<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/NCT03831932</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2019-00572</org_study_id>
    <secondary_id>NCI-2019-00572</secondary_id>
    <secondary_id>OSU 19016</secondary_id>
    <secondary_id>10216</secondary_id>
    <secondary_id>10216</secondary_id>
    <secondary_id>UM1CA186712</secondary_id>
    <nct_id>NCT03831932</nct_id>
  </id_info>
  <brief_title>Telaglenastat Hydrochloride and Osimertinib in Treating Patients With EGFR-Mutated Stage IV Non-small Cell Lung Cancer</brief_title>
  <official_title>A Phase Ib Study of Osimertinib (AZD9291) and Telaglenastat (CB-839) HCl in Patients With EGFR Mutant Non-Small Cell Lung Cancer</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 Ib trial studies the side effects and best dose of telaglenastat hydrochloride&#xD;
      when given together with osimertinib in treating patients with stage IV non-small cell lung&#xD;
      cancer and a mutation in the EGFR gene. Telaglenastat hydrochloride and osimertinib may stop&#xD;
      the growth of tumor cells by blocking some of the enzymes needed for cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I.To assess the safety and tolerability of osimertinib (AZD9291) and telaglenastat (CB-839)&#xD;
      hydrochloride (HCl) and determine the recommended phase II dose (RP2D) in patients with&#xD;
      metastatic, EGFR activating mutation-positive non-small cell lung cancer (NSCLC).&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine toxicity profile of the combination of osimertinib (AZD9291) and&#xD;
      telaglenastat (CB-839) HCl in patients with metastatic EGFR activating mutation positive&#xD;
      NSCLC.&#xD;
&#xD;
      II. To assess the pharmacokinetics (PK) of telaglenastat (CB-839) HCl and osimertinib&#xD;
      (AZD9291) in patients with metastatic EGFR activating mutation positive NSCLC.&#xD;
&#xD;
      EXPLORATORY/CORRELATIVE OBJECTIVES:&#xD;
&#xD;
      I. To determine the progression free survival (PFS) of osimertinib (AZD9291) and&#xD;
      telaglenastat (CB-839) HCl in patients with EGFR mutation positive NSCLC who have developed&#xD;
      progressive disease (PD) on front-line EGFR inhibitor therapy.&#xD;
&#xD;
      II. To determine the overall survival (OS) of osimertinib (AZD9291) and telaglenastat&#xD;
      (CB-839) HCl in patients with EGFR mutation positive NSCLC who have developed PD on&#xD;
      front-line EGFR inhibitor therapy.&#xD;
&#xD;
      III. To assess cell-free deoxyribonucleic acid (DNA) (cfDNA) and measure changes with&#xD;
      response to treatment as well as disease progression (EGFR sensitizing mutations, T790M&#xD;
      resistance mutation, recognized bypass mechanisms).&#xD;
&#xD;
      IV. To assess circulating levels of glutamine, glutamate, aspartate and asparagine, and&#xD;
      measure changes with response to treatment as well as disease progression.&#xD;
&#xD;
      V. To assess 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) parameters&#xD;
      at baseline and after treatment to evaluate changes with response to treatment as well as&#xD;
      emergence of disease resistance or progression. (Expansion cohort, select patients only)&#xD;
&#xD;
      VI. To perform molecular profiling assays on malignant and normal tissues, including, but not&#xD;
      limited to, whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing (RNAseq), in&#xD;
      order to:&#xD;
&#xD;
      VIa. To identify potential predictive and prognostic biomarkers beyond any genomic alteration&#xD;
      by which treatment may be assigned.&#xD;
&#xD;
      VIb. To identify resistance mechanisms using genomic DNA- and RNA-based assessment platforms.&#xD;
&#xD;
      OUTLINE: This is a phase I, dose-escalation study of telaglenastat hydrochloride followed by&#xD;
      a dose-expansion study.&#xD;
&#xD;
      Patients receive telaglenastat hydrochloride orally (PO) twice daily (BID) and osimertinib PO&#xD;
      once daily (QD) (starting cycle 1 day 16 of phase I). Cycles repeat every 28 days in the&#xD;
      absence of disease progression or unacceptable toxicity. Patients undergo blood sample&#xD;
      collection and may undergo x-ray imaging, computed tomography (CT) scan, magnetic resonance&#xD;
      imaging (MRI), or positron emission tomography (PET) scan throughout the study.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 16, 2020</start_date>
  <completion_date type="Anticipated">June 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 1, 2024</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recommended phase II dose (RP2D)</measure>
    <time_frame>Up to 28 days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Dose limiting toxicities (DLT)</measure>
    <time_frame>Up to 28 days</time_frame>
    <description>Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>From initiation of therapy to documented progression or death without progression, assessed up to 30 days after completion of therapy</time_frame>
    <description>Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>From initiation of therapy to death from any cause, assessed up to 30 days after completion of therapy</time_frame>
    <description>Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Post-glutaminase inhibitor CB-839 hydrochloride pharmacokinetics (PK) (CB-839 HCl)</measure>
    <time_frame>Day 15 of cycle 1, day 2 of cycle 2 and day 1 of each subsequent cycle (each cycle = 28 days)</time_frame>
    <description>Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and osimertinib (AZD9291). Will explore PK endpoints such as concentration steady state (Css), area under the curve (AUC), clearance (CL), volume of distribution (Vd), and half-life (t1/2) computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations [GEE]) to assess the PK and pharmacodynamics (PD) markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.</description>
  </other_outcome>
  <other_outcome>
    <measure>Post-AZD9291 pharmacokinetics</measure>
    <time_frame>Day 2 of cycle 2 and day 1 of each subsequent cycle (each cycle = 28 days)</time_frame>
    <description>Will be assessed by AZD9291 drug levels following combination therapy with CB-839 HCl and AZD9291. Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and AZD9291. Will explore PK endpoints such as Css, AUC, CL, Vd, and t1/2 computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, GEE) to assess the PK and PD markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in EGFR mutational status</measure>
    <time_frame>Baseline up to disease progression, assessed up to 30 days after completion of therapy</time_frame>
    <description>Will be assessed by cell-free deoxyribonucleic acid (cfDNA). All continuous measurements will be summarized using mean +/- standard error of mean (SEM), range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in circulating levels of glutamine, glutamate, aspartate, and asparagine</measure>
    <time_frame>Baseline up to time of disease progression, assessed up to 30 days after completion of therapy</time_frame>
    <description>Will be assessed by plasma concentrations of these compounds. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) imaging</measure>
    <time_frame>Baseline up to 2 cycles of treatment (each cycle = 28 days)</time_frame>
    <description>Will be assessed by static (standard uptake value [SUV]max, average SUV, tumor-to-background ratio, metabolic tumor volume, total lesion glycolysis) and dynamic (net influx rate constant and glucose metabolic rate at 30 and 60 minutes) parameters. Will be summarized using mean +/- SEM, range, and median. The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">28</enrollment>
  <condition>Advanced Lung Non-Small Cell Carcinoma</condition>
  <condition>Metastatic Lung Non-Small Cell Carcinoma</condition>
  <condition>Stage IV Lung Cancer AJCC v8</condition>
  <arm_group>
    <arm_group_label>Treatment (telaglenastat HCl, osimertinib)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive telaglenastat hydrochloride PO BID and osimertinib PO QD (starting cycle 1 day 16 of phase I). Patients undergo blood sample collection and may undergo x-ray imaging, CT scan, MRI, or PET scan throughout the study. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biospecimen Collection</intervention_name>
    <description>Undergo blood sample collection</description>
    <arm_group_label>Treatment (telaglenastat HCl, osimertinib)</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>Treatment (telaglenastat HCl, osimertinib)</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 Elastography</intervention_name>
    <description>Undergo MRI</description>
    <arm_group_label>Treatment (telaglenastat HCl, osimertinib)</arm_group_label>
    <other_name>MRE</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Osimertinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (telaglenastat HCl, osimertinib)</arm_group_label>
    <other_name>AZD-9291</other_name>
    <other_name>AZD9291</other_name>
    <other_name>Mereletinib</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Positron Emission Tomography</intervention_name>
    <description>Undergo PET scan</description>
    <arm_group_label>Treatment (telaglenastat HCl, osimertinib)</arm_group_label>
    <other_name>Medical Imaging, Positron Emission Tomography</other_name>
    <other_name>PET</other_name>
    <other_name>PET Scan</other_name>
    <other_name>Positron emission tomography (procedure)</other_name>
    <other_name>Positron Emission Tomography Scan</other_name>
    <other_name>Positron-Emission Tomography</other_name>
    <other_name>proton magnetic resonance spectroscopic imaging</other_name>
    <other_name>PT</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Telaglenastat Hydrochloride</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (telaglenastat HCl, osimertinib)</arm_group_label>
    <other_name>CB-839 HCl</other_name>
    <other_name>Glutaminase Inhibitor CB-839 Hydrochloride</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>X-Ray Imaging</intervention_name>
    <description>Undergo x-ray imaging</description>
    <arm_group_label>Treatment (telaglenastat HCl, osimertinib)</arm_group_label>
    <other_name>Conventional X-Ray</other_name>
    <other_name>Diagnostic Radiology</other_name>
    <other_name>Medical Imaging, X-Ray</other_name>
    <other_name>Plain film radiographs</other_name>
    <other_name>Radiographic Imaging</other_name>
    <other_name>Radiographic imaging procedure (procedure)</other_name>
    <other_name>Radiography</other_name>
    <other_name>RG</other_name>
    <other_name>Static X-Ray</other_name>
    <other_name>X-Ray</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease&#xD;
&#xD;
          -  Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in&#xD;
             combination with other EGFR mutations) as per local assessment of a tissue&#xD;
             biopsy/cytology specimen. The tissue biopsy must have been obtained since the time of&#xD;
             disease progression on most recent targeted therapy. &quot;Liquid&quot; biopsies (i.e. blood&#xD;
             based) biopsies cannot be used for eligibility determination&#xD;
&#xD;
          -  Patients must have had progressive disease on prior EGFR inhibitor therapy (gefitinib,&#xD;
             erlotinib, afatinib, or osimertinib). There is no limit to lines of prior tyrosine&#xD;
             kinase inhibitor (TKI) therapy. Prior osimertinib (AZD9291) therapy is permitted&#xD;
&#xD;
          -  Patients must have measurable disease, defined as at least one lesion that can be&#xD;
             accurately measured in at least one dimension (longest diameter to be recorded for&#xD;
             non-nodal lesions and short axis for nodal lesions) as &gt;= 20 mm (&gt;= 2 cm) by chest&#xD;
             x-ray or as &gt;= 10 mm (&gt;= 1 cm) with computed tomography (CT) scan, magnetic resonance&#xD;
             imaging (MRI), or calipers by clinical exam&#xD;
&#xD;
          -  Age &gt; 18 years. NSCLC is exceedingly rare in patients &lt; 18 years of age. Because no&#xD;
             dosing or adverse event (AE) data are currently available on the use of telaglenastat&#xD;
             (CB-839) HCl in combination with osimertinib (AZD9291) in patients &lt; 18 years of age,&#xD;
             children are excluded from this study&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Must be able to swallow pills&#xD;
&#xD;
          -  Life expectancy &gt; 3 months&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Hemoglobin &gt;= 90 g/L&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x institutional upper limit of normal (ULN) and up to 3 mg/dL&#xD;
             for patients with Gilbert's disease&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 2.5 x institutional ULN and =&lt; 5 x institutional ULN for patients with liver&#xD;
             metastases&#xD;
&#xD;
          -  Creatinine within 1.5 x ULN OR&#xD;
&#xD;
          -  Glomerular filtration rate (GFR) &gt;= 50 mL/min/1.73 m^2 (measured or calculated by&#xD;
             Cockcroft and Gault equation) - confirmation of creatinine clearance is only required&#xD;
             for patients with creatinine levels above institutional upper limit of normal&#xD;
&#xD;
          -  Should participants with hepatitis B virus (HBV) infection be included, patients are&#xD;
             only eligible if they meet all the following criteria:&#xD;
&#xD;
               -  Demonstrated absence of hepatitis C virus (HCV) co-infection or history of HCV&#xD;
                  co-infection&#xD;
&#xD;
               -  Demonstrated absence of human immunodeficiency virus (HIV) infection&#xD;
&#xD;
               -  Participants with active HBV infection are eligible if they are:&#xD;
&#xD;
                    -  Receiving anti-viral treatment for at least 6 weeks prior to study&#xD;
                       treatment, HBV DNA is suppressed to &lt;100 IU/mL and transaminase levels are&#xD;
                       below ULN. Participants with a resolved or chronic infection HBV are&#xD;
                       eligible if they are:&#xD;
&#xD;
                         -  Negative for hepatitis B surface antigen (HBsAg) and positive for&#xD;
                            hepatitis B core antibody [anti-HBc IgG]. In addition, patients must be&#xD;
                            receiving anti-viral prophylaxis for 2-4 weeks prior to study treatment&#xD;
                            and 6-12 months (To be determined [TBD] by hepatologist) post treatment&#xD;
                            OR&#xD;
&#xD;
                         -  Positive for HBsAg, but for &gt; 6 months have had transaminases levels&#xD;
                            below ULN and HBV DNA levels below &lt;100 IU/mL (i.e., are in an inactive&#xD;
                            carrier state). In addition, patients must be receiving anti-viral&#xD;
                            prophylaxis for 2-4 weeks prior to study treatment and 6-12 months (TBD&#xD;
                            by hepatologist) post treatment&#xD;
&#xD;
          -  If history of hepatitis C virus (HCV) infection, must be treated and have an&#xD;
             undetectable HCV viral load&#xD;
&#xD;
          -  Patients with treated brain metastases are eligible if follow-up brain imaging after&#xD;
             central nervous system (CNS) - directed therapy shows no evidence of progression&#xD;
&#xD;
          -  Patients with new or progressive brain metastases (active brain metastases) or&#xD;
             leptomeningeal disease are eligible if the treating physician determines that&#xD;
             immediate CNS specific treatment is not required and is unlikely to be required during&#xD;
             the first cycle of therapy. Patients on corticosteroids for the treatment of brain&#xD;
             metastases will be permitted as long as the dose is =&lt; 10 mg of prednisone-equivalent&#xD;
             and has not been increased within 2 weeks of screening&#xD;
&#xD;
          -  Patients with a prior or concurrent malignancy whose natural history or treatment does&#xD;
             not have the potential to interfere with the safety or efficacy assessment of the&#xD;
             investigational regimen are eligible for this trial&#xD;
&#xD;
          -  Patients with known history or current symptoms of cardiac disease, or history of&#xD;
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac&#xD;
             function using the New York Heart Association Functional Classification. To be&#xD;
             eligible for this trial, patients should be class 2B or better&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
             Participants with impaired decision-making capacity (IDMC) who have a&#xD;
             legally-authorized representative (LAR) and/or family member available will also be&#xD;
             eligible&#xD;
&#xD;
          -  EXPANSION COHORT: Patients must have had progressive disease on prior first line EGFR&#xD;
             inhibitor therapy with osimertinib&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have not recovered from AEs due to prior systemic anti-cancer therapy&#xD;
             (i.e., have residual toxicities &gt; grade 1), with the exception of alopecia. Note:&#xD;
             Subjects with irreversible toxicity that in the opinion of the treating physician is&#xD;
             not reasonably expected to be exacerbated by the investigational treatment may be&#xD;
             included (e.g., hearing loss, hormone deficiency requiring replacement therapy)&#xD;
&#xD;
          -  Previous enrollment in the present study&#xD;
&#xD;
          -  Past medical history of interstitial lung disease, drug-induced interstitial lung&#xD;
             disease, radiation pneumonitis requiring steroid treatment, or any evidence of&#xD;
             clinically active interstitial lung disease&#xD;
&#xD;
          -  Patients who are receiving any other investigational agent within five half-lives of&#xD;
             the compound or 3 months, whichever is greater. Patients who have received prior&#xD;
             immunotherapy may be included only if time from last immunotherapy is at least 3&#xD;
             months (i.e. 90 days)&#xD;
&#xD;
          -  Spinal cord compression, symptomatic and unstable brain metastases except for those&#xD;
             patients who have completed definitive therapy, and have had a stable neurological&#xD;
             status for at least 2 weeks after completion of definitive therapy. Patients may be on&#xD;
             corticosteroids (=&lt; 10 mg of prednisone-equivalent) to control brain metastases if&#xD;
             they have been on a stable dose for 2 weeks (14 days) prior to the start of study&#xD;
             treatment and are clinically asymptomatic&#xD;
&#xD;
          -  Patients with an uncontrolled intercurrent illness&#xD;
&#xD;
          -  Patients with psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to telaglenastat (CB-839) HCl, osimertinib (AZD9291), or other agents used&#xD;
             in study. Patients with hypersensitivity to to any of the inactive excipients thereof&#xD;
             should also be excluded&#xD;
&#xD;
          -  Currently receiving (or unable to stop use prior to receiving the first dose of study&#xD;
             treatment) medications or herbal supplements known to be potent inducers of CYP3A4&#xD;
             (wash-out periods vary). 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;
          -  Pregnant women are excluded from this study because telaglenastat (CB-839) HCl is a&#xD;
             glutaminase inhibitor with the potential for teratogenic or abortifacient effects.&#xD;
             Because there is an unknown but potential risk for AEs in nursing infants secondary to&#xD;
             treatment of the mother with telaglenastat (CB-839) HCl and osimertinib (AZD9291),&#xD;
             breastfeeding should be discontinued if the mother is treated with telaglenastat&#xD;
             (CB-839) HCl and osimertinib (AZD9291). Breastfeeding patients will be excluded. These&#xD;
             potential risks may also apply to other agents used in this study&#xD;
&#xD;
          -  Patients with a significant history of cardiovascular disease (e.g., myocardial&#xD;
             infarction [MI], thrombotic or thromboembolic event in the last 6 months)&#xD;
&#xD;
          -  Any of the following cardiac criteria:&#xD;
&#xD;
               -  Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) &gt; 470&#xD;
                  msec (Fridericia's Criteria for Corrected QT interval [QTc] Calculation:&#xD;
                  Fridericia's formula QTcF = (QT/RR 0.33). RR is the time from the interval of 1&#xD;
                  QRS complex to the next measured in seconds and is commonly calculated as (60/HR)&#xD;
&#xD;
               -  Any clinically important abnormalities in rhythm, conduction or morphology of&#xD;
                  resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third&#xD;
                  degree heart block, 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, electrolyte abnormalities (including: Serum/plasma&#xD;
                  potassium &lt; lower limit of normal (LLN); serum/plasma magnesium &lt; LLN;&#xD;
                  serum/plasma calcium &lt; LLN , congenital long QT syndrome, family history of long&#xD;
                  QT syndrome or unexplained sudden death under 40 years of age in first degree&#xD;
                  relatives, or any concomitant medication known to prolong the QT interval and&#xD;
                  cause Torsades de Pointes&#xD;
&#xD;
               -  Left ventricular ejection fraction (LVEF) &lt; lower limit of normal (LLN) as&#xD;
                  assessed by either multigated acquisition (MUGA) scan or echocardiogram (ECHO)&#xD;
&#xD;
          -  Patients with active malignancies other than NSCLC or patients with prior curatively&#xD;
             treated malignancy at high risk of relapse during the study period with the exception&#xD;
             of localized squamous or basal cell skin cancers, ductal carcinoma in-situ (DCIS), or&#xD;
             indolent cancer currently on observation (i.e. chronic lymphocytic leukemia [CLL] or&#xD;
             low-risk prostate cancer)&#xD;
&#xD;
          -  Any evidence of severe or uncontrolled systemic diseases, including uncontrolled&#xD;
             hypertension and active bleeding diatheses, which in the investigator's opinion makes&#xD;
             it undesirable for the patient to participate in the trial or which would jeopardize&#xD;
             compliance with the protocol, or active infection with human immunodeficiency virus&#xD;
             (HIV). Screening for chronic conditions is not required&#xD;
&#xD;
          -  Patients with symptomatic CNS metastases who are neurologically unstable&#xD;
&#xD;
          -  Patients who are at risk for impaired absorption of oral medication including, but not&#xD;
             limited to, refractory nausea and vomiting, chronic gastrointestinal diseases,&#xD;
             inability to swallow the formulated product or previous significant bowel resection&#xD;
             that would preclude adequate absorption of telaglenastat (CB-839) HCl and osimertinib&#xD;
             (AZD9291)&#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;
&#xD;
          -  Involvement in the planning and/or conduct of the study (applies to both investigator&#xD;
             staff and/or staff at the study site)&#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>Dwight H Owen</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ohio State University Comprehensive Cancer Center LAO</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama at Birmingham Cancer Center</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35233</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>UM Sylvester Comprehensive Cancer Center at Coral Gables</name>
      <address>
        <city>Coral Gables</city>
        <state>Florida</state>
        <zip>33146</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>305-243-2647</phone>
    </contact>
    <investigator>
      <last_name>Richa Dawar</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UM Sylvester Comprehensive Cancer Center at Deerfield Beach</name>
      <address>
        <city>Deerfield Beach</city>
        <state>Florida</state>
        <zip>33442</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>305-243-2647</phone>
    </contact>
    <investigator>
      <last_name>Richa Dawar</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Miami Miller School of Medicine-Sylvester Cancer Center</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>305-243-2647</phone>
    </contact>
    <investigator>
      <last_name>Richa Dawar</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UM Sylvester Comprehensive Cancer Center at Plantation</name>
      <address>
        <city>Plantation</city>
        <state>Florida</state>
        <zip>33324</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>305-243-2647</phone>
    </contact>
    <investigator>
      <last_name>Richa Dawar</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Kentucky/Markey Cancer Center</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>859-257-3379</phone>
    </contact>
    <investigator>
      <last_name>Zhonglin Hao</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Case Western Reserve University</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </contact>
    <investigator>
      <last_name>Debora S. Bruno</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </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>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>800-293-5066</phone>
      <email>Jamesline@osumc.edu</email>
    </contact>
    <investigator>
      <last_name>Dwight H. Owen</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </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>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>412-647-8073</phone>
    </contact>
    <investigator>
      <last_name>Liza C. Villaruz</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </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>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>888-424-2100</phone>
      <email>cancerinfo@hci.utah.edu</email>
    </contact>
    <investigator>
      <last_name>Sonam Puri</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University of Virginia Cancer Center</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22908</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Site Public Contact</last_name>
      <phone>434-243-6303</phone>
      <email>uvacancertrials@hscmail.mcc.virginia.edu</email>
    </contact>
    <investigator>
      <last_name>Richard D. Hall</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>February 5, 2019</study_first_submitted>
  <study_first_submitted_qc>February 5, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 6, 2019</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>Carcinoma</mesh_term>
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osimertinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page</ipd_description>
    <ipd_url>https://grants.nih.gov/policy/sharing.htm</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/NCT03831932
org study id: NCI-2019-00572
secondary id: NCI-2019-00572
secondary id: OSU 19016
secondary id: 10216
secondary id: 10216
secondary id: UM1CA186712
nct id: NCT03831932
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase Ib trial studies the side effects and best dose of telaglenastat hydrochloride
      when given together with osimertinib in treating patients with stage IV non-small cell lung
      cancer and a mutation in the EGFR gene. Telaglenastat hydrochloride and osimertinib may stop
      the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVE:

      I.To assess the safety and tolerability of osimertinib (AZD9291) and telaglenastat (CB-839)
      hydrochloride (HCl) and determine the recommended phase II dose (RP2D) in patients with
      metastatic, EGFR activating mutation-positive non-small cell lung cancer (NSCLC).

      SECONDARY OBJECTIVES:

      I. To determine toxicity profile of the combination of osimertinib (AZD9291) and
      telaglenastat (CB-839) HCl in patients with metastatic EGFR activating mutation positive
      NSCLC.

      II. To assess the pharmacokinetics (PK) of telaglenastat (CB-839) HCl and osimertinib
      (AZD9291) in patients with metastatic EGFR activating mutation positive NSCLC.

      EXPLORATORY/CORRELATIVE OBJECTIVES:

      I. To determine the progression free survival (PFS) of osimertinib (AZD9291) and
      telaglenastat (CB-839) HCl in patients with EGFR mutation positive NSCLC who have developed
      progressive disease (PD) on front-line EGFR inhibitor therapy.

      II. To determine the overall survival (OS) of osimertinib (AZD9291) and telaglenastat
      (CB-839) HCl in patients with EGFR mutation positive NSCLC who have developed PD on
      front-line EGFR inhibitor therapy.

      III. To assess cell-free deoxyribonucleic acid (DNA) (cfDNA) and measure changes with
      response to treatment as well as disease progression (EGFR sensitizing mutations, T790M
      resistance mutation, recognized bypass mechanisms).

      IV. To assess circulating levels of glutamine, glutamate, aspartate and asparagine, and
      measure changes with response to treatment as well as disease progression.

      V. To assess 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) parameters
      at baseline and after treatment to evaluate changes with response to treatment as well as
      emergence of disease resistance or progression. (Expansion cohort, select patients only)

      VI. To perform molecular profiling assays on malignant and normal tissues, including, but not
      limited to, whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing (RNAseq), in
      order to:

      VIa. To identify potential predictive and prognostic biomarkers beyond any genomic alteration
      by which treatment may be assigned.

      VIb. To identify resistance mechanisms using genomic DNA- and RNA-based assessment platforms.

      OUTLINE: This is a phase I, dose-escalation study of telaglenastat hydrochloride followed by
      a dose-expansion study.

      Patients receive telaglenastat hydrochloride orally (PO) twice daily (BID) and osimertinib PO
      once daily (QD) (starting cycle 1 day 16 of phase I). Cycles repeat every 28 days in the
      absence of disease progression or unacceptable toxicity. Patients undergo blood sample
      collection and may undergo x-ray imaging, computed tomography (CT) scan, magnetic resonance
      imaging (MRI), or positron emission tomography (PET) scan throughout the study.

      After completion of study treatment, patients are followed up at 30 days.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recommended phase II dose (RP2D)
time frame: Up to 28 days
measure: Dose limiting toxicities (DLT)
time frame: Up to 28 days
description: Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
measure: Progression-free survival (PFS)
time frame: From initiation of therapy to documented progression or death without progression, assessed up to 30 days after completion of therapy
description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.
measure: Overall survival (OS)
time frame: From initiation of therapy to death from any cause, assessed up to 30 days after completion of therapy
description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.
measure: Post-glutaminase inhibitor CB-839 hydrochloride pharmacokinetics (PK) (CB-839 HCl)
time frame: Day 15 of cycle 1, day 2 of cycle 2 and day 1 of each subsequent cycle (each cycle = 28 days)
description: Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and osimertinib (AZD9291). Will explore PK endpoints such as concentration steady state (Css), area under the curve (AUC), clearance (CL), volume of distribution (Vd), and half-life (t1/2) computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations [GEE]) to assess the PK and pharmacodynamics (PD) markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.
measure: Post-AZD9291 pharmacokinetics
time frame: Day 2 of cycle 2 and day 1 of each subsequent cycle (each cycle = 28 days)
description: Will be assessed by AZD9291 drug levels following combination therapy with CB-839 HCl and AZD9291. Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and AZD9291. Will explore PK endpoints such as Css, AUC, CL, Vd, and t1/2 computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, GEE) to assess the PK and PD markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.
measure: Change in EGFR mutational status
time frame: Baseline up to disease progression, assessed up to 30 days after completion of therapy
description: Will be assessed by cell-free deoxyribonucleic acid (cfDNA). All continuous measurements will be summarized using mean +/- standard error of mean (SEM), range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.
measure: Change in circulating levels of glutamine, glutamate, aspartate, and asparagine
time frame: Baseline up to time of disease progression, assessed up to 30 days after completion of therapy
description: Will be assessed by plasma concentrations of these compounds. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.
measure: Change in 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) imaging
time frame: Baseline up to 2 cycles of treatment (each cycle = 28 days)
description: Will be assessed by static (standard uptake value [SUV]max, average SUV, tumor-to-background ratio, metabolic tumor volume, total lesion glycolysis) and dynamic (net influx rate constant and glucose metabolic rate at 30 and 60 minutes) parameters. Will be summarized using mean +/- SEM, range, and median. The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.
arm group label: Treatment (telaglenastat HCl, osimertinib)
arm group type: Experimental
description: Patients receive telaglenastat hydrochloride PO BID and osimertinib PO QD (starting cycle 1 day 16 of phase I). Patients undergo blood sample collection and may undergo x-ray imaging, CT scan, MRI, or PET scan throughout the study. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
intervention type: Procedure
intervention name: Biospecimen Collection
description: Undergo blood sample collection
arm group label: Treatment (telaglenastat HCl, osimertinib)
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: Treatment (telaglenastat HCl, osimertinib)
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 Elastography
description: Undergo MRI
arm group label: Treatment (telaglenastat HCl, osimertinib)
other name: MRE
intervention type: Drug
intervention name: Osimertinib
description: Given PO
arm group label: Treatment (telaglenastat HCl, osimertinib)
other name: AZD-9291
other name: AZD9291
other name: Mereletinib
intervention type: Procedure
intervention name: Positron Emission Tomography
description: Undergo PET scan
arm group label: Treatment (telaglenastat HCl, osimertinib)
other name: Medical Imaging, Positron Emission Tomography
other name: PET
other name: PET Scan
other name: Positron emission tomography (procedure)
other name: Positron Emission Tomography Scan
other name: Positron-Emission Tomography
other name: proton magnetic resonance spectroscopic imaging
other name: PT
intervention type: Drug
intervention name: Telaglenastat Hydrochloride
description: Given PO
arm group label: Treatment (telaglenastat HCl, osimertinib)
other name: CB-839 HCl
other name: Glutaminase Inhibitor CB-839 Hydrochloride
intervention type: Procedure
intervention name: X-Ray Imaging
description: Undergo x-ray imaging
arm group label: Treatment (telaglenastat HCl, osimertinib)
other name: Conventional X-Ray
other name: Diagnostic Radiology
other name: Medical Imaging, X-Ray
other name: Plain film radiographs
other name: Radiographic Imaging
other name: Radiographic imaging procedure (procedure)
other name: Radiography
other name: RG
other name: Static X-Ray
other name: X-Ray
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Dwight H Owen
role: Principal Investigator
affiliation: Ohio State University Comprehensive Cancer Center LAO
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Osimertinib
sharing ipd: Yes
ipd description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
ipd url: https://grants.nih.gov/policy/sharing.htm