<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/NCT02971501</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2016-01733</org_study_id>
    <secondary_id>NCI-2016-01733</secondary_id>
    <secondary_id>2000021123</secondary_id>
    <secondary_id>10042</secondary_id>
    <secondary_id>10042</secondary_id>
    <secondary_id>10042</secondary_id>
    <secondary_id>UM1CA186689</secondary_id>
    <nct_id>NCT02971501</nct_id>
  </id_info>
  <brief_title>Osimertinib With or Without Bevacizumab in Treating Patients With EGFR Positive Non-small Cell Lung Cancer and Brain Metastases</brief_title>
  <official_title>A Phase II Trial of Osimertinib (AZD9291) With or Without Bevacizumab in Patients With EGFR Mutation Positive NSCLC and Brain Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</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 phase II trial studies how well osimertinib with or without bevacizumab works in&#xD;
      treating patients with EGFR positive non-small cell lung cancer that has spread to the brain&#xD;
      (brain metastases). Osimertinib may stop the growth of tumor cells by blocking some of the&#xD;
      enzymes needed for cell growth. Bevacizumab may stop or slow non-small cell lung cancer by&#xD;
      blocking the growth of new blood vessels necessary for tumor growth. Giving osimertinib with&#xD;
      or without bevacizumab may work better in treating patients with non-small cell lung cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To determine the progression-free survival with osimertinib (AZD9291) plus bevacizumab&#xD;
      compared to osimertinib (AZD9291) alone.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess the safety and tolerability of the combination of osimertinib (AZD9291) and&#xD;
      bevacizumab.&#xD;
&#xD;
      II. To evaluate the time to progression in the central nervous system (CNS) with osimertinib&#xD;
      (AZD9291) plus bevacizumab versus single-agent osimertinib (AZD9291).&#xD;
&#xD;
      III. To determine the overall response rate and the intracranial response rate to the&#xD;
      combination versus single agent.&#xD;
&#xD;
      IV. To assess the overall survival in patients receiving osimertinib (AZD9291) plus&#xD;
      bevacizumab compared to osimertinib (AZD9291) alone.&#xD;
&#xD;
      TRANSLATIONAL OBJECTIVES:&#xD;
&#xD;
      I. To investigate mechanisms of sensitivity and resistance to combination osimertinib&#xD;
      (AZD9291) plus bevacizumab versus osimertinib (AZD9291) by molecularly characterizing tumor&#xD;
      samples including T790M status.&#xD;
&#xD;
      II. To assess whether circulating tumor deoxyribonucleic acid (DNA) in plasma can be used as&#xD;
      an indicator of sensitivity and resistance to treatment.&#xD;
&#xD;
      III. To determine whether an angiogenic signature using a multiplex panel array is associated&#xD;
      with benefit from the combination of osimertinib (AZD9291) plus bevacizumab.&#xD;
&#xD;
      IV. To investigate angiogenesis, immune and signaling pathway markers in tumor samples to&#xD;
      determine biomarkers predictive of benefit from combination therapy.&#xD;
&#xD;
      OUTLINE: Patients are randomized to 1 of 2 arms.&#xD;
&#xD;
      ARM I: Patients receive osimertinib orally (PO) once daily (QD) on days 1-21 and bevacizumab&#xD;
      intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of&#xD;
      disease progression or unacceptable toxicity.&#xD;
&#xD;
      ARM II: Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the&#xD;
      absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), tumor&#xD;
      biopsy and blood sample collection throughout the study.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for a minimum of 4 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 27, 2018</start_date>
  <completion_date type="Anticipated">July 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">July 1, 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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>From start of treatment to time of progression (in CNS or non-CNS disease) or death, whichever occurs first, assessed up to 2 years</time_frame>
    <description>The two study arms will be compared for PFS with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>From start of treatment to death, assessed up to 2 years</time_frame>
    <description>The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OS rate</measure>
    <time_frame>At 12 months</time_frame>
    <description>The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Assessed by Common Terminology Criteria for Adverse Events. Adverse medical events will be tabulated. National Cancer Institute toxicity grade 1 to grade 4 laboratory abnormalities will be listed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response rate</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intracranial response rate</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to intracranial progression</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Will be assessed by Response Assessment in Neuro-Oncology Brain Metastases.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain metastasis response rate</measure>
    <time_frame>Up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to central nervous system (CNS) progression</measure>
    <time_frame>From start of treatment to time of progression in the CNS, assessed up to 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intracranial response</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Assessed by Response Assessment in Neuro-Oncology Criteria-Glioblastoma Multiforme. Will be estimated using the 95% confidence interval CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ratios will be reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response defined as a complete or partial response</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Will be determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Molecular characterization</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Analysis will be completed using Lasso-based elastic net method.</description>
  </other_outcome>
  <other_outcome>
    <measure>Circulating tumor deoxyribonucleic acid assessed in plasma</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Analysis will be completed using Lasso-based elastic net method.</description>
  </other_outcome>
  <other_outcome>
    <measure>Angiogenic signature assessed in plasma by multiplex panel array</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Analysis will be completed using Lasso-based elastic net method.</description>
  </other_outcome>
  <other_outcome>
    <measure>Biomarker analysis of angiogenesis and signaling pathways</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Analysis will be completed using Lasso-based elastic net method.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in the tumor immune microenvironment</measure>
    <time_frame>Baseline to 2 years</time_frame>
    <description>Analysis will be completed using Lasso-based elastic net method.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">112</enrollment>
  <condition>Metastatic Lung Non-Small Cell Carcinoma</condition>
  <condition>Metastatic Malignant Neoplasm in the Brain</condition>
  <condition>Stage IV Lung Cancer AJCC v8</condition>
  <arm_group>
    <arm_group_label>Arm I (osimertinib, bevacizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II (osimertinib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm I (osimertinib, bevacizumab)</arm_group_label>
    <other_name>ABP 215</other_name>
    <other_name>Anti-VEGF</other_name>
    <other_name>Anti-VEGF Humanized Monoclonal Antibody</other_name>
    <other_name>Anti-VEGF Monoclonal Antibody SIBP04</other_name>
    <other_name>Anti-VEGF rhuMAb</other_name>
    <other_name>Avastin</other_name>
    <other_name>BAT 1706</other_name>
    <other_name>BAT-1706</other_name>
    <other_name>BAT1706</other_name>
    <other_name>BAT1706 Biosimilar</other_name>
    <other_name>Bevacizumab awwb</other_name>
    <other_name>Bevacizumab Biosimilar ABP 215</other_name>
    <other_name>Bevacizumab Biosimilar BAT1706</other_name>
    <other_name>Bevacizumab Biosimilar BEVZ92</other_name>
    <other_name>Bevacizumab Biosimilar BI 695502</other_name>
    <other_name>Bevacizumab Biosimilar CBT 124</other_name>
    <other_name>Bevacizumab Biosimilar CT-P16</other_name>
    <other_name>Bevacizumab Biosimilar FKB238</other_name>
    <other_name>Bevacizumab Biosimilar GB-222</other_name>
    <other_name>Bevacizumab Biosimilar HD204</other_name>
    <other_name>Bevacizumab Biosimilar HLX04</other_name>
    <other_name>Bevacizumab Biosimilar IBI305</other_name>
    <other_name>Bevacizumab Biosimilar LY01008</other_name>
    <other_name>Bevacizumab Biosimilar MIL60</other_name>
    <other_name>Bevacizumab Biosimilar Mvasi</other_name>
    <other_name>Bevacizumab Biosimilar MYL-1402O</other_name>
    <other_name>Bevacizumab Biosimilar QL 1101</other_name>
    <other_name>Bevacizumab Biosimilar QL1101</other_name>
    <other_name>Bevacizumab Biosimilar RPH-001</other_name>
    <other_name>Bevacizumab Biosimilar SCT501</other_name>
    <other_name>Bevacizumab Biosimilar Zirabev</other_name>
    <other_name>Bevacizumab-adcd</other_name>
    <other_name>Bevacizumab-awwb</other_name>
    <other_name>Bevacizumab-bvzr</other_name>
    <other_name>BP102</other_name>
    <other_name>BP102 Biosimilar</other_name>
    <other_name>CT-P16</other_name>
    <other_name>HD204</other_name>
    <other_name>Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer</other_name>
    <other_name>Mvasi</other_name>
    <other_name>MYL-1402O</other_name>
    <other_name>QL1101</other_name>
    <other_name>Recombinant Humanized Anti-VEGF Monoclonal Antibody</other_name>
    <other_name>rhuMab-VEGF</other_name>
    <other_name>SCT501</other_name>
    <other_name>SIBP 04</other_name>
    <other_name>SIBP-04</other_name>
    <other_name>SIBP04</other_name>
    <other_name>Vegzelma</other_name>
    <other_name>Zirabev</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biopsy</intervention_name>
    <description>Undergo tumor biopsy</description>
    <arm_group_label>Arm I (osimertinib, bevacizumab)</arm_group_label>
    <other_name>BIOPSY_TYPE</other_name>
    <other_name>Bx</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biospecimen Collection</intervention_name>
    <description>Undergo blood sample collection</description>
    <arm_group_label>Arm I (osimertinib, bevacizumab)</arm_group_label>
    <other_name>Biological Sample Collection</other_name>
    <other_name>Biospecimen Collected</other_name>
    <other_name>Specimen Collection</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Computed Tomography</intervention_name>
    <description>Undergo CT scan</description>
    <arm_group_label>Arm I (osimertinib, bevacizumab)</arm_group_label>
    <other_name>CAT</other_name>
    <other_name>CAT Scan</other_name>
    <other_name>Computed Axial Tomography</other_name>
    <other_name>Computerized Axial Tomography</other_name>
    <other_name>Computerized axial tomography (procedure)</other_name>
    <other_name>Computerized Tomography</other_name>
    <other_name>CT</other_name>
    <other_name>CT Scan</other_name>
    <other_name>tomography</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Magnetic Resonance Imaging</intervention_name>
    <description>Undergo MRI</description>
    <arm_group_label>Arm I (osimertinib, bevacizumab)</arm_group_label>
    <other_name>Magnetic Resonance</other_name>
    <other_name>Magnetic resonance imaging (procedure)</other_name>
    <other_name>Magnetic Resonance Imaging Scan</other_name>
    <other_name>Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance</other_name>
    <other_name>MR</other_name>
    <other_name>MR Imaging</other_name>
    <other_name>MRI</other_name>
    <other_name>MRI Scan</other_name>
    <other_name>NMR Imaging</other_name>
    <other_name>NMRI</other_name>
    <other_name>Nuclear Magnetic Resonance Imaging</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Osimertinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm I (osimertinib, bevacizumab)</arm_group_label>
    <arm_group_label>Arm II (osimertinib)</arm_group_label>
    <other_name>AZD-9291</other_name>
    <other_name>AZD9291</other_name>
    <other_name>Mereletinib</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion,&#xD;
             L858R point mutation, or any other mutation known to be associated with EGFR TKI&#xD;
             sensitivity); presence of an activating EGFR mutation may be documented in tumor&#xD;
             tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act&#xD;
             (CLIA)-certified laboratory&#xD;
&#xD;
          -  No prior treatment with an EGFR TKI; patient may have received prior chemotherapy for&#xD;
             early-stage or advanced disease but this is not required; prior immunotherapy is not&#xD;
             allowed&#xD;
&#xD;
          -  Patients must have at least one measurable CNS lesion that is asymptomatic, untreated,&#xD;
             and does not require local therapy at the time of enrollment; measurable CNS disease&#xD;
             is defined as a brain metastasis that can be accurately measured in at least one&#xD;
             dimension (longest diameter to be recorded) as &gt;= 5 mm (&gt;= 0.5 cm) with brain magnetic&#xD;
             resonance imaging (MRI); if the lesion is 5-10 mm in size and is the only measurable&#xD;
             disease, MRI imaging must be performed with 1.5 mm slice thickness or less; a history&#xD;
             of previously treated brain metastases is allowed, however any lesion present at the&#xD;
             time of whole brain radiotherapy or included in the stereotactic radiotherapy field&#xD;
             (or within 2 mm of the treated lesion) will NOT be considered &quot;untreated&quot; unless it is&#xD;
             new or documented to have progressed unequivocally since treatment&#xD;
&#xD;
          -  Patients are not required to have measurable systemic (i.e. non-CNS) disease; if&#xD;
             present, measurable systemic disease must be able to be accurately measured in at&#xD;
             least one dimension (longest diameter to be recorded for non-nodal lesions and short&#xD;
             axis for nodal lesions) as &gt;= 20 mm (&gt;= 2 cm) with conventional techniques or as &gt;= 10&#xD;
             mm (&gt;= 1 cm) with spiral computed tomography (CT) scan, MRI, or calipers by clinical&#xD;
             exam&#xD;
&#xD;
          -  Age &gt;= 18 years&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2&#xD;
&#xD;
          -  Life expectancy of greater than 3 months&#xD;
&#xD;
          -  The use of anti-convulsants is allowed, as long as the patient is on a stable dose&#xD;
             with no seizure activity for at least 2 weeks prior to initiating trial therapy&#xD;
&#xD;
          -  Female subjects should be using highly effective contraceptive measures, and must have&#xD;
             a negative pregnancy test and not be breast-feeding prior to start of dosing if of&#xD;
             child- bearing potential or must have evidence of non-child-bearing potential by&#xD;
             fulfilling one of the following criteria at screening:&#xD;
&#xD;
               -  Post-menopausal defined as aged more than 50 years and amenorrheic for at least&#xD;
                  12 months following cessation of all exogenous hormonal treatments&#xD;
&#xD;
               -  Women under 50 years old would be consider postmenopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of exogenous hormonal&#xD;
                  treatments and with luteinizing hormone (LH) and follicle stimulating hormone&#xD;
                  (FSH) levels in the post-menopausal range for the institution&#xD;
&#xD;
               -  Documentation of irreversible surgical sterilization by hysterectomy, bilateral&#xD;
                  oophorectomy or bilateral salpingectomy but not tubal ligation&#xD;
&#xD;
          -  Fertile men should be willing to use barrier contraception during and for 4 months&#xD;
             after osimertinib (AZD9291), and fertile women must agree to use adequate&#xD;
             contraceptive measures during and for 6 weeks after osimertinib (AZD9291); fertile men&#xD;
             and women must agree to use adequate contraceptive measures during study therapy and&#xD;
             for at least 6 months after the completion of bevacizumab therapy; should a woman&#xD;
             become pregnant or suspect she is pregnant while she or her partner is participating&#xD;
             in this study, the patient should inform the treating physician immediately&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Symptomatic brain metastases or symptomatic leptomeningeal disease; asymptomatic&#xD;
             leptomeningeal disease is allowed&#xD;
&#xD;
          -  Patients with brain metastases for whom complete surgical resection is clinically&#xD;
             appropriate&#xD;
&#xD;
          -  Prior treatment with any EGFR TKI&#xD;
&#xD;
          -  Prior treatment with agents targeting the VEGF pathway, including bevacizumab&#xD;
&#xD;
          -  The use of corticosteroids to control cerebral edema or treat neurologic symptoms will&#xD;
             not be allowed, and patients who previously required corticosteroids for symptom&#xD;
             control must be off steroids for at least 3 days without recurrence of symptoms prior&#xD;
             to starting trial therapy; corticosteroids for other indications is allowed&#xD;
&#xD;
          -  Patients may not be receiving any other investigational agents and may not have&#xD;
             participated in a study of an investigational agent or using an investigational device&#xD;
             within five half-lives of the compound or 3 months, whichever is greater&#xD;
&#xD;
          -  Any unresolved toxicities from prior therapy greater than Common Terminology Criteria&#xD;
             for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the&#xD;
             exception of alopecia and grade 2 platinum-therapy related neuropathy&#xD;
&#xD;
          -  Concurrent, active malignancies in addition to that being studied (other than&#xD;
             cutaneous squamous cell carcinoma or basal cell carcinoma)&#xD;
&#xD;
          -  Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted&#xD;
             medical devices)&#xD;
&#xD;
          -  Past medical history of interstitial lung disease, drug-induced interstitial lung&#xD;
             disease, radiation pneumonitis which required steroid treatment, or any evidence of&#xD;
             clinically active interstitial lung disease&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to osimertinib (AZD9291) or bevacizumab&#xD;
&#xD;
          -  Urine protein should be screened by urine analysis; if protein is 2+ or higher,&#xD;
             24-hour urine protein should be obtained; patients with 24-hour urine protein &gt;= 1000&#xD;
             mg are excluded&#xD;
&#xD;
          -  Serious or non-healing wound, ulcer or bone fracture&#xD;
&#xD;
          -  History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess&#xD;
             within 6 months prior to day 1&#xD;
&#xD;
          -  Invasive procedures defined as follows:&#xD;
&#xD;
               -  Major surgical procedure, open biopsy or significant traumatic injury within 28&#xD;
                  days prior to day 1 therapy&#xD;
&#xD;
               -  Anticipation of need for major surgical procedures during the course of the study&#xD;
&#xD;
               -  Core biopsy within 7 days prior to day 1 (D1) therapy&#xD;
&#xD;
          -  Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or&#xD;
             recent peripheral arterial thrombosis) within 6 months prior to day 1&#xD;
&#xD;
          -  Patients with clinically significant cardiovascular disease are excluded&#xD;
&#xD;
               -  Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] &gt; 160&#xD;
                  mmHg and/or diastolic blood pressure [DBP] &gt; 90 mmHg despite antihypertensive&#xD;
                  medication)&#xD;
&#xD;
               -  History of cerebrovascular accident (CVA) within 6 months (see additional&#xD;
                  requirement for adjuvant protocols)&#xD;
&#xD;
               -  Myocardial infarction or unstable angina within 6 months (see additional&#xD;
                  requirement for adjuvant protocols)&#xD;
&#xD;
               -  New York Heart Association grade II or greater congestive heart failure&#xD;
&#xD;
               -  Serious and inadequately controlled cardiac arrhythmia&#xD;
&#xD;
               -  Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)&#xD;
&#xD;
               -  Clinically significant peripheral vascular disease&#xD;
&#xD;
          -  Any of the following cardiac criteria:&#xD;
&#xD;
               -  Mean resting corrected QT interval (Fridericia's correction formula [QTcF]) &gt; 470&#xD;
                  ms obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG&#xD;
                  machine derived corrected QT (QTc) value&#xD;
&#xD;
               -  Any clinically important abnormalities in rhythm, conduction or morphology of&#xD;
                  resting ECG (e.g., complete left bundle branch block, third degree heart block,&#xD;
                  second degree heart block)&#xD;
&#xD;
               -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic&#xD;
                  events such as heart failure, hypokalemia, congenital long QT syndrome, family&#xD;
                  history of long QT syndrome or unexplained sudden death under 40 years of age in&#xD;
                  first degree relatives or any concomitant medication known to prolong the QT&#xD;
                  interval&#xD;
&#xD;
          -  Evidence of bleeding diathesis or coagulopathy (including clinically significant&#xD;
             hemoptysis)&#xD;
&#xD;
          -  Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to&#xD;
             swallow the formulated product or previous significant bowel resection that would&#xD;
             preclude adequate absorption of osimertinib (AZD9291)&#xD;
&#xD;
          -  Patients with known hypersensitivity to Chinese hamster ovary cell products or other&#xD;
             recombinant human antibodies&#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 potent inducers of&#xD;
             CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any&#xD;
             medications, herbal supplements and/or ingestion of foods with known inducer effects&#xD;
             on CYP3A4&#xD;
&#xD;
          -  Any evidence of severe or uncontrolled systemic diseases, including, but not limited&#xD;
             to, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina&#xD;
             pectoris, cardiac arrhythmia, or psychiatric illness/social situations which in the&#xD;
             investigator's opinion makes it undesirable for the patient to participate in the&#xD;
             trial or which would jeopardize compliance with the protocol, or active infection&#xD;
             including hepatitis B, hepatitis C and human immunodeficiency virus (HIV); screening&#xD;
             for chronic conditions is not required&#xD;
&#xD;
          -  History of hypersensitivity active or inactive excipients of osimertinib (AZD9291) or&#xD;
             drugs with a similar chemical structure or class to osimertinib (AZD9291)&#xD;
&#xD;
          -  Absolute neutrophil count &lt; 1.5 x 10^9/L&#xD;
&#xD;
          -  Platelet count &lt; 100 x 10^9/L&#xD;
&#xD;
          -  Hemoglobin &lt; 90 g/L&#xD;
&#xD;
          -  Alanine aminotransferase &gt; 2.5 times upper limit of normal (ULN) if no demonstrable&#xD;
             liver metastases or &gt; 5 times ULN in the presence of liver metastases; aspartate&#xD;
             aminotransferase &gt; 2.5 times ULN if no demonstrable liver metastases or &gt; 5 times ULN&#xD;
             in the presence of liver metastases&#xD;
&#xD;
          -  Total bilirubin &gt; 1.5 times ULN if no liver metastases or &gt; 3 times ULN in the&#xD;
             presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver&#xD;
             metastases&#xD;
&#xD;
          -  Serum creatinine &gt; 1.5 times ULN concurrent with creatinine clearance &lt; 50 mL/min&#xD;
             (measured or calculated by Cockcroft and Gault equation)-confirmation of creatinine&#xD;
             clearance is only required when creatinine is &gt; 1.5 times ULN&#xD;
&#xD;
          -  Judgment by the investigator that the patient should not participate in the study if&#xD;
             the patient is unlikely to comply with study procedures, restrictions and requirements&#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>Sarah B Goldberg</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University Cancer Center LAO</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Los Angeles County-USC Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>USC / Norris Comprehensive Cancer Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Keck Medical Center of USC Pasadena</name>
      <address>
        <city>Pasadena</city>
        <state>California</state>
        <zip>91105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California Davis Comprehensive Cancer Center</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95817</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Smilow Cancer Center/Yale-New Haven Hospital</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06510</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yale University</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center-International Plaza</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33607</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Clinical Research Center</name>
      <address>
        <city>Fairway</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas Hospital-Westwood Cancer Center</name>
      <address>
        <city>Westwood</city>
        <state>Kansas</state>
        <zip>66205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nebraska Medicine-Bellevue</name>
      <address>
        <city>Bellevue</city>
        <state>Nebraska</state>
        <zip>68123</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nebraska Medicine-Village Pointe</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68118</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Nebraska Medical Center</name>
      <address>
        <city>Omaha</city>
        <state>Nebraska</state>
        <zip>68198</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ohio State University Comprehensive Cancer Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Oklahoma Health Sciences Center</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh Cancer Institute (UPCI)</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Huntsman Cancer Institute/University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84112</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>November 21, 2016</study_first_submitted>
  <study_first_submitted_qc>November 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 23, 2016</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bevacizumab</mesh_term>
    <mesh_term>Antineoplastic Agents, Immunological</mesh_term>
    <mesh_term>Osimertinib</mesh_term>
    <mesh_term>Endothelial Growth Factors</mesh_term>
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
    <mesh_term>Immunoglobulin G</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02971501
org study id: NCI-2016-01733
secondary id: NCI-2016-01733
secondary id: 2000021123
secondary id: 10042
secondary id: 10042
secondary id: 10042
secondary id: UM1CA186689
nct id: NCT02971501
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies how well osimertinib with or without bevacizumab works in
      treating patients with EGFR positive non-small cell lung cancer that has spread to the brain
      (brain metastases). Osimertinib may stop the growth of tumor cells by blocking some of the
      enzymes needed for cell growth. Bevacizumab may stop or slow non-small cell lung cancer by
      blocking the growth of new blood vessels necessary for tumor growth. Giving osimertinib with
      or without bevacizumab may work better in treating patients with non-small cell lung cancer.
PRIMARY OBJECTIVE:

      I. To determine the progression-free survival with osimertinib (AZD9291) plus bevacizumab
      compared to osimertinib (AZD9291) alone.

      SECONDARY OBJECTIVES:

      I. To assess the safety and tolerability of the combination of osimertinib (AZD9291) and
      bevacizumab.

      II. To evaluate the time to progression in the central nervous system (CNS) with osimertinib
      (AZD9291) plus bevacizumab versus single-agent osimertinib (AZD9291).

      III. To determine the overall response rate and the intracranial response rate to the
      combination versus single agent.

      IV. To assess the overall survival in patients receiving osimertinib (AZD9291) plus
      bevacizumab compared to osimertinib (AZD9291) alone.

      TRANSLATIONAL OBJECTIVES:

      I. To investigate mechanisms of sensitivity and resistance to combination osimertinib
      (AZD9291) plus bevacizumab versus osimertinib (AZD9291) by molecularly characterizing tumor
      samples including T790M status.

      II. To assess whether circulating tumor deoxyribonucleic acid (DNA) in plasma can be used as
      an indicator of sensitivity and resistance to treatment.

      III. To determine whether an angiogenic signature using a multiplex panel array is associated
      with benefit from the combination of osimertinib (AZD9291) plus bevacizumab.

      IV. To investigate angiogenesis, immune and signaling pathway markers in tumor samples to
      determine biomarkers predictive of benefit from combination therapy.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive osimertinib orally (PO) once daily (QD) on days 1-21 and bevacizumab
      intravenously (IV) over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of
      disease progression or unacceptable toxicity.

      ARM II: Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the
      absence of disease progression or unacceptable toxicity.

      Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), tumor
      biopsy and blood sample collection throughout the study.

      After completion of study treatment, patients are followed up for a minimum of 4 weeks.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression free survival (PFS)
time frame: From start of treatment to time of progression (in CNS or non-CNS disease) or death, whichever occurs first, assessed up to 2 years
description: The two study arms will be compared for PFS with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
measure: Overall survival (OS)
time frame: From start of treatment to death, assessed up to 2 years
description: The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
measure: OS rate
time frame: At 12 months
description: The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
measure: Incidence of adverse events
time frame: Up to 2 years
description: Assessed by Common Terminology Criteria for Adverse Events. Adverse medical events will be tabulated. National Cancer Institute toxicity grade 1 to grade 4 laboratory abnormalities will be listed.
measure: Overall response rate
time frame: Up to 2 years
description: Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.
measure: Intracranial response rate
time frame: Up to 2 years
description: Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.
measure: Time to intracranial progression
time frame: Up to 2 years
description: Will be assessed by Response Assessment in Neuro-Oncology Brain Metastases.
measure: Brain metastasis response rate
time frame: Up to 2 years
measure: Time to central nervous system (CNS) progression
time frame: From start of treatment to time of progression in the CNS, assessed up to 2 years
measure: Intracranial response
time frame: Up to 2 years
description: Assessed by Response Assessment in Neuro-Oncology Criteria-Glioblastoma Multiforme. Will be estimated using the 95% confidence interval CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ratios will be reported.
measure: Objective response defined as a complete or partial response
time frame: Up to 2 years
description: Will be determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.
measure: Molecular characterization
time frame: Up to 2 years
description: Analysis will be completed using Lasso-based elastic net method.
measure: Circulating tumor deoxyribonucleic acid assessed in plasma
time frame: Up to 2 years
description: Analysis will be completed using Lasso-based elastic net method.
measure: Angiogenic signature assessed in plasma by multiplex panel array
time frame: Up to 2 years
description: Analysis will be completed using Lasso-based elastic net method.
measure: Biomarker analysis of angiogenesis and signaling pathways
time frame: Up to 2 years
description: Analysis will be completed using Lasso-based elastic net method.
measure: Changes in the tumor immune microenvironment
time frame: Baseline to 2 years
description: Analysis will be completed using Lasso-based elastic net method.
arm group label: Arm I (osimertinib, bevacizumab)
arm group type: Experimental
description: Patients receive osimertinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.
arm group label: Arm II (osimertinib)
arm group type: Experimental
description: Patients receive osimertinib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, MRI, tumor biopsy and blood sample collection throughout the study.
intervention type: Biological
intervention name: Bevacizumab
description: Given IV
arm group label: Arm I (osimertinib, bevacizumab)
other name: ABP 215
other name: Anti-VEGF
other name: Anti-VEGF Humanized Monoclonal Antibody
other name: Anti-VEGF Monoclonal Antibody SIBP04
other name: Anti-VEGF rhuMAb
other name: Avastin
other name: BAT 1706
other name: BAT-1706
other name: BAT1706
other name: BAT1706 Biosimilar
other name: Bevacizumab awwb
other name: Bevacizumab Biosimilar ABP 215
other name: Bevacizumab Biosimilar BAT1706
other name: Bevacizumab Biosimilar BEVZ92
other name: Bevacizumab Biosimilar BI 695502
other name: Bevacizumab Biosimilar CBT 124
other name: Bevacizumab Biosimilar CT-P16
other name: Bevacizumab Biosimilar FKB238
other name: Bevacizumab Biosimilar GB-222
other name: Bevacizumab Biosimilar HD204
other name: Bevacizumab Biosimilar HLX04
other name: Bevacizumab Biosimilar IBI305
other name: Bevacizumab Biosimilar LY01008
other name: Bevacizumab Biosimilar MIL60
other name: Bevacizumab Biosimilar Mvasi
other name: Bevacizumab Biosimilar MYL-1402O
other name: Bevacizumab Biosimilar QL 1101
other name: Bevacizumab Biosimilar QL1101
other name: Bevacizumab Biosimilar RPH-001
other name: Bevacizumab Biosimilar SCT501
other name: Bevacizumab Biosimilar Zirabev
other name: Bevacizumab-adcd
other name: Bevacizumab-awwb
other name: Bevacizumab-bvzr
other name: BP102
other name: BP102 Biosimilar
other name: CT-P16
other name: HD204
other name: Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
other name: Mvasi
other name: MYL-1402O
other name: QL1101
other name: Recombinant Humanized Anti-VEGF Monoclonal Antibody
other name: rhuMab-VEGF
other name: SCT501
other name: SIBP 04
other name: SIBP-04
other name: SIBP04
other name: Vegzelma
other name: Zirabev
intervention type: Procedure
intervention name: Biopsy
description: Undergo tumor biopsy
arm group label: Arm I (osimertinib, bevacizumab)
other name: BIOPSY_TYPE
other name: Bx
intervention type: Procedure
intervention name: Biospecimen Collection
description: Undergo blood sample collection
arm group label: Arm I (osimertinib, bevacizumab)
other name: Biological Sample Collection
other name: Biospecimen Collected
other name: Specimen Collection
intervention type: Procedure
intervention name: Computed Tomography
description: Undergo CT scan
arm group label: Arm I (osimertinib, bevacizumab)
other name: CAT
other name: CAT Scan
other name: Computed Axial Tomography
other name: Computerized Axial Tomography
other name: Computerized axial tomography (procedure)
other name: Computerized Tomography
other name: CT
other name: CT Scan
other name: tomography
intervention type: Procedure
intervention name: Magnetic Resonance Imaging
description: Undergo MRI
arm group label: Arm I (osimertinib, bevacizumab)
other name: Magnetic Resonance
other name: Magnetic resonance imaging (procedure)
other name: Magnetic Resonance Imaging Scan
other name: Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
other name: MR
other name: MR Imaging
other name: MRI
other name: MRI Scan
other name: NMR Imaging
other name: NMRI
other name: Nuclear Magnetic Resonance Imaging
intervention type: Drug
intervention name: Osimertinib
description: Given PO
arm group label: Arm I (osimertinib, bevacizumab)
arm group label: Arm II (osimertinib)
other name: AZD-9291
other name: AZD9291
other name: Mereletinib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sarah B Goldberg
role: Principal Investigator
affiliation: Yale University Cancer Center LAO
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Brain Neoplasms
mesh term: Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Bevacizumab
mesh term: Antineoplastic Agents, Immunological
mesh term: Osimertinib
mesh term: Endothelial Growth Factors
mesh term: Antibodies
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal
mesh term: Immunoglobulin G