to receiving the first dose&#xD;
             of study treatment) medications or herbal supplements known to be strong inducers of&#xD;
             CYP3A4, strong inhibitors of CYP1A2 within 3 weeks of the first dose of study&#xD;
             treatment (including St John's Wort).&#xD;
&#xD;
          -  Participation in another clinical study with a cytotoxic, investigational product&#xD;
             (IP), or other anticancer drug for the treatment of advanced NSCLC if received IP from&#xD;
             that study within 14 days of the first dose of study treatment.&#xD;
&#xD;
          -  Known hypersensitivity to the active or inactive excipients of osimertinib or&#xD;
             savolitinib or drugs with a similar chemical structure or class.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lecia V Sequist, MD MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Myung-Ju Ahn, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Samsung Medical Centre Sungkyunkwan University School of Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>AstraZeneca Clinical Study Information Center</last_name>
    <phone>1-877-240-9479</phone>
    <email>information.center@astrazeneca.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92093</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90024</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Santa Rosa</city>
        <state>California</state>
        <zip>95403</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20016</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Boca Raton</city>
        <state>Florida</state>
        <zip>33486</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21201</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Brooklyn</city>
        <state>New York</state>
        <zip>11220</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19111</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Barretos</city>
        <zip>14784-400</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Curitiba</city>
        <zip>80810-050</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Goiania</city>
        <zip>74093-300</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Porto Alegre</city>
        <zip>90540-140</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Porto Alegre</city>
        <zip>90610-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Rio de Janeiro</city>
        <zip>22271-110</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Salvador</city>
        <zip>41950-640</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Sao Paulo</city>
        <zip>01509-900</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>São José do Rio Preto</city>
        <zip>15090-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>São Paulo</city>
        <zip>01246-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <zip>T2N 4N2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 1Z2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Newmarket</city>
        <state>Ontario</state>
        <zip>L3Y 2P9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>North York</city>
        <state>Ontario</state>
        <zip>M2K 1E1</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4N 3M5</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Santiago</city>
        <zip>7500713</zip>
        <country>Chile</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Santiago</city>
        <zip>7520349</zip>
        <country>Chile</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Santiago</city>
        <zip>8420383</zip>
        <country>Chile</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Herlev</city>
        <zip>2730</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>København Ø</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Næstved</city>
        <zip>4700</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Odense C</city>
        <zip>5000</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Vejle</city>
        <zip>7100</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Ålborg</city>
        <zip>9100</zip>
        <country>Denmark</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Dijon</city>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Marseille Cedex 20</city>
        <zip>13915</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Nantes</city>
        <zip>44093</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Paris Cedex 5</city>
        <zip>75248</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Paris</city>
        <zip>75020</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Rennes</city>
        <zip>35033</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Bangalore</city>
        <zip>560064</zip>
        <country>India</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Chennai</city>
        <zip>600035</zip>
        <country>India</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Kolkata</city>
        <zip>700160</zip>
        <country>India</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New Delhi</city>
        <zip>110085</zip>
        <country>India</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Avellino</city>
        <zip>83100</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Firenze</city>
        <zip>50134</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Milano</city>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Milano</city>
        <zip>20141</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Orbassano</city>
        <zip>10043</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Padova</city>
        <zip>35128</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Parma</city>
        <zip>43126</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Perugia</city>
        <zip>06132</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Peschiera Del Garda</city>
        <zip>37019</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Fukuoka</city>
        <zip>812-8582</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Hiroshima-shi</city>
        <zip>730-8518</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Kanazawa-shi</city>
        <zip>920-8641</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Nagoya-shi</city>
        <zip>464-8681</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Niigata-shi</city>
        <zip>951-8566</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Osakasayama</city>
        <zip>589-8511</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Sapporo-shi</city>
        <zip>003-0804</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Sunto-gun</city>
        <zip>411-8777</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Wakayama-shi</city>
        <zip>641-8510</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Yokohama-shi</city>
        <zip>241-0815</zip>
        <country>Japan</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Goyang-si</city>
        <zip>10408</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seongnam-si</city>
        <zip>13620</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seoul</city>
        <zip>03080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seoul</city>
        <zip>03722</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seoul</city>
        <zip>05505</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Seoul</city>
        <zip>06351</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Suwon</city>
        <zip>16247</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Hato Rey</city>
        <zip>00917</zip>
        <country>Puerto Rico</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Cordoba</city>
        <zip>14004</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Madrid</city>
        <zip>28041</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Madrid</city>
        <zip>28046</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Málaga</city>
        <zip>29010</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>San Sebastian</city>
        <zip>20014</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Valencia</city>
        <zip>46026</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Zaragoza</city>
        <zip>50009</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Hsinchu</city>
        <zip>300</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Kaohsiung</city>
        <zip>83301</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>New Taipei</city>
        <zip>23561</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Taichung City</city>
        <zip>402</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Taichung</city>
        <zip>40705</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Tainan City</city>
        <zip>70403</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Taipei City</city>
        <zip>110</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Taipei</city>
        <zip>10002</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Taipei</city>
        <zip>112</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Taoyuan</city>
        <zip>333</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Ha Noi</city>
        <zip>100000</zip>
        <country>Vietnam</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Ha Noi</city>
        <zip>100000</zip>
        <country>Vietnam</country>
      </address>
    </facility>
    <status>Withdrawn</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Ho Chi Minh City</city>
        <zip>700000</zip>
        <country>Vietnam</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Ho Chi Minh</city>
        <zip>700000</zip>
        <country>Vietnam</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>Brazil</country>
    <country>Canada</country>
    <country>Chile</country>
    <country>Denmark</country>
    <country>France</country>
    <country>India</country>
    <country>Italy</country>
    <country>Japan</country>
    <country>Korea, Republic of</country>
    <country>Puerto Rico</country>
    <country>Spain</country>
    <country>Taiwan</country>
    <country>United States</country>
    <country>Vietnam</country>
  </location_countries>
  <removed_countries>
    <country>Israel</country>
  </removed_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>November 30, 2018</study_first_submitted>
  <study_first_submitted_qc>December 14, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>September 6, 2023</last_update_submitted>
  <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Non Small Cell Lung Cancer</keyword>
  <keyword>epidermal growth factor receptor mutation positive</keyword>
  <keyword>hepatocyte growth factor receptor</keyword>
  <keyword>savolitinib</keyword>
  <keyword>Osimertinib</keyword>
  <keyword>AZD9291</keyword>
  <keyword>AZD6094</keyword>
  <keyword>volitinib</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osimertinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.</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>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03778229
org study id: D5084C00007
secondary id: 2018-003012-51
nct id: NCT03778229
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study (the SAVANNAH study) will investigate the efficacy of osimertinib in combination
      with savolitinib in patients with EGFRm+ and MET+, locally advanced or metastatic NSCLC who
      have progressed following treatment with osimertinib
The combination of osimertinib with savolitinib in this study (the SAVANNAH study) will
      explore if the combination will overcome MET-amplification as a mechanism of resistance. The
      SAVANNAH study will investigate the efficacy of osimertinib in combination with savolitinib
      in patients with EGFRm+ and MET-amplified/overexpressed, locally advanced or metastatic NSCLC
      who have progressed following treatment with osimertinib.

      Eligible patients will be those with histologically or cytologically confirmed diagnosis of
      EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+) NSCLC that is locally advanced or
      metastatic and is not amenable to further surgery or radiotherapy with curative intent. The
      disease must have progressed following treatment with first line osimertinib. Patients must
      have confirmation of MET-amplified/overexpressed tumour by central FISH and IHC testing
      (requirements summarised in the main body of the protocol and fully explained in the Central
      Laboratory Manual). Patients must not have received prior or current treatment with
      savolitinib or another MET inhibitor.

      All patients confirmed as eligible will begin treatment on Day 1 with osimertinib +
      savolitinib combination therapy or placebo to osimertinib + savolitinib. Treatment will
      continue in 28 day cycles until either objective disease progression by investigator per
      RECIST 1.1 is assessed, unacceptable toxicity occurs, consent is withdrawn or another
      discontinuation criterion is met.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Under Protocol versions 1-6 the study model was single arm (open-label).
Starting protocol version 7 patients will be randomised in a double blinded manner to receive savolitinib in combination with osimertinib or savolitinib with placebo to osimertinib with crossover option upon disease progression assessed by Investigator.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1
time frame: The primary (ORR) analysis for the study will be performed at 6 months after the last patient under CSP version 7.0 has been randomised to treatment.
description: To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1
time frame: The primary (ORR) analysis for the study will be performed at 6 months after the last patient under CSP version 7.0 has been randomised to treatment.
description: To determine the efficacy of savolitinib (300 mg od) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.
measure: Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
measure: Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
measure: Overall Survival (OS) by all cause mortality.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg bid) in combination with osimertinib in patients with EGFRm+ and MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To describe the difference in the efficacy of savolitinib (300 mg bid) in combination with osimertinib and savolitinib (300 mg bid) in combination with placebo in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib therapy under CSP version 7.0.
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
measure: Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
measure: Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
measure: Overall Survival (OS) by all cause mortality.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment with 1L osimertinib.
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.
measure: Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.
measure: Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.
measure: Overall Survival (OS) by all cause mortality.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH10+ and/or IHC90+), locally advanced or metastatic NSCLC who have progressed following treatment of ≥ 2L osimertinib.
measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.
measure: Duration of Response (DoR) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.
measure: Progression-free survival (PFS) by investigator assessment in accordance with RECIST 1.1.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.
measure: Overall Survival (OS) by all cause mortality.
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of savolitinib (300 mg od, 300 mg bid, and 600 mg od, respectively) in combination with osimertinib in patients with EGFRm+, MET amplified/overexpressed (FISH5+ and/or IHC50+), locally advanced or metastatic NSCLC who have progressed following osimertinib.
measure: Objective response rate (ORR) assessed by BICR in accordance with RECIST 1.1
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib.
measure: Duration of Response (DoR) assessed by BICR in accordance with RECIST 1.1
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib.
measure: Progression-free survival (PFS) assessed by BICR in accordance with RECIST 1.1
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To determine the efficacy of (1) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/ overexpressed (FISH 10+ and/or IHC90+); (2) 300 mg od, 300 mg bid and 600 mg od of savolitinib in combination with osimertinib in patients with EGFRm+ MET amplified/overexpressed (FISH5+ and/or IHC50+) (3) savolitinib 300 mg bid in combination with osimertinib and savolitinib 300 mg bid in combination with placebo, respectively, in patients with EGFRm+ MET amplified/ overexpressed (FISH10+ and/or IHC90+) following treatment with 1L osimertinib.
measure: Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality-of-life questionnaire (QLQ-C30).
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in this patient population.
measure: Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) complementary 13-item quality-of-life questionnaire - lung cancer symptoms questionnaire (QLQ-LC13).
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in this patient population.
measure: Plasma concentrations of osimertinib, savolitinib and their metabolites.
time frame: Blood sampling on Cycles 1 and 2 on Day 1 pre-dose, 1 hour and 3 hours post-dose; Day 1 of Cycles 3, 6, and 11; discontinuation visit (if discontinued due to liver toxicity) (One cycle = 28 days)
description: To evaluate the pharmacokinetics of osimertinib and savolitinib in this patient population.
measure: Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies).
time frame: From date of first dose until the date of first documented progression, up to approximately 36 months.
description: To determine the prevalence of ctDNA clearance after osimertinib and savolitinib treatment in this patient population.
measure: AEs, SAEs and discontinuation rate due to AEs, as characterized and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event [CTCAE] v5.
time frame: Continuously from first dose to 28 (+/-7) days after discontinuation of study drug, or up to approximately 36 months.
description: To evaluate the safety and tolerability of savolitinib in combination with osimertinib and savolitinib in combination with placebo.
measure: CNS PFS by BICR assessments in accordance with RECIST 1.1
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To assess the efficacy of savolitinib plus osimertinib and savolitinib plus placebo, respectively, on CNS metastases in patients with CNS metastases at baseline.
measure: The presence/absence of CNS lesions at progression by BICR assessments in accordance with RECIST 1.1
time frame: Up to 15 months after the last patient under CSP version 7.0 has been randomised to treatment
description: To assess the efficacy of savolitinib plus osimertinib and savolitinib plus placebo, respectively, on the prevention of CNS metastases in patients without CNS metastases at baseline.
measure: PRO CTCAE symptoms
time frame: From date of consent until the date of first documented progression, up to approximately 36 months.
description: To assess the impact of savolitinib in combination with osimertinib on patient reported treatment-related symptoms.
measure: Patient's Global Impression of Severity (PGIS)
time frame: From date of consent until the date of first documented progression, up to approximately 36 months.
description: To assess patients' overall impression of severity of cancer symptoms. In patients centrally confirmed as MET positive in all patients.
measure: EQ-5D-5L
time frame: From date of consent until the date of first documented progression, up to approximately 36 months.
description: To explore the impact of treatment and disease on health state utility. In patients centrally confirmed as MET positive in all patients.
measure: Longitudinal changes in circulating DNA and/or RNA compared with PFS, OS and ORR.
time frame: Blood samples collected at Screening within 28 days before the first dose of study treatment; on day of first dose of study treatment; at discontinuation 7 days after last dose of study treatment. (One cycle = 28 days)
description: To assess the predictive value of changes in circulating biomarkers on clinical efficacy endpoints.
measure: Pharmacogenetic analyses on blood samples.
time frame: Screening within 28 days before first dose; at first dose; 7 days after last dose. (One cycle = 28 days)
description: To collect and store DNA (according to each country's local and ethical procedures) for future exploratory research into genes/genetic variation that may influence response (ie, distribution, safety, tolerability and efficacy) to study treatments and or susceptibility to disease (optional).
measure: Disease relevant or response markers in tumour tissue and circulating tumour DNA/RNA including but not limited to EGFR mutations and MET amplifications.
time frame: Screening within 28 days before first dose; at first dose; 7 days after last dose. Tumour tissue collected during Pre-screening and at treatment discontinuation 7 days after last dose. (One cycle = 28 days)
description: To collect and store tissue, plasma and serum samples for diagnostic development and exploratory analyses.
measure: HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity).
time frame: On first day of study treatment at Cycle 1 Day 1. (One cycle = 28 days)
description: To collect and store germline DNA for exploration of the role of HLA alleles in developmental toxicity.
arm group label: osimertinib + savolitinib
arm group type: Experimental
description: osimertinib + savolitinib
arm group label: placebo + savolitinib
arm group type: Placebo Comparator
description: placebo + savolitinib
intervention type: Drug
intervention name: osimertinib
description: osimertinib (80 mg oral OD).
arm group label: osimertinib + savolitinib
intervention type: Drug
intervention name: savolitinib
description: savolitinib (300 mg oral OD or 300 mg oral BID or 600 mg oral OD)
arm group label: osimertinib + savolitinib
arm group label: placebo + savolitinib
intervention type: Drug
intervention name: placebo
description: placebo to osimertinib (oral OD)
arm group label: placebo + savolitinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lecia V Sequist, MD MPH
role: Principal Investigator
affiliation: Massachusetts General Hospital
last name: Myung-Ju Ahn, MD
role: Principal Investigator
affiliation: Samsung Medical Centre Sungkyunkwan University School of Medicine
last name: AstraZeneca Clinical Study Information Center
phone: 1-877-240-9479
email: information.center@astrazeneca.com
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Withdrawn
facility: 
status: Withdrawn
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Terminated
facility: 
status: Withdrawn
facility: 
status: Withdrawn
facility: 
status: Terminated
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Terminated
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Completed
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
facility: 
status: Completed
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Completed
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Terminated
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Withdrawn
facility: 
status: Recruiting
facility: 
status: Recruiting
country: Brazil
country: Canada
country: Chile
country: Denmark
country: France
country: India
country: Italy
country: Japan
country: Korea, Republic of
country: Puerto Rico
country: Spain
country: Taiwan
country: United States
country: Vietnam
country: Israel
responsible party type: Sponsor
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